[Printable PDF]
[Federal Register: March 14, 2003 (Volume 68, Number 50)]
[Proposed Rules]
[Page 12405-12497]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr14mr03-18]
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Part II
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 310, 312, et al.
Safety Reporting Requirements for Human Drug and Biological Products;
Proposed Rule
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 310, 312, 314, 320, 600, 601, and 606
[Docket No. 00N-1484]
RIN 0910-AA97
Safety Reporting Requirements for Human Drug and Biological
Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its pre- and postmarketing safety reporting regulations for human drug
and biological products to implement definitions and reporting formats
and standards recommended by the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) and by the World Health
Organization's (WHO's) Council for International Organizations of
Medical Sciences (CIOMS); codify the agency's expectations for timely
acquisition, evaluation, and submission of relevant safety information
for marketed drugs and licensed biological products; require that
certain information, such as domestic reports of medication errors, be
submitted to the agency in an expedited manner; clarify certain
requirements; and make other minor revisions. FDA is also proposing to
amend its postmarketing annual reporting regulations for human drug and
licensed biological products by revising the content for these reports.
FDA is taking this action to strengthen its ability to monitor the
safety of human drugs and biological products. The intended effect of
these changes is to further worldwide consistency in the collection of
safety information and submission of safety reports, increase the
quality of safety reports, expedite FDA's review of critical safety
information, and enable the agency to protect and promote public
health. These proposed changes would be an important step toward global
harmonization of safety reporting requirements and additional efforts
are underway within the Department of Health and Human Services to
harmonize the reporting requirements of U.S. Federal agencies (e.g.,
FDA and the National Institutes of Health (NIH) are continuing to work
together to address the best ways to streamline information sharing and
harmonize, to the extent possible, the safety reporting requirements of
the two agencies).
DATES: Submit written comments by July 14, 2003. Submit written
comments on the collection of information by April 14, 2003.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852, e-mail: FDADockets@oc.fda.gov or to the Internet
at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.accessdata.fda.gov/scripts/oc/dockets/comments/commentdocket.cfm.
FAX written comments on the information collection
provisions to the Office of Information and Regulatory Affairs, Office
of Management and Budget (OMB), New Executive Office Bldg., 725 17th
St. NW., rm. 10235, Washington, DC 20503, Attn: Stuart Shapiro, Desk
Officer for FDA, 202-395-6974.
FOR FURTHER INFORMATION CONTACT:
For information concerning human drug products: Audrey A. Thomas,
Center for Drug Evaluation and Research (HFD-7), Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-5626.
For information concerning human biological products: Miles Braun,
Center for Biologics Evaluation and Research (HFM-220), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-
6079.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Previous Safety Reporting Rulemaking and Current Guidances
II. Introduction
A. Persons Subject to the Safety Reporting Regulations
1. Premarketing Expedited Safety Reporting Regulations
2. Postmarketing Safety Reporting Regulations
3. Terms Used in This Document
B. Rationale for This Proposal
1. International Standards
2. Quality of Postmarketing Safety Reports
3. New Postmarketing Expedited Safety Reports
a. Medication errors
b. Unexpected SADRs with unknown outcome
c. Always expedited reports
d. Blood and blood component safety reports
4. Bioavailability and Bioequivalence Studies Not Subject to an
Investigational New Drug Application (IND)
C. New Safety Reporting Abbreviations
D. Highlights of Proposed Changes to FDA's Safety Reporting
Regulations
III. Description of the Proposed Rule
A. Definitions
1. Suspected Adverse Drug Reaction (SADR)
2. A Life-Threatening SADR
3. Serious SADR, Nonserious SADR, and SADR With Unknown Outcome
4. Contractor
5. Minimum Data Set and Full Data Set for an Individual Case
Safety Report
6. Active Query
7. Spontaneous Report
8. Medication Error
9. Company Core Data Sheet, Company Core Safety Information
(CCSI), Listed SADR, Unlisted SADR, and Unexpected SADR
10. Data Lock Point and International Birth Date
B. IND Safety Reports
1. Review of Safety Information
2. Written IND Safety Reports
a. Minimum data set
b. Serious and unexpected SADRs
c. Information sufficient to consider product administration
changes
d. Reporting format
3. Telephone Safety Reports
4. IND Safety Reporting for Drugs Marketed in the United States
5. Investigator Reporting
C. Postmarketing Safety Reporting
1. Prescription Drugs Marketed for Human Use Without an Approved
Application
2. Review of Safety Information
3. Reporting Requirements
4. Request for Alternative Reporting Frequency
5. Determination of Outcome, Minimum Data Set, and Full Data Set
6. Spontaneous Reports and Reports From Clinical Trials
7. Lack of Efficacy Reports
D. Postmarketing Expedited Reports
1. Serious and Unexpected SADRs
2. Information Sufficient to Consider Product Administration
Changes
3. Unexpected SADRs With Unknown Outcome
4. Always Expedited Reports
5. Medication Errors
6. Followup Reports
7. Supporting Documentation
8. Scientific Literature
9. Contractors and Shared Manufacturers
10. Prescription Drugs Marketed for Human Use Without an
Approved Application
11. Class Action Lawsuits
12. Blood and Blood Component Safety Reports
E. Postmarketing Periodic Safety Reporting
1. Traditional Periodic Safety Reports (TPSRs)
a. Narrative summary and analysis of individual case safety
reports
b. Individual case safety reports
c. Increased frequency reports
d. Safety-related actions to be taken
e. Summary tabulations
f. History of safety-related actions taken
g. Location of safety records
h. Contact person
2. Periodic Safety Update Reports (PSURs)
a. Title page, table of contents, and introduction
b. Worldwide marketing status
c. Actions taken for safety reasons
[[Page 12407]]
d. Changes to CCSI
e. Worldwide patient exposure
f. Individual case safety reports
i. Line listings
ii. Summary tabulations
g. Safety studies
h. Other information
i. Overall safety evaluation
j. Conclusion
k. Appendices
i. Company core data sheet
ii. U.S. labeling
iii. Spontaneous reports submitted to the applicant by an
individual other than a health care professional
iv. SADRs with unknown outcome
v. Class action lawsuits
vi. Lack of efficacy reports
vii. Information on resistance to antimicrobial drug products
viii. Medication errors
ix. U.S. patient exposure
x. Location of safety records
xi. Contact person
3. Interim Periodic Safety Reports (IPSRs)
4. Semiannual Submission of Individual Case Safety Reports
5. Reporting Requirements
a. Reporting intervals
b. Submission date
c. Cover letter
d. International birth date for combination products
F. Reporting Format
1. Forms Versus Narrative Format
2. Medical Dictionary for Regulatory Activities (MedDRA)
3. Single Form for Each Identifiable Patient
4. Contact Person
5. Computer-Generated Facsimile of FDA Form 3500A or Vaccine
Adverse Event Reporting System (VAERS) Form
6. Other Revisions
G. Patient Privacy
H. Recordkeeping
I. Abbreviated New Drug Application (ANDA) Products
J. Postmarketing Approved New Drug Application (NDA) and
Biologics License Application (BLA) Annual Reports
K. Safety Reporting for In Vivo Bioavailability and
Bioequivalence Studies
L. Proposed Implementation Scheme
IV. Environmental Impact
V. Analysis of Impacts
A. Background and Summary
B. Market Failure
C. Benefits
1. Expanded Safety Information
2. Improved Uniformity and Quality of Safety Information
3. Potential Savings from Reduced SADR-Related Hospitalizations
a. Reduced rate of SADR-related hospitalizations
b. Reduced rate of in-hospital SADRs
c. Indirect benefits of reducing the hospital costs of SADRs
d. Sum of SADR-related costs
4. Cost Savings and More Efficient Use of Resources
a. Savings related to maintaining and building data bases of
SADRs and intercompany transfers of drug safety data
b. Savings related to greater ease in entering into intercompany
agreements
c. Savings related to eventual international harmonization to
the PSUR format
d. Potential savings in clinical trial management
e. Leveraging specialized knowledge
f. Total benefits
D. Costs of Compliance
1. Costs of New Recordkeeping and Reporting Requirements
a. Number of reports
b. New time burden
i. Expedited reports
ii. Followup reports
iii. Blood products
iv. IND and bioavailability/bioequivalence safety reports
v. Semiannual submissions of postmarketing individual case
safety reports
vi. Postmarketing period safety reports (TPSR, PSUR, and IPSR)
vii. Other reports
c. Annual cost of the reporting and recordkeeping provisions
2. Costs of MedDRA
a. One-time costs
i. Planning and coordination
ii. Development of information technology support structure
iii. Purchase or development of an autoencoder
iv. Conversion of legacy safety data
v. Training of personnel
vi. Revision of standard operating procedures (SOPs)
b. Recurring costs
i. MedDRA core subscription
ii. MedDRA versions and quarterly updates
iii. Maintenance of existing dictionaries
E. Small Business Analysis
1. Need for and Objectives of the Rule
2. Description and Estimate of Small Entities
3. Projected Reporting, Recordkeeping, and Other Compliance
Requirements
a. Reporting and recordkeeping requirements
b. Implementing MedDRA
4. Alternatives and Steps to Minimize the Impact on Small
Entities
a. Do nothing
b. Do not require a medical dictionary
c. Do not require medication errors as expedited reports
d. Do not require blood establishments to submit reports for all
serious SADRs associated with blood collection and transfusion
e. Do not require certain bioavailability and bioequivalence
reports as expedited reports
f. Waivers for economic hardship
g. Small business outreach, training, and assistance
F. Unfunded Mandates Reform Act of 1995
G. References
VI. Paperwork Reduction Act of 1995
A. Expedited Safety Reporting
B. Periodic Safety Reports
C. Other Reports
D. Recordkeeping
VII. Executive Order 13132: Federalism
I. Previous Safety Reporting Rulemaking and Current Guidances
FDA has undertaken a major effort to clarify and revise its
regulations regarding pre- and postmarketing safety reporting for human
drug and biological products. Since 1990, several rules and guidances
have been issued regarding these regulations. Some of these guidances
have been issued by international organizations (i.e., ICH and CIOMS),
while others have been issued by FDA. In figure 1 of this document, FDA
illustrates how these rules and guidances relate to the current
proposed rule.
BILLING CODE 4160-01-P
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In the Federal Register of October 27, 1994 (59 FR 54046), FDA
published a proposed rule to amend its expedited and periodic pre- and
postmarketing safety reporting regulations for human drug and
biological products (the October 1994 proposal). In the Federal
Register of October 7, 1997 (62 FR 52237), FDA published a final rule
amending its expedited pre- and postmarketing safety reporting
regulations for human drug and biological products (the October 1997
final rule). The October 1997 final rule implemented certain
international standards recommended in an ICH guidance entitled
``Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting'' (60 FR 11284, March 1, 1995) (the ICH E2A
guidance). FDA is now proposing additional amendments to its expedited
pre- and postmarketing safety reporting regulations based on
recommendations in the ICH E2A guidance that were not included in the
October 1994 proposal. Although the ICH E2A guidance pertains to
expedited safety reporting during the premarketing phase of drug
development, the agency has determined that many of the definitions and
standards also should apply to FDA's expedited postmarketing safety
reporting requirements.
The proposed amendments to the postmarketing periodic safety
reporting requirements in the October 1994 proposal were based on
recommendations in a CIOMS II report issued in 1992 (``International
Reporting of Periodic Drug-Safety Update Summaries'') (Ref. 28). As
explained in the October 1997 final rule, the agency decided not to
finalize these proposed amendments (62 FR 52237 and 52238) until FDA
considered ICH's recommendations on this topic. These recommendations
were published in an ICH final guidance entitled ``Clinical Safety Data
Management: Periodic Safety Update Reports for Marketed Drugs''
''(PSURs) (the ICH E2C guidance) (62 FR 27470, May 19, 1997). After
review of the ICH E2C guidance, FDA decided to repropose the
postmarketing periodic safety reporting amendments in the October 1994
proposal. These amendments are being reproposed in this rulemaking
based on recommendations in the ICH E2C guidance and comments submitted
in response to the October 1994 proposal.
An addendum to the ICH E2C guidance has been prepared by ICH based
on experience gained over the past 5 years in preparation of PSUR
reports by companies and review of them by regulators (the ICH V1 draft
guidance) (67 FR 79939; December 31, 2002). FDA is interested in
harmonizing, to the extent possible, its postmarketing periodic safety
reporting regulations with the recommendations in the ICH V1 draft
guidance. In this regard, FDA is interested in comment from the public
on whether the agency should implement these recommendations (e.g.,
permit use of summary bridging reports, include an executive summary in
PSURs, permit use of different versions of reference safety information
within a reporting interval or use of the version in effect at the end
of the reporting interval).
Some of the comments submitted in response to the October 1994
proposal noted that several of the proposed amendments to the
postmarketing periodic safety reporting regulations would result in
duplicative reporting of information currently required in
postmarketing approved new drug application (NDA) annual reports. The
comments questioned the value of submitting similar information to FDA
in two different reports and requested that the agency require
inclusion of this information in either one report or the other, but
not in both of them. In light of these comments, FDA is proposing to
revoke the requirement for safety-related information in postmarketing
approved NDA annual reports.
In the Federal Register of December 2, 1998 (63 FR 66632), FDA
issued a final rule amending its postmarketing approved NDA annual
reports regulations to require reporting of specific information
regarding studies in pediatric populations (the 1998 pediatric final
rule). The 1998 pediatric final rule also required a new annual report
for biological products with approved biologics license applications
(BLAs) that contains the same type of information on studies of
licensed biological products in pediatric populations. FDA is proposing
to amend the annual reporting requirements for licensed biological
products to revoke the requirement to submit safety-related information
in these reports. This proposal is consistent with the proposed
amendments to the postmarketing approved NDA annual reporting
requirements.
In the Federal Register of June 25, 1997 (62 FR 34166), FDA
published a final rule revoking the postmarketing safety reporting
requirement for submission of increased frequency reports in an
expedited manner (the increased frequency reports final rule). These
reports contained information regarding a significant increase in
frequency of an adverse drug experience (synonymous with adverse
experience) that is both serious and expected for marketed human drug
and licensed biological products. FDA is now proposing to amend its
regulations to require submission of increased frequency type
information for marketed human drugs and licensed biological products
in postmarketing periodic safety reports.
In the Federal Register of August 27, 1997 (62 FR 45425), FDA
published a notice of availability of a guidance for industry entitled
``Postmarketing Adverse Experience Reporting for Human Drug and
Licensed Biological Products; Clarification of What to Report'' (the
clarification guidance of 1997). This guidance clarifies the agency's
policy concerning certain postmarketing safety reporting requirements
for human drugs and licensed biological products. The guidance: (1)
Describes the information that should be obtained before an individual
case safety report (i.e., FDA Form 3500A, CIOMS I Form, Vaccine Adverse
Event Reporting System (VAERS) Form) of an adverse experience should be
considered for submission to FDA; (2) clarifies how solicited safety
information from planned contacts with patients should be handled; and
(3) informs applicants that FDA will entertain waiver requests for
periodic submission of individual case safety reports for adverse
experiences that are determined to be nonserious and expected.
FDA received 28 comments from medical centers, physicians, and
consumers regarding the clarification guidance of 1997. All of these
comments pertained to the item regarding waiver requests for periodic
submission of individual case safety reports for adverse experiences
that are determined to be nonserious and expected. The agency
considered these comments in developing this proposed rule. All of the
comments requested that FDA postpone granting these waivers until this
new policy receives more complete public scrutiny and debate. The
comments stated that the new waiver policy would deprive the public of
access to important safety information about adverse reactions to
approved drugs and biological products. The comments noted that, in
some cases, adverse reactions classified as ``nonserious'' may, in
fact, be related to very serious reactions. The comments also indicated
that the new waiver policy provides industry with an incentive to
classify serious reactions as ``nonserious'' so that the reactions
would not have to be reported to FDA.
Even though applicants may currently request waivers for submission
of individual case safety reports for nonserious, expected adverse
experiences, the agency should continue to receive information
regarding these experiences. The clarification guidance
[[Page 12410]]
of 1997 provides that summary tabulations of nonserious, expected
adverse experiences be included in postmarketing periodic safety
reports. If warranted, FDA could request submission of an individual
case safety report for any nonserious, expected adverse experience.
Thus, even if a waiver is granted, the agency will continue to receive
sufficient information to monitor the safety of marketed drugs and
licensed biological products. FDA is now proposing amendments to its
postmarketing periodic safety reporting regulations that would require
that nonserious, expected adverse experiences \1\ be submitted to the
agency in summary tabulations consistent with the clarification
guidance of 1997. At this time, FDA is also proposing to codify the
other recommendations in the clarification guidance of 1997 (i.e.,
require a minimum data set for individual case safety reports, describe
how solicited safety information from planned contacts with patients
must be handled).
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\1\ Adverse experiences are proposed to be called suspected
adverse drug reactions (SADRs) in this proposed rule; see section
III.A.1 of this document; the term ``adverse experiences'' or
``adverse drug experiences'' will be used in this document when
discussions pertain to FDA's current regulations and the term
``SADR'' will be used in this document when discussions pertain to
proposals in this rule.
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In the Federal Register of March 12, 2001 (66 FR 14391), FDA
published a notice of availability of a draft guidance for industry
entitled ``Postmarketing Safety Reporting for Human Drug and Biological
Products Including Vaccines'' (the draft guidance of 2001). The draft
guidance of 2001 represents the agency's current thinking on reporting
of postmarketing adverse drug experiences for human marketed drug and
biological products including vaccines in accordance with FDA's
postmarketing safety reporting regulations for these products in effect
at the time the draft guidance of 2001 was issued. The draft guidance
of 2001 consolidates the agency's existing guidances on this topic and
revises them based on the October 1997 final rule and the increased
frequency reports final rule. The draft guidance of 2001, once
finalized, will replace FDA's guidances entitled ``Postmarketing
Reporting of Adverse Drug Experiences'' (57 FR 61437, December 24,
1992) (the guidance of 1992), ``Adverse Experience Reporting for
Licensed Biological Products'' (the guidance of 1993), and the
clarification guidance of 1997. The agency will issue a final guidance
for industry on this topic after considering the comments received on
the draft guidance of 2001.
FDA is now proposing to codify certain expectations described in
the draft guidance of 2001 to improve the quality of postmarketing
safety reports submitted to the agency for human marketed drug and
biological products, and also to clarify certain postmarketing safety
reporting requirements. Once this proposed rule is finalized, the draft
guidance of 2001, as finalized, will be updated to provide industry
with assistance in fulfilling the new safety reporting requirements for
human marketed drug and biological products.
In June 2001, CIOMS issued a new report entitled ``Current
Challenges in Pharmacovigilance: Pragmatic Approaches'' (CIOMS V
report) (Ref. 29). This report provides recommendations for
simplification, clarification, and harmonization of certain drug safety
practices. Many of these recommendations serve to provide guidance for
industry and would not be subject to requirements of individual
regulatory authorities (e.g., FDA). Those that are the subject of our
proposed rule are essentially consistent with what we are proposing.
However, in some cases, there may be differences (see section III.A.6
of this document for discussion of use of active query and written
requests for acquisition of followup information).
In the Federal Register of November 5, 1998 (63 FR 59746), FDA
published an advance notice of proposed rulemaking announcing that it
is considering a proposal to require persons subject to the
postmarketing safety reporting regulations to submit postmarketing
expedited individual case safety reports and individual case safety
reports contained in postmarketing periodic safety reports to the
agency electronically using a standardized medical terminology,
standardized data elements, and electronic transmission standards
recommended by the ICH. Under the auspices of ICH, standard medical
terminology for regulatory purposes, MedDRA, the medical dictionary for
regulatory activities (ICH M1), has been developed (63 FR 59746 at
59748). On November 24, 1998, an international maintenance and support
services organization (MSSO) was established to maintain and update
MedDRA in response to medical/scientific advances and regulatory
changes and to serve as the licensing agent for distribution of MedDRA.
This proposed rule on safety reporting would require that postmarketing
individual case safety reports be coded using MedDRA prior to
submission to the agency. In a separate rulemaking, FDA plans to
propose that postmarketing individual case safety reports be submitted
to the agency electronically using standardized data elements and
electronic transmission standards. The proposed amendments for
electronic submissions are beyond the scope of this proposed rule.
II. Introduction
II.A. Persons Subject to the Safety Reporting Regulations
II.A.1. Premarketing Expedited Safety Reporting Regulations
Section 312.32 (21 CFR 312.32), requires expedited reports of
premarketing adverse experiences associated with the use of an
investigational human drug or biological product (see table 1).
Sponsors of INDs are subject to the premarketing expedited safety
reporting regulations.
Table 1.--Currently Required Premarketing Expedited Safety Reports
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Type of 21 CFR Persons with reporting
Safety report information section Submission timeframe responsibility
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Written IND safety report.... [sbull] Serious 312.32 15 calendar days......... Sponsors.
and unexpected
adverse
experience
associated with
the use of the
drug.
[sbull] Findings
from tests in
laboratory
animals that
suggest a
significant
risk for humans.
Telephone and facsimile Unexpected fatal 312.32 7 calendar days.......... Sponsors.
transmission safety report. or life-
threatening
experience
associated with
the use of the
drug.
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[[Page 12411]]
II.A.2. Postmarketing Safety Reporting Regulations
Sections 310.305, 314.80, 314.98, and 600.80 (21 CFR 310.305,
314.80, 314.98, and 600.80) require expedited reports of postmarketing
adverse drug experiences (see table 2). The following persons are
subject to these postmarketing expedited safety reporting regulations:
[sbull] Applicants with approved NDAs (Sec. 314.80) and
abbreviated new drug applications (ANDAs) (Sec. 314.98);
[sbull] Licensed manufacturers with approved BLAs (Sec. 600.80);
[sbull] Manufacturers, packers, and distributors (also shared
manufacturers, joint manufacturers, or any other participant involved
in divided manufacturing for Sec. 600.80) whose name appears on the
label of a product with an approved NDA, ANDA, or BLA (Sec. Sec.
314.80, 314.98 and 600.80); and
[sbull] Manufacturers, packers, and distributors whose name appears
on the label of a prescription drug product marketed without an
approved NDA or ANDA (Sec. 310.305). In this document, the term
``applicant'' will be used instead of the term ``licensed
manufacturer'' for persons with approved BLAs.
Table 2.--Currently Required Postmarketing Safety Reports
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Persons with reporting
Type of report Safety report Type of information 21 CFR section Submission timeframe responsibility
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Expedited report...... 15-day Alert report... Serious and 310.305, 314.80, 15 calendar days.............. Manufacturers \2\ and
unexpected adverse 314.98, 600.80. applicants \3\.
drug experience \1\.
15-day Alert report- New information for 310.305, 314.80, 15 calendar days.............. Manufacturers \2\ and
followup. 15-day Alert report. 314.98, 600.80. applicants \3\.
Reports to Serious adverse drug 310.305.............. 5 calendar days............... Packers and distributors.
manufacturer instead experiences \1\.
of FDA.
Reports to applicant Serious adverse 314.80, 314.98, 5 calendar days............... Manufacturers, packers,
instead of FDA. experiences \1\. 600.80. and distributors (Sec.
Sec. 314.80, 314.98,
and 600.80) and joint
manufacturers, shared
manufacturers, or any
participant involved in
divided manufacturing
(Sec. 600.80).
Expedited report...... Blood safety report... Fatalities........... 606.170.............. As soon as possible (oral or Blood establishments.
written) and 7 days (written).
Periodic report....... Periodic adverse drug [sbull] Narrative 314.80, 314.98, Quarterly for 3 years from the Applicants.
experience report. summary and analysis 600.80. date of U.S. approval of the
of adverse drug application and then annually
experiences that thereafter.
occurred during the
reporting interval
including 15-day
Alert reports
previously submitted
to FDA \1\.
[sbull] Individual
case safety report
for each adverse
drug experience not
submitted to FDA as
a 15-day Alert
report, excluding
reports from
postmarketing
studies, reports in
the scientific
literature, and
foreign marketing
experience \1\.
[sbull] History of
actions taken..
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\1\ For spontaneous reports, adverse drug experiences are submitted whether or not they are considered drug related; for study reports, adverse drug
experiences are submitted if there is a reasonable possibility that the drug caused the adverse drug experience.
\2\ Section 310.305 also includes packers and distributors.
\3\ Sections 314.80 and 314.98 also include manufacturers, packers and distributors. Section 600.80 also includes manufacturers, packers, distributors,
joint manufacturers, shared manufacturers, or any participant involved in divided manufacturing.
Applicants with approved NDAs, ANDAs, and BLAs must also submit
periodic reports of postmarketing adverse drug experiences under
Sec. Sec. 314.80, 314.98 and 600.80 (see table 2). Manufacturers of
prescription drug products marketed without an approved NDA or ANDA are
not required to submit periodic reports of postmarketing adverse drug
experiences (Sec. 310.305).
Existing regulations, under Sec. 606.170 (21 CFR 606.170), require
expedited reports of fatalities associated with
[[Page 12412]]
blood collection or transfusion (see table 2). The report must be
submitted to FDA by the collecting facility in the event of a donor
reaction and by the facility that performed the compatibility tests in
the event of a transfusion reaction.
Current safety reporting regulations under Sec. Sec. 310.305,
314.80, 314.98, 600.80 and 606.170, as well as the provisions of this
proposed rule, do not apply to voluntary reporting of adverse drug
experiences to companies or regulatory authorities (e.g., FDA) by an
individual (e.g., health care professional, consumer).
II.A.3. Terms Used in This Document
The terms ``sponsors,'' ``manufacturers,'' and ``applicants'' are
used in this proposed rule to describe, as appropriate, persons with
safety reporting responsibilities. ``Sponsors'' is used to describe
persons subject to the premarketing safety reporting regulations.
``Manufacturers'' is used, unless otherwise specified, to describe
persons subject to the postmarketing safety reporting regulations under
Sec. 310.305 for prescription drug products marketed without an
approved NDA or ANDA. ``Applicants'' is used to describe persons
subject to the postmarketing safety reporting regulations under
Sec. Sec. 314.80, 314.98, and 600.80 for products with an approved
NDA, ANDA, or BLA; for Sec. 600.80, ``applicants'' includes
participants involved in divided manufacturing.
II.B. Rationale for This Proposal
II.B.1. International Standards
Many of the amendments that are being proposed in this rulemaking
are intended to harmonize our safety reporting requirements with
international standards developed by CIOMS and ICH (see table 4 of this
document). These organizations were formed to facilitate international
consideration of issues, particularly safety issues, concerning the use
of global data in the development and use of drugs and biological
products.
The CIOMS working groups have been comprised of representatives
from regulatory authorities, including FDA, and the pharmaceutical
industry. These groups have worked to develop recommendations for
standardization of international reporting of postmarketing adverse
reactions by the pharmaceutical industry to regulatory authorities.
ICH was organized to provide an opportunity for tripartite
harmonization initiatives to be developed with input from regulatory
and industry representatives. ICH has worked to promote the
harmonization of technical requirements for the registration of
pharmaceutical products among three regions: The European Union, Japan,
and the United States. The six ICH sponsors are the European
Commission; the European Federation of Pharmaceutical Industry
Associations; the Japanese Ministry of Health and Welfare; the Japanese
Pharmaceutical Manufacturers Association; FDA; and the Pharmaceutical
Research and Manufacturers of America.
One ICH initiative is to harmonize certain safety reporting
requirements of the three regions. Through the ICH process,
recommendations have been developed regarding the content, format, and
reporting frequency for expedited and periodic safety reports for human
drugs and biological products (the ICH E2A and E2C guidances). In
addition, a standard medical terminology for regulatory purposes,
MedDRA, has been developed (ICH M1). Worldwide implementation of this
initiative is in process. FDA, which has been actively involved in the
development of these recommendations, has implemented some of them (the
October 1997 final rule) and is proposing to implement others in this
rulemaking.
FDA believes the changes recommended by ICH and CIOMS will result
in more effective and efficient safety reporting to regulatory
authorities worldwide. For example, postmarketing periodic safety
reports are, for the most part, currently submitted to regulatory
authorities in the three regions at different times with different
formats and content. International harmonization efforts are beginning
to decrease some of these differences, but harmonization of the format
and content, as well as the reporting frequency, of these reports by
all countries in the three regions is essential to eliminate
unnecessary reporting burdens on industry so that companies can focus
on the safety profiles of their products and not on the different
reporting requirements of different regions. The PSUR recommended for
postmarketing periodic safety reporting in the ICH E2C guidance
provides regulatory authorities with a comprehensive overview of the
safety profile of a product along with other relevant information such
as estimates of worldwide patient exposure and worldwide marketing
status of the product. In this rulemaking, FDA is proposing to require
submission of PSURs for certain products (see sections III.E.2 and
III.E.5.a of this document). FDA is also interested in receipt of
additional information and is proposing to require that such
information be submitted with these reports as appendices (e.g., copy
of current U.S. approved labeling, information on medication errors,
resistance to antimicrobial drug products and class action lawsuits)
(see section III.E.2.k of this document). Thus, companies can prepare
the same core document for all three regions and any additional
information required by FDA would simply be attached to this document.
Another international harmonization effort is standardization of
medical terminology used for regulatory purposes. As noted previously,
ICH has developed MedDRA for this purpose. Currently, companies use
various medical terminologies for safety reporting purposes (e.g.,
WHO's Adverse Reaction Terminology (WHOART), Coding Symbols for a
Thesaurus of Adverse Reaction Terms (COSTART), Japan's Adverse Reaction
Terminology (J-ART)). The established terminologies have been
criticized for a number of reasons, including: Lack of specificity,
limited data retrieval options, and an inability to effectively handle
complex combinations of signs and symptoms (syndromes). In addition,
use of different terminologies at different stages in the development
and use of products complicates data retrieval and analysis of
information and makes it difficult to effectively cross-reference data
through the lifetime of a product. Internationally, communication is
impaired between regulatory authorities because of the delays and
distortions caused by the translation of data from one terminology to
another.
Use of different terminologies also has significant consequences
for pharmaceutical firms. Companies operating in more than one
jurisdiction have had to adjust to subsidiaries or clinical research
organizations that use different terminologies because of variations in
data submission requirements. The difficulty of analyzing data
comprehensively may be compounded by use of incompatible terminologies
and could lead to delays in recognizing potential public health
problems.
For these reasons, it is critical that a single medical terminology
be used internationally for coding postmarketing safety reports. FDA is
proposing to use MedDRA for this purpose (see section III.F.2 of this
document). MedDRA is the best choice because it was developed with
input from regulatory authorities and industry and the problems
associated with the other terminologies were taken into consideration
during development of MedDRA. Some companies have begun to voluntarily
[[Page 12413]]
submit their postmarketing safety reports to FDA coded using MedDRA.
Even though FDA is proposing to use MedDRA as the standard medical
terminology for reporting purposes under this rule, the agency
recognizes that alternative standard classification systems for
clinical information exist in the United States and supports the
national health data standardization initiatives underway in the United
States under the Health Insurance Portability and Accountability Act.
Although this proposed rule does not impose reporting requirements
on health care providers, the agency recognizes that clinicians,
medical centers, hospitals and others may report safety information to
pharmaceutical companies. These third parties may employ clinical
terminology standards that differ from those proposed here. Therefore,
the agency invites comment on the unintended potential impact of this
proposed rule on those parties not subject to FDA's safety reporting
requirements. The agency also invites comment on the potential
strategies and approaches for facilitating seamless cross-standard
communications, such as mapping between alternative terminologies and
MedDRA.
II.B.2. Quality of Postmarketing Safety Reports
In light of the recommendations of ICH and CIOMS, FDA has reviewed
its postmarketing safety reporting regulations for human drugs and
licensed biological products and identified additional changes that the
agency believes would further enhance surveillance of marketed
products. Many of the postmarketing safety reports that FDA receives
are complete and of very high quality. Others are incomplete, of
mediocre or poor quality or both, making it difficult to ascertain the
significance of these reports. In the latter cases, FDA is
unnecessarily spending considerable amounts of time trying to collect
additional information for the reports.
To address this problem, FDA is proposing amendments to its
postmarketing safety reporting requirements. For most of these
amendments, a risk-based approach is being proposed (i.e., greater
emphasis and effort would be required for reports of serious adverse
drug experiences while less information would be required for
nonserious adverse drug experiences (adverse drug experiences proposed
to be called SADRs in this proposed rule; see section III.A.1 of this
document)). For example, FDA is proposing that complete information be
submitted for reports of serious SADRs (see section III.C.5 of this
document). If complete information is not available, in some cases, a
followup report would be required (e.g., for serious, unexpected SADRs)
(see section III.D.6 of this document). On the other hand, for SADRs
that are determined to be nonserious, not as much information would
need to be acquired (see section III.C.5 of this document).
Another amendment would require direct contact with the initial
reporter of an SADR by a health care professional at the company for
collection of certain postmarketing safety information (e.g.,
collection of followup information for a serious SADR) (see section
III.A.6 of this document). Currently, some companies use this approach
for collecting information, whereas others send the initial reporter a
letter. The latter case is a passive approach which, in FDA's
experience, results in limited acquisition of new information. In most
cases, the initial reporter simply does not respond to the letter.
Instead, using an active approach, as proposed by FDA, companies would
more likely obtain the additional information needed for an SADR. Thus,
use of this approach should result in submission of higher quality
reports to FDA for review.
Another amendment would require that a licensed physician at the
company be responsible for the content of postmarketing safety reports
submitted to FDA (see sections III.E.1.h, III.E.2.k.xi, and II.F.4 of
this document). As in the previous examples, some companies currently
use licensed physicians for this purpose, whereas others have their
postmarketing safety reports prepared and submitted by clerical
personnel with no health care training. The medical significance of
postmarketing safety reports warrants review by a licensed physician.
The agency believes that licensed physicians would ensure submission of
high quality reports to FDA that articulately conveys all clinically
relevant information associated with an SADR.
II.B.3. New Postmarketing Expedited Safety Reports
FDA currently requires postmarketing expedited safety reports for
serious and unexpected adverse drug experiences (adverse drug
experiences proposed to be called SADRs in this proposed rule; see
section III.A.1 of this document). To facilitate identification of
significant safety problems, FDA is proposing that additional safety
information be submitted expeditiously to the agency for marketed drugs
and biological products. Some of this information is currently
submitted to the agency but not in an expedited manner. In other cases,
the information is not currently required to be submitted to the
agency.
II.B.3.a. Medication errors. In 1999, the Institute of Medicine
(IOM) issued a report, ``To Err is Human: Building a Safer Health
System,'' that cited studies and articles estimating the number of
Americans dying each year as a result of medical mistakes to be between
44,000 and 98,000 (Ref. 10). The IOM report concluded that preventable
adverse drug events impose significant medical, personal, and economic
costs to the United States.
Requiring medication errors to be reported in an expedited manner
to a centralized location would provide a systematic approach for
collecting comprehensive information on these errors and result in
timely assessment of the information. Various organizations and health
care professional associations, including the 1999 IOM report, have
advocated mandatory medication error reporting efforts, as well as
encouragement of voluntary efforts, aimed at making sure the system
continues to be made safer for patients. Such a system would provide
the public with a higher level of protection by assuring that the most
serious errors are investigated and reported, and that appropriate
followup action is taken both by FDA and the company whose product is
associated with the error. Second, it would provide companies with an
incentive to improve patient safety regarding medication errors
associated with their products. Finally, it would require that FDA and
the pharmaceutical industry make some level of investment in preventing
medication errors and improving patient safety. In some instances,
information gathered through this type of a reporting system and
analyzed for root causes can lead to various changes within the health
care system to prevent or minimize recurrence.
Currently, FDA maintains both a voluntary adverse event reporting
system for health care professionals, through MedWatch (the Medical
Products Reporting Program), and a mandatory adverse event reporting
system for companies subject to the agency's postmarketing safety
reporting regulations. Through these systems, FDA receives only about
3,000 reports of medication errors annually. FDA believes that these
safety reporting systems do not adequately address the nature and
extent of problems caused by medication errors. In most cases, safety
reports associated with a medication error are not identified in the
report as being associated with an error. Instead, the report only
highlights the effect of
[[Page 12414]]
the medication error (e.g., patient experienced a seizure). This
information is not sufficient for FDA to identify medication errors
that could be avoided in the future. For cases that involve a
medication error, the safety report needs to be identified as a
suspected medication error so that the report can be appropriately
analyzed and addressed. FDA concludes that an explicit requirement for
reporting medication errors by companies subject to the agency's
postmarketing safety reporting regulations is needed to adequately
assess and respond to the problem.
FDA is therefore proposing to require that these companies submit
to the agency expeditiously all domestic reports of actual and
potential medication errors (see section III.D.5 of this document). FDA
would review information about suspected medication errors to determine
an appropriate risk management plan (e.g., changes to the proprietary
name, labels, labeling or packaging of the drug or biological product
or educational initiatives to protect public health). This proposal,
which is consistent with one of the Department of Health and Human
Services' major health initiatives, would allow FDA to form the
framework for building a comprehensive risk assessment and management
system for preventable SADRs. This proposal is also responsive to the
1999 IOM report, which states that ``the Food and Drug Administration
(FDA) should increase attention to the safe use of drugs in both pre-
and postmarketing process'' by ``establishing appropriate responses to
problems identified through post-marketing surveillance, especially for
concerns that are perceived to require immediate response to protect
the safety of patients.''
II.B.3.b. Unexpected SADRs with unknown outcome. FDA is also
proposing to require that companies subject to the agency's
postmarketing safety reporting regulations submit to FDA in an
expedited report SADRs that are unexpected and for which a
determination of serious or nonserious cannot be made (i.e., SADR with
unknown outcome) (see section III.D.3 of this document). This
information is currently submitted to FDA, but, in most cases, not in
an expedited manner. A company that receives a report of an adverse
drug experience is able, in most cases, to determine if it is serious
or nonserious (i.e., whether it meets the regulatory definition of
serious), but in some cases, this may not be possible. Currently, most
companies that are not able to make this determination designate the
adverse drug experience as nonserious and include it in their next
quarterly or annual postmarketing periodic safety report. In some of
these cases, the adverse drug experience is, in fact, serious even
though the company was not able to make this determination. FDA needs
to receive reports of SADRs with unknown outcome expeditiously if the
SADR is unexpected so that the agency can evaluate the report in light
of other data and information available to FDA to attempt to determine
if the SADR is serious. FDA would do this by comparing information on
the unexpected SADR with unknown outcome with information on other
similar unexpected SADRs with a known serious outcome that are on file
with the agency.
II.B.3.c. Always expedited reports. FDA is also proposing that
companies subject to the agency's postmarketing safety reporting
regulations always submit to FDA in an expedited report certain SADRs,
which may jeopardize the patient or subject and/or require medical or
surgical intervention to treat the patient or subject (e.g.,
ventricular fibrillation, liver necrosis, transmission of an infectious
agent by an approved product) (see section III.D.4 of this document).
Currently, all of these adverse drug experiences are submitted to the
agency for review, but only some of them are submitted in an expedited
safety report (i.e., if the adverse drug experience is serious and
unexpected). FDA is proposing that all of them be submitted
expeditiously whether the SADR is unexpected or expected and whether or
not the SADR leads to a serious outcome. This is because of the medical
gravity of these SADRs. For example, even though the labeling for a
product indicates that ventricular fibrillation may be associated with
use of the product and thus not subject to expedited reporting to FDA
(i.e., SADR is expected), the agency needs to review each new report of
ventricular fibrillation for this product as quickly as possible to
ascertain if there is a qualitative or quantitative change in the
nature of the SADR. Information from these reports could result in
either new studies being undertaken to evaluate the SADR or appropriate
regulatory action by FDA (e.g., labeling change, distribution of Dear
Health Care Professional letter, restriction on distribution of
product, withdrawal of product from the market).
II.B.3.d. Blood and blood component safety reports. With regard to
blood and blood components (e.g., red blood cells, plasma, platelets,
cryoprecipitated AHF), FDA is proposing that blood establishments
submit reports to the agency for all serious SADRs associated with
blood collection and transfusion, in addition to their current
requirement at Sec. 606.170(b) (21 CFR 606.170(b)) to submit reports
of fatalities (see section III.D.12 of this document). This proposed
safety reporting requirement would not impose significant new burdens
on blood establishments. This is because under Sec. 606.170(a) (21 CFR
606.170(a)) blood collection and transfusion facilities are currently
required to conduct investigations and prepare and maintain reports of
all adverse events associated either with the collection or transfusion
of blood or blood components. The proposal would simply require that
reports of serious SADRs that are currently maintained by the facility,
be submitted to the agency within 45 calendar days of occurrence rather
than only having these reports be reviewed by FDA at the time of an
inspection. Thus, not all serious SADRs are reported to FDA for blood
and blood components. FDA believes that it is critical that we receive
all such reports to enhance donor safety and also to ensure the safety,
purity and potency of blood and blood components for administration to
patients.
In the past, the agency has received some voluntary reports that
have helped to identify errors in manufacturing and defects in products
used to collect blood. For example, in 1997, FDA received reports from
a blood establishment of allergic adverse reactions to red blood cells
that had been leukoreduced using a bedside filtration method in
hematology or oncology patients receiving multiple transfusions. The
reactions were related to several lots of Hemasure Leukonet filters.
The symptoms included bilateral conjunctival edema, severe headaches,
eye pain, nausea sometimes associated with vomiting and joint pain.
After investigation and analysis of the reports by FDA, the
manufacturer discontinued production of the filter. Voluntary reporting
of the adverse reactions by the blood establishment brought the issue
to the attention of FDA. However, the time to resolution may have been
shortened had these been required to be reported to FDA from all blood
centers.
With regard to the safety of donors, FDA review of adverse event
reports is important and has resulted in detection and correction of
problematic collection procedures. During an inspection, FDA field
officers identified a blood collection center that had numerous donors
with vasovagal reactions that required treatment by emergency medical
personnel. In some of these cases, the donors had to be transported to
a hospital emergency room for treatment. Upon investigation, FDA
[[Page 12415]]
determined that the center had failed to establish a lower limit for
blood pressure measurements for donors as required by 21 CFR 640.3. Had
these serious adverse events been required to be reported to FDA,
immediate analysis of them is likely to have identified the problem
sooner.
Thus, required reporting of all serious SADRs related to blood
collection and transfusion would enhance FDA's ability to take
appropriate action to protect the blood supply more consistently.
Currently, there is no assurance that FDA will receive reports of
serious SADRs that have the potential to adversely affect both the
donors and recipients of the nation's blood supply. Such information is
essential for evaluating the agency's scientific and regulatory
policies and for monitoring industry practices and their implications
on blood safety.
II.B.4. Bioavailability and Bioequivalence Studies Not Subject to
an Investigational New Drug Application (IND).
FDA is also proposing to amend its bioavailability and
bioequivalence regulations under part 320 (21 CFR part 320) (see
section III.K of this document). Under the existing regulations at
Sec. 320.31, persons conducting a bioavailability or bioequivalence
study in humans are only required to comply with the IND requirements
of part 312 (21 CFR part 312) for certain products or for certain types
of studies. This proposed rule would require submission of expedited
safety reports for serious, unexpected adverse experiences (adverse
experiences proposed to be called SADRs in this proposed rule; see
section III.A.1 of this document) as prescribed under Sec. 312.32 for
human bioavailability and bioequivalence studies that are not being
conducted under an IND. FDA believes that bioavailability and
bioequivalence studies that are not being conducted under an IND are,
in general, safe. However, the agency is occasionally made aware of
safety-related information associated with these types of studies. This
information could either reflect a problem with the drug product being
evaluated or with the study design being used. Timely review of
serious, unexpected SADRs from these studies is critical to ensure the
safety of study subjects. FDA would use this information to determine
if the study design needs to be altered or if the study needs to be
stopped.
II.C. New Safety Reporting Abbreviations
Table 3 provides a list of new safety reporting abbreviations that
are used in this document.
Table 3.--New Safety Reporting Abbreviations
----------------------------------------------------------------------------------------------------------------
Reference in section III of this
Phrase Abbreviation document
----------------------------------------------------------------------------------------------------------------
Company core safety information........ CCSI......................... A.9
Interim periodic safety report......... IPSR......................... E.3
Medical dictionary for regulatory MedDRA....................... F.2
activities.
Periodic safety update report.......... PSUR......................... E.2
Suspected adverse drug reaction........ SADR......................... A.1
Traditional periodic safety report..... TPSR......................... E.1
----------------------------------------------------------------------------------------------------------------
II.D. Highlights of Proposed Changes to FDA's Safety Reporting
Regulations
Specific changes to FDA's safety reporting requirements, as
described in this proposed rule, are identified in table 4.
Table 4.--Highlights of Proposed Changes to FDA's Safety Reporting Requirements
----------------------------------------------------------------------------------------------------------------
Proposed Change (reference in section III Is the change based on ICH (ICH
21 CFR Section of this document) guidance)?
----------------------------------------------------------------------------------------------------------------
Changes apply to: 310.305, [sbull] ``Associated with the use of the Yes (E2A)
312.32, 314.80, 314.98, and drug'' and ``adverse drug experience''
600.80.\1\ changed to ``suspected adverse drug
reaction (SADR)'' and ``adverse
experience'' changed to ``suspected
adverse reaction (SAR)'' (A.1).
[sbull] Minimum data set required for all Yes (E2A)
individual case safety reports of SADRs
(A.5, B.2.a, C.5, E.4).
[sbull] Reporting requirements for lack of Yes (E2A and E2C)
efficacy reports revised (B.2.c, C.7, D.2,
E.1.c, E.2.h, E.2.k.vi).
[sbull] Sources of safety information No
revised (B.1, C.2, D.8).
[sbull] Individual case safety reports from Yes (E2A)
clinical trials based on opinion of either
the sponsor/applicant or investigator
(B.2.b, B.3, C.6).
[sbull] Narrative format required for No
safety reports of overall findings or data
in the aggregate (B.2.d, F.1).
Changes only apply to 312.32.... [sbull] Determination of a life-threatening Yes (E2A)
SADR based on opinion of either sponsor or
investigator (A.2).
[sbull] Expedited reports of findings from Yes (E2A)
tests in laboratory animals revised to
include other information sufficient to
consider product administration changes
(B.2.c).
Changes only apply to 310.305, New Safety Reports......................... Yes (E2A)
314.80, 314.98, 600.80. [sbull] Expedited report for information
sufficient to consider product
administration changes (D.2).
[sbull] Expedited report for unexpected No
SADRs with unknown outcome (A.3, D.3).
[[Page 12416]]
[sbull] Always expedited reports for No
certain medically significant SADRs
whether unexpected or expected and whether
or not the SADR leads to a serious outcome
(D.4).
[sbull] Expedited report for medication No
errors (D.5).
[sbull] 30-day followup report for initial No
serious and unexpected SADR reports,
always expedited reports, and medication
error reports that do not contain a full
data set (D.6).
Other Changes.............................. No
[sbull] Active query required to acquire
certain safety information (A.6, C.5, D.6,
D.7).
[sbull] Full data set required for reports No
of serious SADRs, always expedited
reports, and medication error reports
(A.5, C.5, D.1, D.4, D.5, E.4).
[sbull] Safety reporting requirements for No
contractors and shared manufacturers (A.4,
D.9).
Changes only apply to 310.305, [sbull] Reporting requirements for Yes (E2A and E2C)
314.80, 314.98, and 600.80. spontaneous reports codified (A.7, C.6).
[sbull] Supporting documentation required No
for expedited reports concerning a death
or hospitalization (D.7).
[sbull] FDA request for submission of No
safety reports at times other than
prescribed by regulations (C.4).
[sbull] Individual case safety reports Yes (M1)
required to be coded using MedDRA (F.2)..
[sbull] SADR information from class action No
lawsuits (A.7, E.1.e, E.2.k.v, E.3).
[sbull] Contact person for postmarketing No
safety reports (E.1.h, E.2.k.xi, E.3, F.4).
[sbull] Use of computer-generated facsimile No
of FDA Form 3500A or VAERS form permitted
without approval by FDA (F.5).
[sbull] Location of safety records (D.10, No
E.1.g, E.2.k.x, E.3).
[sbull] FDA request for submission of No
safety related records (D.7, H)..
Changes only to apply to 314.80, New or Revised Safety Reports.............. No
314.98 and 600.80. [sbull] Semiannual submission of certain No
spontaneously reported individual case
safety reports (E.4, E.5.a).
[sbull] TPSR, PSUR, or IPSR for No
applications approved prior to January 1,
1998 (E.1, E.2, E.3, E.5.a).
[sbull] PSUR/IPSR for applications approved Yes (E2C)
on or after January 1, 1998 (E.2, E.3,
E.5.a).
[sbull] PSUR/IPSR for pediatric use No
supplements (E.5.a).
Other Changes.............................. Yes (E2C)
[sbull] Periodicity of periodic safety
reports (E.5.a, I).
[sbull] Submission date for periodic safety Yes (E2C)
reports (A.10, E.5.b, I).
[sbull] CCSI for determination of listed Yes (E2C)
and unlisted SADRs for certain periodic
safety reports (A.9, E.2, E.3, E.4).
[sbull] Information in addition to the No
minimum data set not required to be
acquired for nonserious SADRs, except for
nonserious SADRs resulting from a
medication error, which require a full
data set (A.3, C.5, E.4).
[sbull] Individual case safety reports No
forwarded to applicant by FDA required to
be included in comprehensive safety
analysis (C.2).
[sbull] Information on resistance to No
antimicrobial drug products (E.2.k.vii,
E.3).
[sbull] Number of copies of periodic safety No
reports required to be submitted to FDA
(C.3).
Change only applies to 314.81 [sbull] Requirement to submit safety- No
and 601.28 \2\. related information in postmarketing
annual report revoked (J).
Change only applies to 312.64(b) [sbull] Investigator safety reporting No
\3\. requirements revised.
Change only applies to 320.31(d) [sbull] Submission of expedited safety No
\4\. reports required for human bioequivalence
and bioavailability studies which are
exempt from submission of an IND (K).
Change only applies to 606.170 [sbull] All serious SARs required to be No
\5\. submitted to FDA for blood and blood
products (D.12).
----------------------------------------------------------------------------------------------------------------
\1\ Section 310.305 describes postmarketing safety reporting regulations for prescription drug products marketed
for human use without an approved application; Sec. 312.32 describes premarketing safety reporting
regulations for investigational drugs and biological products; Sec. 314.80 describes postmarketing safety
reporting regulations for human drugs with approved NDAs; Sec. 314.98 describes postmarketing safety
reporting regulations for human drugs with approved ANDAs; and Sec. 600.80 describes postmarketing safety
reporting regulations for human licensed biological products with approved BLAs.
\2\ Section 314.81 describes postmarketing annual reporting regulations for human marketed drugs with approved
NDAs; Sec. 601.28 describes postmarketing annual reporting regulations for pediatric studies of human
licensed biological products with approved BLAs.
\3\ Section 312.64(b) describes requirements for safety reporting to sponsors by investigators.
\4\ Section 320.31 (d) describes bioequivalence and bioavailability requirements for studies which are exempt
from submission of an IND.
\5\ Section 606.170 describes safety reporting and recordkeeping requirements for blood and blood products.
[[Page 12417]]
III. Description of the Proposed Rule
III.A. Definitions
III.A.1. Suspected Adverse Drug Reaction (SADR)
FDA's existing premarketing safety reporting regulations in Sec.
312.32(a) define ``associated with the use of the drug'' to mean:
``There is a reasonable possibility that the experience may have been
caused by the drug.''
FDA's existing postmarketing safety reporting regulations in
Sec. Sec. 310.305(b), 314.80(a), and 600.80(a) define ``adverse drug
experience (``adverse experience'' for Sec. 600.80(a))'' to mean:
Any adverse event associated with the use of a drug
(``biological product'' for Sec. 600.80(a)) in humans, whether or
not considered drug (``product'' for Sec. 600.80(a)) related,
including the following: An adverse event occurring in the course of
the use of a drug (``biological'' for Sec. 600.80(a)) product in
professional practice; an adverse event occurring from drug overdose
(``from overdose of the product'' for Sec. 600.80(a)) whether
accidental or intentional; an adverse event occurring from drug
abuse (``from abuse of the product'' for Sec. 600.80(a)), an
adverse event occurring from drug withdrawal (``from withdrawal of
the product'' for Sec. 600.80(a)); and any failure of expected
pharmacological action.
Proposed Sec. 312.32(a) would replace the term ``associated with
the use of the drug'' with the term ``suspected adverse drug reaction
(SADR).'' Proposed Sec. Sec. 310.305(a) and 314.80(a) would replace
the term ``adverse drug experience'' with the term ``suspected adverse
drug reaction (SADR)'' (see section III.C.1 of this document regarding
reorganization of Sec. 310.305). Proposed Sec. 600.80(a) would
replace the term ``adverse experience'' with the term ``suspected
adverse reaction (SAR).'' In this document the term ``adverse drug
experience'' is synonymous with the term ``adverse experience'' and the
abbreviation ``SADR'' will be used for both ``SADR'' and ``SAR,''
except when reference is only being made to an ``SAR,'' in which case
the abbreviation ``SAR'' will be used. Proposed Sec. Sec. 310.305(a),
312.32(a), 314.80(a), and 600.80(a) would also replace the definitions
for ``associated with the use of the drug,'' ``adverse drug
experience'' and ``adverse experience'' with the following definition
for ``SADR'':
A noxious and unintended response to any dose of a drug
(``biological'' for proposed Sec. 600.80(a)) product for which
there is a reasonable possibility that the product caused the
response. In this definition, the phrase ``a reasonable
possibility'' means that the relationship cannot be ruled out.
The phrase ``the relationship cannot be ruled out'' clarifies which
individual cases would be reported to FDA. Classifying a case as
``probably related,'' ``possibly related,'' ``remotely related,'' or
``unlikely related'' to the drug or biological product would signify
that a causal relationship between the product and an adverse event
could not be ruled out and, thus, the adverse event would be considered
an SADR. For example, in some cases an adverse event may most probably
have occurred as a result of a patient's underlying disease and not as
a result of a drug or biological product the patient was taking, but it
cannot usually be said with certainty that the product did not cause
the adverse event. Therefore, such an adverse event would be classified
as an SADR because there would be at least a ``reasonable possibility''
that the drug or biological product may have caused the adverse event.
Of course, this classification would not establish causality
(attributability) by itself, it would only indicate that causality
could not be ruled out with certainty.
These proposed changes are consistent with the ICH E2A guidance (60
FR 11284 at 11285), which defines ``adverse drug reaction'' as:
All noxious and unintended responses to a medicinal product
related to any dose should be considered adverse drug reactions. The
phrase ``response to medicinal products'' means that a causal
relationship between a medicinal product and an adverse event is at
least a reasonable possibility, i.e., the relationship cannot be
ruled out.
These proposed amendments would harmonize the agency's premarketing
and postmarketing safety reporting definition for SADR, as well as
safety reporting worldwide.
Even though FDA has harmonized its proposed definition of SADR with
the definition of adverse drug reaction recommended by ICH, the agency
would like comment on an alternative definition for SADR: ``A noxious
and unintended response to any dose of a drug product for which a
relationship between the product and the response to the product cannot
be ruled out''. The alternative and proposed definitions for SADR have
the same meaning (i.e., a response to a product is an SADR unless one
is sure that the product did not cause the response). The difference
between these definitions is that the alternative definition of SADR
does not include the phrase ``a reasonable possibility.'' This is
because use of this phrase is potentially confusing. The phrase ``a
reasonable possibility'' might be interpreted differently than the
phrase ``the relationship cannot be ruled out.'' The agency defines ``a
reasonable possibility'' as ``the relationship cannot be ruled out'' to
be consistent with ICH. FDA seeks comment as to whether the agency
should use the alternative definition of SADR instead of the proposed
definition of SADR. The agency also requests comment from sponsors,
manufacturers and applicants if their interpretation of these
definitions is different than FDA's interpretation.
As explained in the following paragraphs, FDA believes that the
proposed definition of SADR would not affect the number of safety
reports that are currently submitted to FDA from spontaneous sources,
but it could increase the number of safety reports that would be
submitted from clinical studies. FDA seeks comment as to whether use of
the proposed or alternative definition of SADR would lead to
significant increases in reporting to the agency beyond what FDA has
identified in the following paragraphs. FDA is particularly interested
in learning of examples of events beyond those identified by the agency
that are not currently reported to FDA but would be required to be
reported under these definitions.
Although FDA is proposing to remove the definition for ``adverse
drug experience'' from its postmarketing safety reporting regulations
and replace it with the proposed definition for ``SADR,'' this change
would not affect the number of safety reports from spontaneous sources
that would be submitted to the agency because every spontaneous report
currently must be submitted to FDA, irrespective of whether the
manufacturer or applicant considers it to be drug related (see current
definition of adverse drug experience at Sec. Sec. 310.305(c),
314.80(c), and 600.80(c)). Under this proposed rule, every spontaneous
report would continue to be submitted to FDA, because, for spontaneous
reports, manufacturers and applicants would always be required to
assume, for safety reporting purposes only, that there was at least a
reasonable possibility in the opinion of the initial reporter that the
drug or biological product caused the spontaneously reported event (see
sections III.A.7 and III.C.6 of this document for the proposed
definition of spontaneous report and for discussion of the proposed
reporting requirement for SADRs from spontaneous sources).
On the other hand, with regard to clinical studies of
investigational and marketed drugs and biological products, the
proposed definition of SADR is likely to result in an increase in the
number of safety reports that are currently submitted to FDA from some
[[Page 12418]]
studies. Current regulations at Sec. Sec. 310.305(c)(1)(ii),
312.32(c)(1), 314.80(e)(1), and 600.80(e)(1) require that serious,
unexpected adverse experiences from a study be reported to FDA only if
there is a reasonable possibility that the drug caused the adverse
experience. The phrase ``reasonable possibility'' is typically
interpreted by sponsors, manufacturers and applicants to mean that
there is a possible causal relationship between an adverse experience
and a drug or biological product. It would not include adverse
experiences considered to be unlikely or remotely related to the
product. The proposed definition of SADR maintains the phrase
``reasonable possibility'' as part of the definition, but defines the
phrase to mean that the relationship between a product and a response
to the product cannot be ruled out. In some cases, this proposed change
would result in submission of more safety reports to FDA. For example,
under the current regulations if a sponsor or applicant concludes that
the existence of a causal relationship between a drug and an adverse
event is unlikely or remote, but not impossible, (e.g., because the
event is a recognized consequence of the patient's underlying disease)
it would not submit a safety report to FDA. In contrast, under the
proposed rule, the sponsor or applicant would be required to submit a
safety report to the agency for this SADR, because, although the
relationship of the adverse event to the drug is unlikely or remote
because of the patient's underlying disease, a causal relationship
cannot, nonetheless, be ruled out. FDA is proposing the new definition
for SADR to minimize situations in which an adverse event that proves
ultimately to be due to a drug or biological product is not reported as
soon as possible to the agency because the etiology of the adverse
event is attributed to the patient's underlying disease by the sponsor,
manufacturer or applicant (e.g., a patient's hepatic deterioration is
judged to be related to the patient's viral hepatitis and not to the
hepatotoxicity of the drug the patient received.)
FDA recognizes, however, that particularly for those patients who
have certain diseases (e.g., fatal diseases such as cancer), the
proposed definition of SADR may result in submission of numerous safety
reports to the agency for which the reported SADR is not informative as
a single report because it is very likely to have been a consequence of
the patient's disease. This would be true, for example, for most non-
acute deaths in a clinical trial evaluating a drug in cancer patients.
These deaths would have to be reported to FDA as SADRs because a
relationship between the drug and the deaths could not be ruled out
with certainty. Because such ``over-reporting'' may make it more
difficult for FDA and the sponsor, manufacturer or applicant to
recognize adverse events that are really caused by a drug or biological
product, the agency wants to minimize receipt of this type of safety
report, but in a way that does not compromise receipt of useful safety
reports that are perceived as remotely related to an administered drug
or biological product but that occur, in fact, as a result of the
product. If sponsors, manufacturers or applicants believe that, in a
specific situation, there is an alternative way(s) to handle adverse
events occurring during clinical studies that would minimize ``over-
reporting'' while assuring that reporting of SADRs would not be
compromised, they are invited to propose any such alternative(s)
reporting method to the agency. In such situations, if FDA does not
oppose the proposed alternative reporting method, the sponsor,
manufacturer or applicant would be permitted to report SADRs to the
agency according to the alternative method. For example, one such
alternative would be to include in study protocols or other
documentation a list of known consequences of the disease that would
not be submitted to FDA in an expedited manner as individual case
safety reports (e.g., events that are the endpoints of the study).
These adverse events would, however, be monitored by the sponsor,
manufacturer, or applicant and, if they indicated in the aggregate by
comparison to a control group or historical experience, that the
product in the clinical study may be causing these events, the
information would be submitted to FDA in an expedited manner as an
information sufficient to consider product administration changes
report (see sections III.B.2.c and III.D.2 of this document for
discussion of this type of report). FDA invites comment from the public
on this alternative and requests suggestions for other alternatives as
well that would minimize ``over-reporting'' of uninformative events and
assure submission of meaningful reports of unexpected events. FDA also
invites comment on reporting of these types of clinical events that
occur in studies not being conducted under an IND (e.g., drug or
biological product is marketed in the United States for a particular
indication and being investigated in a clinical trial abroad for the
same or other indication).
The proposed definition of SADR may result in submission to FDA of
some reports from clinical studies and the scientific literature in
which the reported SADR is suspected to be associated with the product,
but, in fact, it is ultimately demonstrated not to be due to the
product. This is also true for reports from spontaneous sources in
which manufacturers and applicants must always assume, for safety
reporting purposes, that there is at least a reasonable possibility
that the drug or biological product caused the spontaneously reported
event and submit the report to FDA. Thus, SADR reports are required to
be submitted to FDA based on a suspected, not established, causal
relationship between an adverse event and a drug. This type of
reporting program allows the agency to determine more quickly which
SADRs warrant regulatory action by FDA to protect public health (e.g.,
change in product labeling, withdrawal of product from the market). FDA
receives hundreds of thousands of such reports each year, most of which
do not result in any regulatory action. But for those reports that do
represent a significant change in the benefit-to-risk profile of a
product, this system is critical for developing a signal necessitating
further evaluation of an SADR.
Some members of the public have maintained that submission of
voluntary SADR reports by health care professionals or consumers to
manufacturers or to FDA might be discouraged because of concern that a
person or entity might be implicated in a product liability action. In
addition, industry has expressed its concern that these reports, taken
out of context and used in a manner for which they were never intended,
can create a product liability vulnerability. FDA is concerned that
such liability misuse of these reports could imperil the credibility
and functionality of this critical public health reporting system.
Our current safety reporting regulations at Sec. Sec. 310.305(g),
312.32(e), 314.80(k), and 600.80(l) provide manufacturers, applicants,
and sponsors with a disclaimer that permits them to deny that the
safety report or other information required to be submitted to FDA
under these regulatory provisions constitutes an admission that the
drug or biological product caused or contributed to an adverse effect.
For example, Sec. 314.80(k) currently reads in pertinent part:
Disclaimer. A report or information submitted by an applicant
under this section (and any release by FDA of that report or
information) does not necessarily reflect a
[[Page 12419]]
conclusion by the applicant or FDA that the report or information
constitutes an admission that the drug caused or contributed to an
adverse effect. An applicant need not admit, and may deny, that the
report or information submitted under this section constitutes an
admission that the drug caused or contributed to an adverse effect.
Additionally, a ``disclaimer'' is included on the first page of the
voluntary reporting form used by health care professionals and
consumers, FDA Form 3500, stating ``Submission of a report does not
constitute an admission that medical personnel or the product caused or
contributed to the event.'' A similar disclaimer is included on the
mandatory reporting form used by manufacturers and applicants, FDA Form
3500A. In its notice of availability announcing FDA Form 3500 and
3500A, the agency reiterated that ``Although the underlying information
may be relevant to product liability issues, submitting the form
itself, as is clearly stated on the form, does not constitute an
admission that the product caused the adverse event'' (58 FR 31596 at
31600, June 3, 1993).
FDA seeks comment as to whether these ``disclaimers'' are
sufficient to protect manufacturers, applicants, and sponsors, from the
use of SADR reports in product liability actions. For instance, perhaps
the agency should consider also prohibiting use of SADR reports the
agency receives in product liability actions. Accordingly, FDA seeks
comment on the need for any further action to promote submission of
SADR reports to the agency and guard against their misuse, as well as
FDA's legal authority to take any such action.
FDA is proposing to remove the current provisions in Sec. Sec.
310.305(c)(1)(ii), 314.80(e)(1), and 600.80(e)(1). The agency is
proposing this amendment because the information contained in these
paragraphs is included in the proposed definition of SADR.
III.A.2. A Life-Threatening SADR
FDA's existing premarketing safety reporting regulations at Sec.
312.32(a) define a life-threatening adverse drug experience as:
Any adverse drug experience that places the patient or subject,
in the view of the investigator, at immediate risk of death from the
reaction as it occurred, i.e., it does not include a reaction that,
had it occurred in a more severe form, might have caused death.
FDA is proposing to amend this definition by adding the phrase ``or
sponsor'' after the word ``investigator.'' Thus, reports of life-
threatening SADRs would be based on the opinion of either the
investigator or sponsor. In some cases, the opinions of the
investigator and sponsor may be discordant. In these situations, the
sponsor would submit an IND safety report to FDA for the life-
threatening SADR and include in the report the reason(s) for any
differences in opinions. This proposed revision is consistent with the
ICH E2A guidance (60 FR 11286): ``Causality assessment is required for
clinical investigation cases. All cases judged by either the reporting
health care professional or the sponsor as having a reasonable
suspected causal relationship to the medicinal product qualify as ADR's
[adverse drug reactions].''
FDA's existing postmarketing safety reporting regulations at
Sec. Sec. 310.305(b), 314.80(a), and 600.80(a) define a ``life-
threatening adverse drug experience'' as:
Any adverse [drug] experience that places the patient, in the
view of the initial reporter, at immediate risk of death from the
adverse [drug] experience as it occurred, i.e., it does not include
an adverse [drug] experience that, had it occurred in a more severe
form, might have caused death.
Proposed Sec. Sec. 310.305(a), 312.32(a), 314.80(a), and 600.80(a)
would amend the premarketing and postmarketing definition of life-
threatening adverse drug experience by making minor revisions. FDA is
proposing to move the phrase ``places the patient'' (``patient or
subject'' for proposed Sec. 312.32(a)) before the phrase ``at
immediate risk of death'' and also to replace the phrase ``adverse drug
experience'' with the abbreviation ``SADR.''
III.A.3. Serious SADR, Nonserious SADR, and SADR With Unknown Outcome
FDA's existing premarketing and postmarketing safety reporting
regulations at Sec. Sec. 310.305(b), 312.32(a), 314.80(a), and
600.80(a) define a serious adverse drug experience as:
Any adverse [drug] experience occurring at any dose that results
in any of the following outcomes: Death, a life-threatening adverse
[drug] experience, inpatient hospitalization or prolongation of
existing hospitalization, a persistent or significant disability/
incapacity, or a congenital anomaly/birth defect. * * *
Proposed Sec. Sec. 310.305(a), 312.32(a), 314.80(a), and 600.80(a)
would amend this definition by removing the phrase ``occurring at any
dose,'' because the proposed definition of SADR includes the phrase
``response to any dose of a drug (``biological'' for proposed Sec.
600.80(a)) product'' and it is unnecessary to refer to ``any dose'' in
both definitions. FDA is also proposing to amend this definition by
replacing the phrase ``adverse drug experience'' with the abbreviation
``SADR'' for consistency as proposed previously.
Under proposed Sec. Sec. 310.305(a), 314.80(a), and 600.80(a), FDA
would amend its postmarketing safety reporting regulations to define
the term ``nonserious SADR'' to mean: ``Any SADR that is determined not
to be a serious SADR.'' FDA is proposing to add this definition to
clarify what constitutes a nonserious SADR. SADRs would only be
classified as ``nonserious'' if manufacturers and applicants have
determined that the reaction does not meet the definition of a serious
SADR. If the outcome for an SADR is not known, a determination of
seriousness cannot be made; the SADR would not default to a
``nonserious'' designation, but would rather be classified as an ``SADR
with unknown outcome'' as described below.
Under proposed Sec. Sec. 310.305(a), 314.80(a), and 600.80(a), FDA
would amend its postmarketing safety reporting regulations to define
the term ``SADR with unknown outcome'' to mean: ``An SADR that cannot
be classified, after active query, as either serious or nonserious.''
FDA is proposing to define this term to describe those SADRs for which
an outcome (i.e., classification as either serious or nonserious)
cannot be determined. FDA believes that, in most cases, manufacturers
and applicants are usually able to determine the outcome of an SADR.
However, in a few cases, this may not be possible, even after active
query, and these SADRs would be designated as ``SADR with unknown
outcome'' (see section III.A.6 of this document for proposed definition
of active query).
III.A.4. Contractor
Under proposed Sec. 310.305(a), FDA would amend its postmarketing
safety reporting regulations to define the term ``contractor'' to mean:
Any person (e.g., packer or distributor whether or not its name
appears on the label of the product; licensee; contract research
organization) that has entered into a contract with the manufacturer
to manufacture, pack, sell, distribute, or develop the drug or to
maintain, create, or submit records regarding SADRs or medication
errors.
Under proposed Sec. 314.80(a), the term ``contractor'' is defined
as persons (e.g., manufacturer, packer, or distributor whether or not
its name appears on the label of the product; licensee; contract
research organization) that have entered into a contract with the
applicant. Under proposed Sec. 600.80(a), the term ``contractor'' is
defined as persons (e.g.,
[[Page 12420]]
manufacturer, joint manufacturer, packer, or distributor whether or not
its name appears on the label of the product; licensee; contract
research organization) that have entered into a contract with the
applicant (includes participants involved in divided manufacturing).
FDA would define this term to specify which contractors would be
subject to the agency's postmarketing safety reporting requirements
under proposed Sec. Sec. 310.305(c)(2)(xi), 314.80(c)(2)(x), and
600.80(c)(2)(x) (see section III.D.9 of this document). Persons under
contract to manufacture, pack, sell, distribute, or develop the drug or
licensed biological product, or to maintain, create, or submit records
regarding SADRs or medication errors (whether or not the medication
error results in an SADR; see section III.A.8 of this document) would
have postmarketing safety reporting responsibilities.
III.A.5. Minimum Data Set and Full Data Set for an Individual Case
Safety Report
Proposed Sec. Sec. 310.305(a), 312.32(a), 314.80(a), and
600.80(a), would amend FDA's premarketing and postmarketing safety
reporting regulations to define the term ``minimum data set.'' A
``minimum data set'' for an individual case safety report of an SADR
would include: an identifiable patient, an identifiable reporter, a
suspect drug (biological for proposed Sec. 600.80(a)) product, and an
SADR.
Proposed Sec. Sec. 310.305(a), 314.80(a), and 600.80(a), would
also amend FDA's postmarketing safety reporting regulations to define
the term ``full data set.'' A ``full data set'' for a postmarketing
individual case safety report would include:
Completion of all the applicable elements on FDA Form 3500A (or
the Vaccine Adverse Event Reporting System (VAERS) form for proposed
Sec. 600.80(a)) (or on a Council for International Organizations of
Medical Sciences (CIOMS) I form for reports of foreign SADRs)
including a concise medical narrative of the case (i.e., an accurate
summary of the relevant data and information pertaining to an SADR
or medication error).
The proposed rule would define these terms to clarify the type of
information that manufacturers and applicants would be required to
submit to FDA for SADRs and medication errors. The proposed rule would,
as described below, require at least a minimum data set for all
individual case safety reports, except for certain reports of
medication errors (see sections III.B.2.a and III.C.5 of this
document). In addition, a full data set would be required for
postmarketing individual case safety reports of serious SADRs, always
expedited reports, and medication error reports (see sections III.C.5,
III.D.1, III.D.4, III.D.5, and III.E.4 of this document). Reports of
nonserious SADRs with a minimum data set would include all safety
information received or otherwise obtained by the manufacturer or
applicant for the SADR. However, except for reports of nonserious SADRs
resulting from a medication error, information in addition to the
minimum data set would not be required to be acquired by the
manufacturer or applicant (see sections III.C.5 and III.E.4 of this
document). Manufacturers and applicants would be required to submit a
full data set for reports of nonserious SADRs resulting from a
medication error (see sections III.C.5 and III.D.5 of this document).
As noted previously, for each individual case safety report, a
suspect product would be required to be identified. Reports from
blinded clinical studies (i.e., the sponsor and investigator are
blinded to individual patient treatment) should be submitted to FDA
only after the code is broken for the patient or subject that
experiences an SADR. The blind should be broken for each patient or
subject who experiences a serious, unexpected SADR unless arrangements
have been made otherwise with the FDA review division that has
responsibility for review of the IND (e.g., the protocol or other
documentation clearly defines specific alternative arrangements for
maintaining the blind). Exceptions to breaking the blind for a study
usually involve situations in which mortality or certain serious
morbidities are indeed the clinical endpoint of the study. This is
consistent with the discussion of managing blinded therapy cases in the
ICH E2A guidance (60 FR 11266):
* * * Although it is advantageous to retain the blind for all
patients prior to final study analysis, when a serious adverse
reaction is judged reportable on an expedited basis, it is
recommended that the blind be broken only for the specific patient
by the sponsor even if the investigator has not broken the blind. *
* * However, when a fatal or other ``serious'' outcome is the
primary efficacy endpoint in a clinical investigation, the integrity
of the clinical investigation may be compromised if the blind is
broken. Under these and similar circumstances, it may be appropriate
to reach agreement with regulatory authorities in advance concerning
serious events that would be treated as disease-related and not
subject to routine expedited reporting.
In addition to the exception for breaking the blind mentioned above,
FDA is also interested in considering whether the blind should be
broken for other serious SADRs that are not the clinical endpoint of
the study, but occur at a rate high enough that the overall study blind
would be threatened if each such case were individually unblinded. FDA
invites comment from the public on how reporting of these SADRs should
be handled.
III.A.6. Active Query
Under proposed Sec. Sec. 310.305(a), 314.80(a), and 600.80(a), FDA
would amend its postmarketing safety reporting regulations to define
the term ``active query'' to mean:
Direct verbal contact (i.e., in person or by telephone or other
interactive means such as a videoconference) with the initial
reporter of a suspected adverse drug reaction (SADR) or medication
error by a health care professional (e.g., physician, physician
assistant, pharmacist, dentist, nurse, any individual with some form
of health care training) representing the manufacturer (applicant
for proposed Sec. Sec. 314.80(a) and 600.80(a)). For SADRs, active
query entails, at a minimum, a focused line of questioning designed
to capture clinically relevant information associated with the drug
product (licensed biological product for proposed Sec. 600.80(a))
and the SADR, including, but not limited to, information such as
baseline data, patient history, physical exam, diagnostic results,
and supportive lab results.
The agency would define this term to describe the process that
manufacturers and applicants would be required to use to acquire safety
information expeditiously. Active query would be used to:
[sbull] Determine whether an SADR is serious or nonserious if the
manufacturer or applicant is not able to immediately make this
determination (see section III.C.5 of this document),
[sbull] Obtain at least the minimum data set for all SADRs and the
minimum information for medication errors that do not result in an SADR
if the manufacturer or applicant is not able to immediately obtain this
information (see section III.C.5 of this document),
[sbull] Obtain a full data set for individual case safety reports
of serious SADRs, always expedited reports, and medication error
reports if a full data set is not available for the report (see section
III.C.5 of this document), and
[sbull] Obtain supporting documentation for a report of a death or
hospitalization (e.g., autopsy report, hospital discharge summary) (see
section III.D.7 of this document).
Active query would entail direct verbal contact either in person or
by telephone or other interactive means (e.g., a videoconference) with
the initial reporter of an SADR or medication error. FDA believes that,
in many cases, use of active query during initial contact with these
reporters would provide
[[Page 12421]]
manufacturers and applicants with adequate safety information and could
eliminate or decrease followup time expended by manufacturers,
applicants, and the agency. The agency does not believe that it is
sufficient for manufacturers and applicants just to send a letter to
reporters of SADRs and medication errors requesting further
information. These reporters could, however, submit written materials
to manufacturers and applicants to clarify or provide support for
verbal discussions.
Even though the agency is not proposing that manufacturers and
applicants request followup information for SADR and medication error
reports in writing, the CIOMS V report describes instances when it
might be appropriate to do so. FDA seeks comment as to whether the
agency should permit written requests for followup information and, if
so, in which situations should these requests be permitted.
Active query would be conducted by a health care professional, such
as a physician, physician's assistant, pharmacist, dentist, nurse, or
any individual with some form of health care training. The agency
believes that a health care professional would be able to understand
better the medical consequences of a case and ask reporters of SADRs
and medication errors appropriate questions to acquire more complete
safety information effectively and rapidly.
The proposed definition of active query would provide that, at a
minimum, a focused line of questioning be used to acquire further
information on SADRs. For this purpose, questions would be designed to
capture clinically relevant information associated with the drug or
licensed biological product and the SADR. This information would
include, but would not be limited to, baseline data, patient history,
physical exam, diagnostic results, and supportive lab results.
III.A.7. Spontaneous Report
Under proposed Sec. Sec. 310.305(a), 314.80(a), and 600.80(a), FDA
would amend its postmarketing safety reporting regulations to define
the term ``spontaneous report'' to mean:
A communication from an individual (e.g., health care
professional, consumer) to a company or regulatory authority that
describes an SADR or medication error. It does not include cases
identified from information solicited by the manufacturer or
contractor (applicant or contractor for proposed Sec. 314.80(a);
applicant, shared manufacturer, or contractor for proposed Sec.
600.80(a)), such as individual case safety reports or findings
derived from a study, company-sponsored patient support program,
disease management program, patient registry, including pregnancy
registries, or any organized data collection scheme. It also does
not include information compiled in support of class action
lawsuits.
The agency would define this term to clarify which reports would be
considered ``spontaneous.'' Over the years, changes in marketing
practices in the United States have led to expanded contacts between
consumers and manufacturers, applicants, contractors, and shared
manufacturers. This has resulted in the acquisition of new types of
solicited safety information. Under the proposed rule, only unsolicited
safety information from an individual, such as a health care
professional or consumer, to a company or regulatory authority would be
considered a ``spontaneous report.''
Cases identified from information solicited by companies, such as
individual case safety reports or findings obtained from a study,
company-sponsored patient support program, disease management program,
patient registry, including pregnancy registries, or any organized data
collection scheme would not be considered spontaneous. Instead, safety
information from these sources would be considered ``study''
information and would be handled according to the postmarketing safety
reporting requirements for a ``study.'' As proposed, study information
would be subject to reporting as discussed below:
[sbull] Expedited reports for serious and unexpected SADRs from a
study (see section III.D.1 of this document),
[sbull] Expedited reports for information from a study that would
be sufficient to consider product administration changes (see section
III.D.2 of this document),
[sbull] Expedited reports for an unexpected SADR with unknown
outcome from a study (see section III.D.3 of this document),
[sbull] Always expedited reports from a study (see section III.D.4
of this document),
[sbull] Medication error reports from a study (see section III.D.5
of this document),
[sbull] Summary tabulations of all serious SADRs from studies or
individual patient INDs in PSURs (see section III.E.2.f.ii of this
document), and
[sbull] Discussion of important safety information from studies in
PSURs and IPSRs (see sections III.E.2.g and III.E.3 of this document).
The proposed rule would consider SADR information compiled in
support of class action lawsuits to be neither spontaneous nor
``study'' information. FDA believes that the vast majority of SADR
information from class action lawsuits is duplicative (i.e., the same
SADR information is reported by multiple individuals). In many cases,
information in addition to the minimum data set is not available for
these SADR reports and followup is unlikely to result in acquisition of
new information. For these reasons, the agency is proposing to require
in TPSRs, PSURs and IPSRs summary information for SADRs from class
action lawsuits (see sections III.E.1.e, III.E.2.k.v, and III.E.3 of
this document).
Any safety information obtained from an individual (e.g., health
care professional, consumer) who has initiated contact with a company
or regulatory authority would be considered spontaneous. For example,
if an individual calls a company and asks if a particular SADR has been
observed with one of the company's drug or licensed biological products
because the individual or someone the individual knows has experienced
such an SADR, the call would be considered spontaneous. The agency
would consider these calls spontaneous because the individual making
the call has a belief or suspicion that the drug or licensed biological
product may have caused the SADR.
The proposed definition for spontaneous report is consistent with
the definition of ``spontaneous report or spontaneous notification'' in
the ICH E2C guidance (62 FR 27475)):
An unsolicited communication to a company, regulatory authority,
or other organization that describes an adverse reaction in a
patient given one or more medicinal products and which does not
derive from a study or any organized data collection scheme.
III.A.8. Medication Error
Proposed Sec. Sec. 310.305(a), 314.80(a), and 600.80(a) would
amend FDA's postmarketing safety reporting regulations to define the
terms ``medication error,'' ``actual medication error,'' and
``potential medication error.'' A ``medication error'' would be defined
as:
Any preventable event that may cause or lead to inappropriate
medication use or patient harm while the medication is in the
control of the health care professional, patient, or consumer. Such
events may be related to professional practice, health care
products, procedures, and systems including: Prescribing; order
communication; product labeling, packaging, and nomenclature;
compounding; dispensing; distribution; administration; education;
monitoring; and use.
[[Page 12422]]
An ``actual medication error'' would be defined as:
A medication error that involves an identifiable patient whether
the error was prevented prior to administration of the product or,
if the product was administered, whether the error results in a
serious SADR, nonserious SADR, or no SADR.
A ``potential medication error'' would be defined as:
An individual case safety report of information or complaint
about product name, labeling, or packaging similarities that does
not involve a patient.
The proposed rule would define these terms to clarify what would be
considered a medication error. The proposed definition for ``medication
error'' was developed by the National Coordinating Council for
Medication Error Reporting and Prevention, of which FDA is a member.
FDA would not consider a case in which a patient deliberately took an
overdose of a drug to be a ``medication error'' because the agency does
not believe that this type of situation is ``preventable.'' Instead, it
would be considered a ``non-accidental overdose.''
The proposed definitions for actual and potential medication errors
were developed by FDA. Actual medication errors involve an identifiable
patient whether or not the product is administered and, if the product
is administered, whether or not an SADR occurs. Potential medication
errors do not involve a patient, but rather describe information or
complaint about product name, labeling, or packaging similarities that
could result in a medication error in the future.
III.A.9. Company Core Data Sheet, Company Core Safety Information
(CCSI), Listed SADR, Unlisted SADR, and Unexpected SADR
Proposed Sec. Sec. 314.80(a) and 600.80(a) would amend FDA's
postmarketing safety reporting regulations to define the terms
``company core data sheet,'' ``company core safety information
(CCSI),'' ``listed SADR,'' and ``unlisted SADR.'' The ``company core
data sheet'' would be defined as:
A document prepared by the applicant containing, in addition to
safety information, material relating to indications, dosing,
pharmacology, and other information concerning the drug substance
(biological product for proposed Sec. 600.80(a)). The only purpose
of this document is to provide the company core safety information
(CCSI) for periodic safety update reports (PSURs), interim periodic
safety reports (IPSRs), and certain individual case safety reports--
semiannual submissions (i.e., if PSURs are submitted for the
product).
The ``CCSI'' would be defined as:
All relevant safety information contained in the company core
data sheet that the applicant proposes to include in the approved
product labeling in all countries where the applicant markets the
drug substance (biological product for proposed Sec. 600.80(a)). It
is the reference information by which an SADR is determined to be
``listed'' or ``unlisted'' for PSURs, IPSRs, and certain individual
case safety reports--semiannual submissions (i.e., if PSURs are
submitted for the product).
A ``listed SADR'' would be defined as: ``an SADR whose nature,
specificity, severity, and outcome are consistent with the information
in the CCSI.''
An ``unlisted SADR'' would be defined as: ``an SADR whose nature,
specificity, severity, or outcome is not consistent with the
information included in the CCSI.''
The proposed rule would define these terms to help applicants
determine which SADRs must be reported in PSURs, IPSRs, and certain
individual case safety reports--semiannual submissions (i.e., if PSURs
are submitted for the product) (see sections III.E.2, III.E.3, and
III.E.4 of this document). For this purpose, the CCSI would be used as
the reference document by which an SADR would be judged as ``listed''
or ``unlisted.''
Company core data sheets would usually be prepared by applicants
for a drug substance rather than a drug product because postmarketing
PSURs and IPSRs would be based on a drug substance. Under the existing
regulations at Sec. 314.3(b) (21 CFR 314.3(b)), a drug substance is
defined as:
An active ingredient that is intended to furnish pharmacological
activity or other direct effect in the diagnosis, cure, mitigation,
treatment, or prevention of disease or to affect the structure or
any function of the human body, but does not include intermediates
use[d] in the synthesis of such ingredient.
Under these same regulations, a drug product is defined as:
a finished dosage form, for example, tablet, capsule, or solution,
that contains a drug substance, generally, but not necessarily, in
association with one or more other ingredients.
Thus, drug substances refer to active moieties of drug products.
In the United States, the company core data sheet would be used
only to provide the CCSI for a drug or biological product to determine
whether an SADR is listed or unlisted. Company core data sheets would
not require approval from FDA, unlike the U.S. labeling for a marketed
drug or licensed biological product which does require approval from
FDA. Company core data sheets would not be used in the United States as
the labeling for an approved drug or licensed biological product. FDA
believes that preparation of a company core data sheet would not impose
a new burden on most applicants because it codifies a common practice
in the pharmaceutical industry (see the ICH E2C guidance, 62 FR 27470
at 27472).
Postmarketing PSURs may be submitted by applicants to multiple
countries, and the drug or licensed biological product may have
different approved labeling in the different countries. The CCSI for
the product should not be a compilation of all the safety information
contained in the various approved labelings for the product. Instead,
the CCSI should contain the critical safety information for the product
that would be relevant in all countries where the product is approved
for marketing. In some cases, the CCSI and an approved labeling for the
product would contain the same safety information (i.e., all the safety
information in an approved labeling for the product is relevant in all
countries where the product is approved for marketing or the product is
only approved for marketing in one country). In other cases, an
approved labeling for a product may contain more safety information
than the CCSI for the product because the labeling may contain safety
information specific to the country in which the product is approved
for marketing (e.g., safety information regarding a specific indication
for which the product is approved for marketing in one country but not
other countries). In these cases, the use of the CCSI as the reference
document for determining whether an SADR is listed or unlisted for the
postmarketing PSURs may result in overreporting of some SADRs to FDA as
``unlisted'' when they actually are ``expected'' by the approved U.S.
labeling.
This proposal would not affect the reference document used to
determine expectedness (i.e., unexpected or expected SADR) for SADRs
reported in premarketing IND safety reports, postmarketing expedited
reports, postmarketing TPSRs, and certain postmarketing individual case
safety reports--semiannual submissions (i.e., if TPSRs are submitted
for the product) (see table 5 and sections III.B, III.D, III.E.1, and
III.E.4 of this document). Under the existing regulations at Sec. Sec.
310.305(b), 314.80(a), and 600.80(a), the definition of ``unexpected
adverse drug experience'' designates the current approved labeling for
the drug or licensed biological product as the reference document to be
used to determine what would be considered
[[Page 12423]]
``unexpected.'' Proposed Sec. Sec. 310.305(a), 314.80(a), and
600.80(a) would include in the definition of ``unexpected SADR'' the
abbreviation ``U.S.'' before the word ``labeling'' to clarify that the
approved U.S. labeling would be used to determine whether or not an
SADR is ``unexpected.'' FDA would also amend this definition by
replacing the word ``event'' with the word ``reaction'' and by
clarifying that the phrase ``differ from the event because of greater
severity or specificity'' refers to a ``labeled reaction.'' Under
proposed Sec. Sec. 310.305(a), 312.32(a), 314.80(a), and 600.80(a),
the agency would also replace the word ``listed'' with the word
``included'' in the definition of ``unexpected SADR'' to minimize
confusion with ``listed SADRs'' in the CCSI. FDA would also revise the
sentence ``Unexpected, as used in this definition, refers to an SADR
that has not been previously observed * * * rather than from the
perspective of such reaction not being anticipated from the
pharmacological properties of the drug product'' in this definition for
clarity.
Table 5.--Proposed Reference Documents for Safety Reports
------------------------------------------------------------------------
Marketing status Safety report Reference document
------------------------------------------------------------------------
Premarketing................ IND safety report... Investigator's
brochure. If not
available, risk
information in
general
investigational
plan or elsewhere
in the current
application.
Postmarketing............... Expedited reports... U.S. labeling.
TPSRs............... U.S. labeling.
PSURs and IPSRs..... CCSI.
Individual case
safety reports--
semiannual
submission:
If TPSR is U.S. labeling.
submitted for
the product.
If PSUR is CCSI.
submitted for
the product.
------------------------------------------------------------------------
These proposed amendments are consistent with the ICH E2C guidance
(62 FR 27470 at 27472):
For purposes of periodic safety reporting, CCSI forms the basis
for determining whether an ADR is already Listed or is still
Unlisted, terms that are introduced to distinguish them from the
usual terminology of ``expectedness'' or ``labeledness'' that is
used in association with official labeling. Thus, the local approved
product information continues to be the reference document upon
which labeledness/expectedness is based for the purpose of local
expedited postmarketing safety reporting.
Under proposed Sec. Sec. 310.305(a), 312.32(a), 314.80(a), and
600.80(a), FDA would include the following sentence in the definition
of ``unexpected SADR:''
SADRs that are mentioned in the U.S. labeling (investigator's
brochure for proposed Sec. 312.32(a)) as occurring with a class of
drugs (products for proposed Sec. 600.80(a)) but not specifically
mentioned as occurring with the particular drug (product for
proposed Sec. 600.80(a)) are considered unexpected.
This information is currently included in the draft guidance of
2001. FDA is now proposing to codify this information to clarify which
SADRs would be considered ``unexpected.''
III.A.10. Data Lock Point and International Birth Date
Proposed Sec. Sec. 314.80(a) and 600.80(a) would amend FDA's
postmarketing safety reporting requirements to define the terms ``data
lock point'' and ``international birth date.'' The ``data lock point''
would be defined as:
The date designated as the cut-off date for data to be included
in a postmarketing periodic safety report.
The ``international birth date'' would be defined as:
The date the first regulatory authority in the world approved
the first marketing application for a human drug product containing
the drug substance (human biological product for proposed Sec.
600.80(a)).
The agency would define these terms to help standardize the
submission date (i.e., month and day of submission) for postmarketing
periodic safety reports (i.e., PSURs, IPSRs, TPSRs, individual case
safety reports--semiannual submissions). The data lock point would
signify the end of a reporting period for data to be included in a
specific postmarketing periodic safety report. The month and day of the
international birth date would serve as a reference point for
determining the data lock point. On the date of the data lock point,
safety information that is available to applicants would be reviewed
and evaluated prior to being submitted to FDA. Postmarketing periodic
safety reports would be submitted to FDA within 60 days of the data
lock point (see section III.E.5.b of this document). For example, for a
drug or biological product approved by FDA on June 15 with a 6-month
periodic reporting period and an international birth date of April 1,
the first data lock point would be October 1, which is less than 6
months after FDA approval, but is the 6-month anniversary of the
international birth date. Therefore, the first postmarketing periodic
safety report would cover the period from April 1 through October 1
even though the product had only been approved in the United States on
June 15. The second periodic report would cover the period from October
2 through April 1.
An international birth date would be determined and declared by
applicants. Applicants would determine an international birth date for
a product based on the date of approval of the first marketing
application in the world for a human drug product containing the drug
substance or a biological product. A single international birth date
would encompass all different dosage forms, formulations, or uses
(e.g., indications, routes of administration, populations) of a drug
substance or licensed biological product. Thus, postmarketing periodic
safety reports for different drug products containing the same drug
substance would be submitted to FDA at the same time.
The month and day of the international birth date would be used, as
noted previously, to determine the data lock point (i.e., month and
day) for postmarketing periodic safety reports. It would not, except as
noted below, be used to determine the frequency for submission of these
reports (i.e., 6-month intervals or multiples of 6 months). Instead,
the date (i.e., year) of U.S. approval of the application for the drug
or biological product (e.g., NDA, ANDA, BLA) would be used to determine
the frequency for submission of postmarketing periodic safety reports
to FDA (see section III.E.5.a of this document). The international
birth date would be used to determine both the data lock point and
reporting frequency for postmarketing periodic safety reports only when
the U.S. approval date is used to determine the international birth
date (e.g., FDA is the first
[[Page 12424]]
regulatory authority in the world to approve the human drug product
containing the drug substance or biological product for marketing).
The use of a standardized submission date (i.e., month and day),
which is consistent with the ICH E2C guidance (62 FR 27470 at 27472),
would enable applicants to submit a single core report (PSUR excluding
appendices) to regulatory authorities worldwide. Currently, different
regulatory authorities require submission of postmarketing periodic
safety reports on varying time schedules. The submission of a single
core report to multiple regulatory authorities would significantly
reduce the time spent preparing these reports, thereby permitting more
time for the evaluation of the medical significance of any safety
information reported.
III.B. IND Safety Reports
III.B.1. Review of Safety Information
Current IND safety reporting regulations in Sec. 312.32(b) require
that sponsors promptly review all information relevant to the safety of
the drug under investigation obtained or otherwise received by the
sponsor from any source, foreign or domestic. Sources of information
include any clinical or epidemiological investigations, animal
investigations, commercial marketing experience, reports in the
scientific literature, and unpublished scientific papers, and reports
from foreign regulatory authorities that have not already been
previously reported to FDA by the sponsor. FDA is proposing to amend
this requirement by adding ``in vitro studies'' to the list of examples
because some in vitro studies report relevant safety-related
information (e.g., carcinogenicity studies performed in cell lines).
FDA is also proposing to move the phrase ``commercial marketing
experience'' to the end of the list and to revise it to read ``and
reports of foreign commercial marketing experience for drugs that are
not marketed in the United States'' to clarify that sponsors are not
required to review safety information from commercial marketing
experience for drugs that are marketed in the United States and are
being further studied under an IND. Safety reports from commercial
marketing experience for these drugs would be reviewed for safety
information as prescribed by FDA's postmarketing safety reporting
regulations (see section III.C.2 of this document). This proposed
revision is consistent with existing regulations at Sec. 312.32(c)(4)
and proposed amendments to Sec. 312.32(c)(4) described below (see
section III.B.4 of this document). The proposed amendments would
further clarify some of the types of safety information that must be
examined to determine whether the information must be submitted in an
IND safety report.
III.B.2. Written IND Safety Reports
Current IND safety reporting regulations at Sec. 312.32(c)(1)(i)
require sponsors to notify FDA and all participating investigators in a
written IND safety report of any adverse experience associated with the
use of the drug that is both serious and unexpected or any finding from
tests in laboratory animals that suggests a significant risk for human
subjects, including reports of mutagenicity, teratogenicity, or
carcinogenicity. These written IND safety reports must be made as soon
as possible and in no event later than 15 calendar days after the
sponsor's initial receipt of the information. For clarity, FDA is
proposing to amend Sec. 312.32(c)(1) by reorganizing and renumbering
this paragraph.
III.B.2.a. Minimum data set. FDA is proposing to amend Sec.
312.32(c) to state that sponsors must not submit an IND safety report
for an SADR to the agency if the report does not contain a minimum data
set (i.e., identifiable patient, identifiable reporter, suspect drug or
biological product, and SADR). If a minimum data set is not available,
a sponsor would be required to maintain records of any information
received or otherwise obtained for the SADR along with a record of its
efforts to obtain a minimum data set for the IND safety report. This
proposed amendment would clarify for sponsors that, at a minimum,
certain information must be submitted to FDA for each IND safety report
of an SADR to allow an initial evaluation of the significance of the
SADR. This proposed revision is consistent with the ICH E2A guidance
(60 FR 11284 at 11287):
The minimum information required for expedited reporting
purposes is: an identifiable patient; the name of a suspect
medicinal product; an identifiable reporting source; and an event or
outcome * * *.
III.B.2.b. Serious and unexpected SADRs. FDA is also proposing to
amend Sec. 312.32(c)(1)(i) by replacing the phrase ``any adverse
experience associated with the use of the drug that is both serious and
unexpected'' with the phrase ``any SADR that, based on the opinion of
the investigator or sponsor, is both serious and unexpected, as soon as
possible, but in no case later than 15 calendar days after receipt by
the sponsor of the minimum data set for the serious, unexpected SADR.''
This proposed amendment would require that the determination of the
possibility of causality (attributability) of an SADR to an
investigational drug be based on the opinion of either the investigator
or sponsor, which is consistent with the ICH E2A guidance (60 FR 11284
at 11286):
Causality assessment is required for clinical investigation
cases. All cases judged by either the reporting health care
professional or the sponsor as having a reasonable suspected causal
relationship to the medicinal product qualify as ADR's.
In situations in which a sponsor does not believe that there is a
reasonable possibility that an investigational drug caused a response,
but an investigator believes that such a possibility exists, the
proposed rule would require that the sponsor submit a written IND
safety report to FDA for the SADR. In the opposite situation, the same
would also be true.
The proposed rule would also require that written IND safety
reports be submitted to FDA no later than 15 calendar days after
receipt by the sponsor of the minimum data set for the serious,
unexpected SADR. This proposed revision would clarify when the 15
calendar day timeframe would begin. FDA expects sponsors to use due
diligence to acquire immediately the minimum data set for a report and
to determine the outcome (whether the SADR is serious or nonserious)
and expectedness of an SADR upon initial receipt of the SADR. Sponsors
should include in any written IND safety reports subsequently filed
with FDA a chronological history of their efforts to acquire this
information if there is a delay in obtaining the information (it is not
necessary to include the chronological history in IND safety reports
sent to investigators). This proposed amendment is consistent with the
ICH E2A guidance (60 FR 11284 at 11286):
Information for final description and evaluation of a case
report may not be available within the required timeframes for
reporting * * *. Nevertheless, for regulatory purposes, initial
reports should be submitted within the prescribed time as long as
the following minimum criteria are met: An identifiable patient; a
suspect medicinal product; an identifiable reporting source; and an
event or outcome that can be identified as serious and unexpected,
and for which, in clinical investigation cases, there is a
reasonable suspected causal relationship. * * *
FDA is also proposing to amend Sec. 312.32(c)(1)(i) by removing
the following sentence: ``Each notification shall be made as soon as
possible and
[[Page 12425]]
in no event later than 15 calendar days after the sponsor's initial
receipt of the information.'' The agency is proposing this revision
because the information in this sentence is redundant with a provision
of proposed Sec. 312.32(c)(1)(i).
III.B.2.c. Information sufficient to consider product
administration changes. Under proposed Sec. 312.32(c)(1)(ii), FDA
would amend Sec. 312.32(c)(1)(i) by replacing the phrase ``Any finding
from tests in laboratory animals that suggests a significant risk for
human subjects including reports of mutagenicity, teratogenicity, or
carcinogenicity'' with the sentence:
The sponsor must also notify FDA and all participating
investigators in a written IND safety report of information that,
based upon appropriate medical judgment, might materially influence
the benefit-risk assessment of an investigational drug or that would
be sufficient to consider changes in either product administration
or in the overall conduct of a clinical investigation. The sponsor
must submit this information to FDA and all participating
investigators as soon as possible, but in no case later than 15
calendar days after determination by the sponsor that the
information qualifies for reporting under this paragraph. Examples
of such information include any significant unanticipated safety
finding or data in the aggregate from an in vitro, animal,
epidemiological, or clinical study, whether or not conducted under
an IND, that suggests a significant human risk, such as reports of
mutagenicity, teratogenicity, or carcinogenicity or reports of a
lack of efficacy with a drug product used in treating a life-
threatening or serious disease.
This proposed amendment is consistent with the ICH E2A guidance (60
FR 11284 at 11286):
There are situations in addition to single case reports of
``serious'' adverse events or reactions that may necessitate rapid
communication to regulatory authorities; appropriate medical and
scientific judgment should be applied for each situation. In
general, information that might materially influence the benefit-
risk assessment of a medicinal product or that would be sufficient
to consider changes in medicinal product administration or in the
overall conduct of a clinical investigation represents such
situations. Examples include:
a. For an ``expected, serious ADR, [''] an increase in the rate
of occurrence which is judged to be clinically important.
b. A significant hazard to the patient population, such as lack
of efficacy with a medical product used in treating life-threatening
disease.
c. A major safety finding from a newly completed animal study
(such as carcinogenicity).
In contrast to the ICH recommendations, the proposed rule would not
require reports of an increase in the rate of occurrence of expected,
serious SADRs to be submitted to the agency in an expedited manner.
However, sponsors should report this information to FDA in their IND
annual reports under Sec. 312.33(b)(1). Proposed Sec.
312.32(c)(1)(ii) would be consistent with the increased frequency
reports final rule that revoked the postmarketing safety reporting
requirement for submission of increased frequency reports in an
expedited manner. Although the increased frequency reports final rule
pertains to postmarketing expedited safety reporting, FDA has decided
to apply this rule to its requirements for premarketing expedited
safety reports because of the limited reliability of increased
frequency reports. See the increased frequency reports final rule (62
FR 34166) for a discussion of the limited reliability of increased
frequency reports. With regard to premarketing clinical trials in
progress, FDA does not believe that baseline incidence rates would be
available for serious expected SADRs which would make it difficult for
sponsors to predict an increase in the rate of occurrence of these
SADRs.
III.B.2.d. Reporting format. Current IND safety reporting
regulations at Sec. 312.32(c)(1)(i) require sponsors to submit written
IND safety reports from animal or epidemiological studies in a
narrative format. Proposed Sec. 312.32(c)(1)(iii) would amend these
regulations by replacing the phrase ``reports from animal or
epidemiological studies'' with the phrase ``reports of overall findings
or data in the aggregate from published and unpublished in vitro,
animal, epidemiological, or clinical studies.'' The proposed rule would
require sponsors to submit reports of overall findings or data in the
aggregate in a narrative format rather than on FDA Form 3500A because
the form is designed for reporting safety information for an individual
case.
III.B.3. Telephone Safety Reports
Current IND safety reporting regulations at Sec. 312.32(c)(2)
require sponsors to notify FDA by telephone or by facsimile
transmission of any unexpected fatal or life-threatening experience
associated with the use of an investigational drug as soon as possible
but in no event later than 7 calendar days after the sponsor's initial
receipt of the information. FDA is proposing to amend this requirement
to read:
The sponsor must also notify FDA by telephone or by facsimile
transmission of any unexpected fatal or life-threatening SADR based
on the opinion of the investigator or sponsor as soon as possible
but in no case later than 7 calendar days after receipt by the
sponsor of the minimum data set for the unexpected fatal or life-
threatening SADR.
These proposed revisions are consistent, as described previously,
with the proposed amendments to Sec. 312.32(c)(1)(i) for written IND
safety reports and the ICH E2A guidance (60 FR 11284 at 11286).
III.B.4. IND Safety Reporting for Drugs Marketed in the United States
Current IND safety reporting regulations at Sec. 312.32(c)(4)
state that a sponsor of a clinical study of a marketed drug is not
required to make a safety report for any adverse experience associated
with the use of the drug that is not from the clinical study itself.
FDA is proposing to amend this regulation by making the following
revisions:
A sponsor of a clinical study under an IND for a drug marketed
in the United States is only required to submit IND safety reports
to FDA (review division that has responsibility for the IND) for
SADRs from the clinical study itself, whether from domestic or
foreign study sites of the IND. The sponsor must also submit to FDA
safety information from these clinical studies as prescribed by the
postmarketing safety reporting requirements under Sec. Sec.
310.305, 314.80, and 600.80 of this chapter.
FDA is proposing this change to clarify, for sponsors investigating
under an IND drugs and biological products that are already marketed in
the United States, what SADRs must be reported in IND safety reports
under Sec. 312.32. The agency notes that sponsors investigating under
an IND drug and biological products that are not marketed in the United
States are required, under Sec. 312.32, to report to FDA safety
information obtained or otherwise received for the product from any
source, domestic or foreign, including safety information from foreign
commercial marketing experience (see section III.B.1 of this document).
Proposed Sec. 312.32(c)(4) also clarifies that sponsors investigating
under an IND drugs and biological products that are already marketed in
the United States must submit safety information for these clinical
studies as prescribed by the postmarketing safety reporting
requirements in Sec. Sec. 310.305, 314.80, and 600.80.
III.B.5. Investigator Reporting
Current investigator safety reporting regulations at Sec.
312.64(b) state that the investigator shall promptly report to the
sponsor any adverse effect that may reasonably be regarded as caused
by, or probably caused by, the drug. If the adverse effect is alarming,
the investigator shall report the adverse
[[Page 12426]]
effect immediately. FDA is proposing to revise this requirement as
follows:
An investigator must report to the sponsor any serious SADR (as
defined in Sec. 312.32(a)) immediately and any other SADR (as
defined in Sec. 312.32(a)) promptly unless the protocol or
investigator's brochure specifies a different timetable for
reporting the SADR.
FDA is proposing this revision to be consistent with the proposed
definition for SADR and to clarify what information investigators must
submit to sponsors expeditiously.
III.C. Postmarketing Safety Reporting
III.C.1. Prescription Drugs Marketed for Human Use Without an Approved
Application
Current regulations (Sec. 310.305) require manufacturers, packers,
and distributors of marketed prescription drug products that are not
the subject of an approved NDA or ANDA to establish and maintain
records of and report to FDA all serious, unexpected adverse drug
experiences associated with the use of their drug products. The
proposed rule would amend these regulations by revising the language in
this section to be consistent with the language for the postmarketing
expedited safety reporting requirements under Sec. 314.80. FDA is also
proposing to reorganize and renumber Sec. 310.305 to be consistent
with Sec. 314.80. FDA is proposing these revisions to harmonize, to
the extent possible, the postmarketing expedited safety reporting
requirements for human marketed drugs with approved applications (i.e.,
NDAs, ANDAs) and prescription drugs marketed for human use without an
approved application.
III.C.2. Review of Safety Information
Current postmarketing safety reporting regulations under Sec. Sec.
314.80(b) and 600.80(b) require applicants to promptly review all
safety information obtained or otherwise received from any source,
foreign or domestic, including information derived from commercial
marketing experience, postmarketing clinical investigations,
postmarketing epidemiological/surveillance studies, reports in the
scientific literature, and unpublished scientific papers. FDA is
proposing to amend these regulations by adding ``animal and in vitro
studies,'' ``electronic communications with applicants via the Internet
(e.g., e-mail),'' and ``reports from foreign regulatory authorities
that have not been previously reported to FDA by the applicant'' to the
list of examples. FDA is proposing to add animal and in vitro studies
to the list of examples because many of these studies report relevant
safety-related information (e.g., carcinogenicity, mutagenicity,
teratogenicity).
FDA is proposing to add electronic communications with applicants
via the Internet (e.g., e-mail) to the list of examples to clarify for
applicants what safety information on the Internet would be required to
be reviewed. An applicant would be required to review information
received on an Internet site(s) that it sponsors, but would not be
required to review Internet sites that it does not sponsor. However, if
an applicant becomes aware of safety information on an Internet site
that it does not sponsor, the applicant would be responsible for
reviewing the information.
FDA would not expect applicants to review safety data bases
generated by foreign regulatory authorities. However, proposed
Sec. Sec. 314.80(b)(1) and 600.80(b)(1) would require that any safety
information acquired or received from a foreign regulatory authority be
reviewed to determine whether the information must be reported to FDA.
The agency is proposing these amendments to further clarify some of the
types of safety information that must be examined to determine whether
the information must be submitted in postmarketing safety reports.
Proposed Sec. 310.305(b)(1) would amend FDA's postmarketing safety
reporting regulations for prescription drugs marketed for human use
without an approved application by adding the following sentence:
Each manufacturer of a prescription drug product marketed for
human use without an approved application must promptly review all
safety information pertaining to its product obtained or otherwise
received by the manufacturer from any source, foreign or domestic,
including information derived from commercial marketing experience,
postmarketing clinical investigations, postmarketing epidemiology/
surveillance studies, animal or in vitro studies, electronic
communications with manufacturers via the Internet (e.g., e-mail),
reports in the scientific literature, and unpublished scientific
papers, as well as reports from foreign regulatory authorities that
have not been previously reported to FDA by the manufacturer.
This proposed amendment would further clarify some of the types of
safety information that must be examined to determine whether the
information must be submitted in postmarketing expedited safety reports
(see section III.D of this document). This proposed revision would
provide uniformity between FDA's safety reporting requirements for
human marketed drugs with approved applications (i.e., NDAs, ANDAs) and
prescription drugs marketed for human use without an approved
application (i.e., without an approved NDA or ANDA).
Current postmarketing safety reporting regulations in Sec. Sec.
314.80(b) and 600.80(b) state that applicants are not required to
resubmit to FDA safety reports forwarded to the applicant by FDA;
however, applicants must submit all followup information on such
reports. Proposed Sec. Sec. 314.80(b)(2) and 600.80(b)(2) would amend
these regulations to state that individual case safety reports
forwarded to the applicant by FDA must not be resubmitted to the agency
by applicants. FDA is proposing this revision to prevent duplicate
reports from being entered into the agency's safety reporting database.
Applicants that inadvertently resubmit such reports to FDA will be
informed not to do so in the future.
Proposed Sec. Sec. 314.80(b)(2) and 600.80(b)(2) would also amend
these regulations to require that applicants include information from
individual case safety reports forwarded to the applicant by FDA in any
comprehensive safety analysis subsequently submitted to the agency.
This proposed amendment, which was discussed in the preamble but
inadvertently omitted from the codified section of the October 1994
proposal (59 FR 54046 at 54053), would clarify how safety information
received from FDA must be handled.
Current postmarketing safety reporting regulations at Sec. Sec.
314.80(b) and 600.80(b) state that applicants must develop written
procedures for the surveillance, receipt, evaluation, and reporting of
postmarketing adverse drug experiences to FDA. FDA is proposing to
amend this provision by adding the phrase ``and maintain'' after the
phrase ``must develop.'' This proposed amendment would clarify that
applicants must maintain records of the written procedures for review
by FDA. FDA would review the written procedures either upon request by
the agency (proposed Sec. Sec. 314.80(f) and 600.80(f)) or during
inspections by the agency. FDA is also proposing to replace the phrase
``adverse drug experiences'' with the phrase ``postmarketing safety
information.'' For organizational purposes, FDA is proposing to move
the written procedures provision to proposed Sec. Sec. 314.80(g) and
600.80(g). FDA is proposing the same type of amendments to Sec.
310.305.
Current Sec. 314.80(b) applies to applicants having an approved
application under Sec. 314.50 or, in the case of a 505(b)(2)
application, an effective approved application. FDA is proposing to
amend this provision by replacing the phrase ``under Sec. 314.50 or,
[[Page 12427]]
in the case of a 505(b)(2) application, an effective approved
application'' with the phrase ``under section 505(c) of the act.''
Although NDAs, including those referred to in section 505(b)(2) of the
Federal Food, Drug and Cosmetic Act (the act) (21 U.S.C. 355(b)(2)) are
filed under section 505(b)(1) of the act, they are approved under
section 505(c) of the act. FDA is proposing to use the phrase ``section
505(c) of the act'' because it more appropriately references the cite
for approval of NDAs.
The agency is proposing to remove the phrase ``in the case of a
505(b)(2) application, an effective approved application'' because FDA
no longer issues approvals with a delayed effective date for 505(b)(2)
applications, as it did at the time this regulation was issued. The
agency now issues tentative approvals for 505(b)(2) applications when
the (final) approval is blocked by patent or exclusivity rights. As
described in the preamble to the final rule on ``Abbreviated New Drug
Application Regulations; Patent and Exclusivity Provisions'' (59 FR
50338 at 50351 to 50352, October 3, 1994), a 505(b)(2) application that
has a tentative approval is not approved for marketing until a final
approval letter for the drug product is received from FDA. Thus,
applicants having a 505(b)(2) application with a tentative approval
would not be subject to the postmarketing safety reporting requirements
under Sec. 314.80 until final approval of the application is in
effect. For consistency, FDA is proposing a similar change to Sec.
314.98(a).
III.C.3. Reporting Requirements
Current postmarketing safety reporting requirements at Sec. Sec.
310.305(c), 314.80(c), and 600.80(c) state that persons subject to
these requirements shall report to FDA adverse drug experience
information as described under these sections. FDA is proposing to
remove these provisions from its postmarketing safety reporting
regulations because they are redundant (see proposed Sec. Sec.
310.305(c), 314.80(c), and 600.80(c)).
Current postmarketing safety reporting requirements at Sec. Sec.
314.80(c) and 600.80(c) state that two copies of each report must be
submitted to FDA. For drug products, proposed Sec. 314.80(c) would
require that applicants submit to FDA two copies of each postmarketing
expedited report and one copy of each postmarketing periodic safety
report of an individual case safety reports--semiannual submission
pertaining to its product (see tables 6 and 7 for proposed
postmarketing expedited and periodic safety reports). For nonvaccine
biological products, proposed Sec. 600.80(c) would require that
applicants submit to FDA two copies of each postmarketing expedited
report and each postmarketing periodic safety report of an individual
case safety reports--semiannual submission pertaining to its product.
For drugs and nonvaccine biologics, proposed Sec. Sec. 314.80(c) and
600.80(c) would also require that one copy of a PSUR, IPSR, or TPSR be
submitted to FDA along with one copy for each approved application for
a human drug or licensed biological product (e.g., NDA, ANDA, BLA)
covered by the report (see table 7 for proposed postmarketing periodic
safety reports). For vaccines, proposed Sec. 600.80(c) would require
that applicants submit to VAERS two copies of each safety report
required under Sec. 600.80 and pertaining to its product. These
proposed amendments would provide FDA with enough copies of safety
reports for efficient review by the agency. Electronic submission of
these reports will obviate the need for submission of two copies. At
this time, manufacturers and applicants can voluntarily submit certain
postmarketing safety reports in an electronic format (see Docket 92S-
0251 regarding postmarketing expedited and periodic individual case
safety reports; available on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/dockets/92s0251/92s0251.htm
). Capabilities for electronic
submission of other postmarketing safety reports (e.g., safety reports
for vaccines) will be available in the future.
Table 6.--Proposed Postmarketing Expedited Safety Reports
--------------------------------------------------------------------------------------------------------------------------------------------------------
Persons with
Expedited Safety Report Type of Information Submission to FDA-- Reporting Reference in Section III
Timeframe Responsibility of this Document
--------------------------------------------------------------------------------------------------------------------------------------------------------
Serious & unexpected SADRs........ Individual case safety reports............... 15 calendar days.... Manufacturers and D.1
applicants.
Information sufficient to consider Information based upon appropriate medical 15 calendar days.... Manufacturers and D.2
product administration changes. judgment. For example, any significant applicants.
unanticipated safety finding or data in the
aggregate from an in vitro, animal,
epidemiological, or clinical study that
suggests a significant human risk.
Unexpected SADRs with unknown Individual case safety reports of unexpected 45 calendar days.... Manufacturers and D.3
outcome. SADRs for which a determination of serious applicants.
or nonserious cannot be made..
Always expedited reports.......... Individual case safety reports of certain 15 calendar days.... Manufacturers and D.4
medically significant SADRs whether applicants.
unexpected or expected and whether or not
the SADR leads to a serious outcome.
Medication errors................. All domestic reports of medication errors, 15 calendar and days Manufacturers and D.5
whether actual or potential.. applicants.
30-day followup................... Followup report for initial serious and 30 calendar days.... Manufacturers and D.6
unexpected SADR reports, always expedited applicants.
reports and medication error reports that do
not contain a full data set.
15-day followup................... New information for expedited or followup 15 calendar days.... Manufacturers and D.6
reports, except initial expedited reports applicants.
for which 30-day followup reports must be
submitted.
SADR reports to manufacturer...... All SADRs.................................... 5 calendar days to Contractors......... D.9
manufacturer.
SADR reports to applicant......... All SADRs.................................... 5 calendar days to Contractors and D.9
applicant. shared
manufacturers.
[[Page 12428]]
Blood safety--oral or written..... Fatalities................................... As soon as possible. Blood establishments D.12
Blood safety--written............. Fatalities................................... 7 calendar days .................... .........................
All serious SARs except fatalities........... 45 calendar days.... .................... .........................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Table 7.--Proposed Postmarketing Periodic Safety Reports
----------------------------------------------------------------------------------------------------------------
Persons with
Periodic safety report Type of information Submission to reporting Reference in section
FDA--timeframe responsibility III of this document
----------------------------------------------------------------------------------------------------------------
Individual case safety [sbull] Serious, Every 6 months Applicants...... E.4
reports--semiannual expected SADRs after U.S.
submission. (domestic and approval of
foreign) and application.\3\.
nonserious,
unexpected SADRs
(domestic) if TPSR
is submitted for the
product.\1\.
[sbull] Serious,
listed SADRs
(domestic and
foreign) and
nonserious, unlisted
SADRs (domestic) if
PSUR is submitted
for the product.\2\.
TPSR--for applications [sbull] Narrative At 5, 7.5, 10, Applicants...... E.1
approved before January 1, summary and analysis 12.5, and 15
1998.\4\. of individual case years after
safety reports U.S. approval
[sbull] Increased of application
frequency reports. and then every
[sbull] Safety- 5 years
related actions to thereafter.\3\.
be taken.
[sbull] Summary
tabulations of
individual case
safety reports.
[sbull] History of
safety-related
actions taken.
[sbull] Location of
safety records.
[sbull] Contact
person information.
PSUR--for applications Core Document Every 6 months Applicants...... E.2
approved on or after January [sbull] Introduction. after U.S.
1, 1998. [sbull] Worldwide approval of
marketing status. application for
[sbull] Actions taken 2 years,
for safety reasons. annually for
[sbull] Changes to the next 3
CCSI. years, and then
[sbull] Worldwide every 5 years
patient exposure. thereafter.\3\.
[sbull] Summary
tabulations.
[sbull] Safety
studies.
[sbull] Other
information.
[sbull] Overall
safety evaluation.
[sbull] Conclusion...
Appendices...........
[sbull] Company core
data sheet.
[sbull] U.S. labeling
[sbull] Spontaneous
reports from
individuals other
than health care
professionals.
[sbull] SADRs with
unknown outcome.
[sbull] SADRs from
class action
lawsuits.
[sbull] Lack of
efficacy reports.
[sbull] Information
on resistance to
antimicrobial drug
products.
[sbull] Medication
errors.
[sbull] U.S. patient
exposure.
[sbull] Location of
safety records.
[sbull] Contact
person.
IPSR--for applications An ``abbreviated At 7.5 and 12.5 Applicants...... E.3
approved on or after January PSUR;'' same years after
1, 1998. information as PSUR U.S. approval
excluding summary of
tabulations. application.\3\.
----------------------------------------------------------------------------------------------------------------
\1\ Nonserious, expected SARs (domestic) and expected SARs with unknown outcome (domestic) would also be
submitted for vaccines.
\2\ Nonserious, listed SARs (domestic) and listed SARs with unknown outcome (domestic) would also be submitted
for vaccines.
\3\ The data lock point for the report would be the month and day of the international birth date or any other
month and day agreed on by the applicant and FDA. The submission date for the report would be within 60
calendar days of the data lock point.
\4\ A PSUR may be submitted in lieu of a TPSR if an applicant so desires.
Current Sec. Sec. 310.305(c), 314.80(c), 314.98(b), and 600.80(c)
provide mailing addresses for the submission of postmarketing safety
reports. FDA is proposing to remove the mailing addresses from
Sec. Sec. 310.305(c), 314.80(c), 314.98(b), and 600.80(c) because this
information is provided in the draft guidance of 2001.
[[Page 12429]]
III.C.4. Request for Alternative Reporting Frequency
FDA is proposing to amend its postmarketing safety reporting
regulations at Sec. Sec. 310.305(c), 314.80(c), and 600.80(c) to state
that, upon written notice, the agency may require, when appropriate,
that manufacturers and applicants submit postmarketing safety reports
(i.e., expedited, followup, or periodic safety reports) to FDA at times
other than prescribed by the regulations (see tables 8 and 9 regarding
proposed reporting frequencies for postmarketing safety reports). In
most cases, FDA would not request alternative reporting periods for
these safety reports. In some cases, however, FDA may need to receive
reports more frequently (e.g., marketed product approved for a new
indication, dosage form, or population) or less frequently (e.g.,
product on the market for over 30 years with no new safety concerns
identified).
Table 8.--Proposed Reporting Frequency for Postmarketing Expedited Safety Reports
----------------------------------------------------------------------------------------------------------------
Submit as soon as Submit within 5 Submit within 7 Submit within 15 Submit within 30 Submit within 45
possible calendar days calendar days calendar days calendar days calendar days
----------------------------------------------------------------------------------------------------------------
[sbull] Blood [sbull] [sbull] Blood [sbull] Serious [sbull] 30-day [sbull] Unexpected
safety report-- Individual case safety report-- and unexpected followup report SADR with unknown
telephone safety reports written SADR report (D.6). outcome (D.3).
(fatality) from contractors (fatality) (D.1). [sbull] Blood safety
(D.12).\1\ to manufacturer (D.12). [sbull] report--written
(D.9). Information (all serious SARs
[sbull] sufficient to except fatalities)
Individual case consider (D.12).
safety reports product
from contractors administration
and shared changes (D.2).
manufacturers to [sbull] Always
applicant (D.9). expedited
report (D.4).
[sbull]
Medication
error report
(D.5).
[sbull] 15-day
followup report
(D.6).
----------------------------------------------------------------------------------------------------------------
\1\ References in parentheses refer to location in section III of this document.
Table 9.--Proposed Reporting Frequency for Postmarketing Periodic Safety Reports
----------------------------------------------------------------------------------------------------------------
Submit at 0.5, 1, Submit at 10
Persons with reporting Submit every 6 1.5, 2, 3, 4, and 5 Submit at 7.5 and years and every 5
responsibility months years 12.5 years years thereafter
----------------------------------------------------------------------------------------------------------------
Applicants with NDAs \1\ or Individual case PSUR (E.2)........... IPSR (E.3)........... PSUR.
BLAs approved on or after 1/ safety reports--
1/98 and applicants with semiannual
approved pediatric use submission
supplements. (E.4)\2\.
Applicants with NDAs or BLAs Individual case NA................... TPSR (E.1) or IPSR... TPSR or PSUR.
approved before 1/1/98. safety reports--
semiannual
submission.
----------------------------------------------------------------------------------------------------------------
\1\ Applicants with approved ANDAs would determine the type of postmarketing periodic safety report required to
be submitted to FDA (i.e., TPSR, PSUR, IPSR) and the frequency of submission for these reports based on the
U.S. approval date of the application for the innovator NDA product (see section III.I of this document).
\2\ References in parentheses refer to section III of this document.
FDA is also proposing to amend its postmarketing safety reporting
regulations at Sec. Sec. 314.80(c) and 600.80(c) to state that
applicants who wish to submit postmarketing safety reports at times
other than prescribed by these regulations may request a waiver for
this purpose under Sec. Sec. 314.90 or 600.90. This proposed revision
does not represent a new provision, but rather provides a cross-
reference to the existing waiver requirements under Sec. Sec. 314.90
and 600.90.
FDA is also proposing to amend its postmarketing periodic safety
reporting regulations at Sec. Sec. 314.80(c)(2)(i) and 600.80(c)(2)(i)
by removing the third and fourth sentences in these paragraphs. These
sentences state that, upon written notice, FDA may request submission
of periodic safety reports at different times than stated under
Sec. Sec. 314.80(c)(2)(i) and 600.80(c)(2)(i) (e.g., following the
approval of a major supplement). FDA is proposing to remove these
sentences because this information would now be stated under proposed
Sec. Sec. 314.80(c) and 600.80(c). This proposed revision represents
an organizational change that clarifies that FDA may request a
different time period for submission of not only postmarketing periodic
safety reports, but also postmarketing expedited safety reports.
III.C.5. Determination of Outcome, Minimum Data Set, and Full Data Set
Proposed Sec. Sec. 310.305(c)(1)(i)(A), 314.80(c)(1)(i)(A), and
600.80(c)(1)(i)(A) would amend FDA's postmarketing safety reporting
regulations to require that manufacturers and applicants immediately,
upon initial receipt of an SADR report, determine the outcome for the
SADR (whether the SADR is serious or nonserious) and at least the
minimum data set for the individual case safety report (i.e.,
identifiable patient, identifiable reporter, suspect drug or biological
product, and SADR). If the manufacturer or applicant is not able to
immediately determine this information, active query would be required
to be used by the manufacturer or applicant to obtain the information
as soon as possible. FDA is proposing this change to clarify that
timely acquisition of information is critical to determine whether an
SADR must be submitted to FDA and, for those reactions that would be
reported, whether the SADR would be submitted in a postmarketing
expedited safety report or a postmarketing periodic safety report.
Proposed Sec. Sec. 310.305(c)(1)(i)(A), 314.80(c)(1)(i)(A), and
600.80(c)(1)(i)(A) would also require manufacturers and applicants to
immediately determine the
[[Page 12430]]
minimum information for actual medication errors that do not result in
an SADR and potential medication errors (minimum information described
below and at proposed Sec. Sec. 310.305(c)(1)(iii)(B) and
(c)(1)(iii)(C), 314.80(c)(1)(iii)(B) and (c)(1)(iii)(C), and
600.80(c)(1)(iii)(B) and (c)(1)(iii)(C)). If the manufacturer or
applicant is not able to immediately determine this information, active
query would be required to be used by the manufacturer or applicant to
obtain the information as soon as possible.
Proposed Sec. Sec. 310.305(c)(1)(ii), 314.80(c)(1)(ii), and
600.80(c)(1)(ii) would require manufacturers and applicants who are
unable to immediately determine the outcome of an SADR (whether the
SADR is serious or nonserious) to continue to use active query to
attempt to determine the outcome within 30 calendar days after initial
receipt of the SADR report by the manufacturer or applicant. The
proposed rule would require that manufacturers and applicants maintain
records of their efforts to obtain this information. These proposed
revisions clarify that due diligence must be used to obtain the outcome
for SADRs. Unknown outcomes should not be classified arbitrarily as
nonserious SADRs. Instead, each of the outcomes in the definition of
serious SADR should be considered as a possibility.
Under proposed Sec. Sec. 310.305(c)(1)(iii)(A),
314.80(c)(1)(iii)(A), and 600.80(c)(1)(iii)(A), individual case safety
reports for SADRs that do not contain a minimum data set would not be
submitted to the agency. Instead, the proposed rule would require that
manufacturers and applicants maintain records of any information
received or otherwise obtained for the SADR along with a record of
their efforts to obtain a minimum data set for the individual case
safety report. These proposed amendments are consistent with proposed
revisions to the premarketing safety reporting regulations at proposed
Sec. 312.32(c) (see section III.B.2.a of this document). This change
would clarify that, at a minimum, certain information must be submitted
to FDA to provide the agency with enough information to allow an
initial evaluation of the significance of an SADR.
Proposed Sec. Sec. 310.305(c)(1)(iii)(B), 314.80(c)(1)(iii)(B),
and 600.80(c)(1)(iii)(B) would require that reports of actual
medication errors that do not result in an SADR be submitted to FDA
even though the report does not contain a minimum data set (i.e., does
not have an SADR). In these cases, individual case safety reports would
be required to contain at least an identifiable patient, an
identifiable reporter, and a suspect drug or biological product.
Proposed Sec. Sec. 310.305(c)(1)(iii)(C), 314.80(c)(1)(iii)(C),
and 600.80(c)(1)(iii)(C) would require that reports of potential
medication errors be submitted to FDA even though the report does not
contain a minimum data set (i.e., does not have an identifiable patient
or an SADR). In these cases, individual case safety reports would be
required to contain at least an identifiable reporter and a suspect
drug or biological product.
FDA is requiring submission of individual case safety reports for
actual medication errors that do not result in an SADR and potential
medication errors because of their potential significance and the need
for intervention to minimize future errors. For example, if an adult is
given the wrong medication, no SADR may occur, but if the same error
occurs with a child, an SADR may occur. Also, if an error is prevented
prior to administration of a product, this information could be used to
prevent the error from occurring in other situations. For example, the
proprietary name, label, labeling or packaging of the product could be
changed if sufficient evidence suggests such a change is warranted, or
education announcements could be communicated to health care
professionals and/or consumers.
Proposed Sec. Sec. 310.305(c)(1)(iv), 314.80(c)(1)(iv), and
600.80(c)(1)(iv) state that, for reports of serious SADRs, always
expedited reports, and medication error reports, manufacturers and
applicants would be required to submit a full data set for the report
(see section III.D.4 of this document for discussion of always
expedited reports and section III.D.5 of this document for discussion
of medication error reports). If a full data set is not available for
the report, the manufacturer or applicant would be required to use
active query to obtain this information. If a full data set is not
available, after active query, the manufacturer or applicant would
provide the following information:
[sbull] All safety information, received or otherwise obtained, for
the report;
[sbull] The reason(s) for their inability to acquire a full data
set; and
[sbull] Documentation of their efforts to obtain a full data set
(i.e., description of unsuccessful steps taken to obtain this
information).
In some cases, the agency has received incomplete safety reports for
serious SADRs, making interpretation of their significance difficult.
This proposed amendment would require submission of complete
information for reports of serious SADRs, always expedited reports, and
medication error reports, which would facilitate their expeditious
review.
Proposed Sec. Sec. 310.305(c)(1)(v), 314.80(c)(1)(v), and
600.80(c)(1)(v) state that:
For a serious SADR that was not initially reported to the
manufacturer (applicant for proposed Sec. Sec. 314.80(c)(1)(v) and
600.80(c)(1)(v)) by a health care professional (e.g., report from a
consumer), the manufacturer (applicant for proposed Sec. Sec.
314.80(c)(1)(v) and 600.80(c)(1)(v)) must contact the health care
professional associated with the care of the patient using active
query to gather further medical perspective on the case and to
acquire a full data set for the report. If the manufacturer
(applicant for proposed Sec. Sec. 314.80(c)(1)(v) and
600.80(c)(1)(v)) is unable to contact the health care professional,
it must include in the report for the serious SADR: (A) The
reason(s) for its inability to contact the health care professional
and (B) a description of its efforts to contact the health care
professional.
The agency believes that contact with a health care professional is
warranted for serious SADRs because of the critical nature of these
reactions. However, in those situations in which a manufacturer or
applicant is unable to contact the health care professional (e.g.,
health care professional does not return phone calls, consumer does not
permit manufacturer or applicant to contact its health care provider),
it would include in its report to FDA the reason(s) for its inability
to contact the health care professional and a description of its
efforts to contact the health care professional.
For nonserious SADRs with a minimum data set, proposed Sec. Sec.
314.80(c)(1)(vi) and 600.80(c)(1)(vi) would require applicants to
submit to FDA all safety information received or otherwise obtained.
Applicants would not be required to acquire information in addition to
the minimum data set, except that reports of nonserious SADRs resulting
from a medication error would require a full data set. Thus, followup
would not be required for reports of nonserious SADRs that contain a
minimum data set and do not occur because of a medication error.
III.C.6. Spontaneous Reports and Reports From Clinical Trials
Proposed Sec. Sec. 310.305(c)(1)(i)(B), 314.80(c)(1)(i)(B), and
600.80(c)(1)(i)(B) would require that, for spontaneous reports,
manufacturers and applicants must always assume, for safety reporting
purposes only, that there is at least a reasonable possibility, in the
opinion of the initial reporter, that the drug or
[[Page 12431]]
biological product caused the spontaneously reported event. Proposed
Sec. Sec. 310.305(c)(1)(i)(C), 314.80(c)(1)(i)(C), and
600.80(c)(1)(i)(C) state that, for a clinical trial, the possibility
that the drug or biological product caused the SADR or that a
medication error has occurred would be assumed if either the
investigator or the applicant/manufacturer believes that such a
reasonable possibility exists.
These proposed changes would clarify that all spontaneous reports
received by manufacturers and applicants that contain a minimum data
set (minimum information for a report of a medication error that does
not result in SADR) would be reported to FDA (i.e., as an individual
case safety report and/or in a summary tabulation). These changes are
consistent with the premarketing safety reporting requirements
described in section III.B.2.b of this document (i.e., determination of
the possibility of causality (attributability) of an SADR to the drug
or biological product in a clinical investigation would be based on the
opinion of either the applicant/sponsor or investigator). These
proposed amendments are also consistent with the ICH E2A guidance (60
FR 11284 at 11286):
Causality assessment is required for clinical investigation
cases. All cases judged by either the reporting health care
professional or the sponsor as having a reasonable suspected causal
relationship to the medicinal product qualify as ADR's. For purposes
of reporting, adverse event reports associated with marketed drugs
(spontaneous reports) usually imply causality.
III.C.7. Lack of Efficacy Reports
With regard to reports of a lack of efficacy for an approved drug
or biological product, the guidance of 1992 and guidance of 1993 advise
applicants to submit all individual cases of such reports that occur in
the United States in postmarketing periodic safety reports. In this
proposed rule, FDA would not require submission of individual case
safety reports for reports of a lack of efficacy. Instead, applicants
would be required to submit to FDA expedited reports of information
sufficient to consider a product administration change, based upon
appropriate medical judgement, for any significant unanticipated safety
finding or data in the aggregate from a study that suggests a
significant human risk. For example, applicants would be required to
submit information concerning reports of a lack of efficacy with a drug
or biological product used in treating a life-threatening or serious
disease (see section III.D.2 of this document). In addition, applicants
would be required to include in postmarketing periodic safety reports
(i.e., TPSRs, PSURs, IPSRs) an assessment of whether it is believed
that the frequency of lack of efficacy reports is greater than would be
predicted by the premarketing clinical trials for the drug or
biological product (see sections III.E.1.c, III.E.2.k.vi, and III.E.3
of this document). This assessment would be provided for reports of a
lack of efficacy whether a serious SADR, nonserious SADR, or no SADR
occurs. Applicants that submit PSURs and IPSRs to FDA would also
include in these reports a discussion of medically relevant lack of
efficacy reports (e.g., might represent a significant hazard to the
treated population) for a product(s) used to treat serious or life-
threatening diseases (see sections III.E.2.h and III.E.3 of this
document).
III.D. Postmarketing Expedited Reports
Current postmarketing expedited safety reporting regulations at
Sec. Sec. 310.305(c), 314.80(c), and 600.80(c) require submission of
``15-day Alert reports'' to FDA. FDA is proposing to amend these
regulations by removing the term ``15-day Alert report'' and replacing
it with the term ``expedited report'' to be consistent with terminology
used in the ICH E2A guidance. FDA is also proposing the following
revisions to its postmarketing expedited safety reporting regulations.
III.D.1. Serious and Unexpected SADRs
Under the existing postmarketing expedited safety reporting
regulations at Sec. 310.305(c)(1)(i), persons subject to this
requirement must report to FDA each adverse drug experience received or
otherwise obtained that is both serious and unexpected as soon as
possible, but in no case later than 15 calendar days of initial receipt
of the information by the person. Under the existing postmarketing
expedited safety reporting regulations at Sec. Sec. 314.80(c)(1)(i)
and 600.80(c)(1)(i), persons subject to these requirements must report
each adverse drug experience that is both serious and unexpected,
whether foreign or domestic, as soon as possible, but in no case later
than 15 calendar days of initial receipt of the information by the
person.
FDA is proposing minor revisions to these regulations for
consistency. Proposed Sec. 310.305(c)(2)(i) would amend Sec.
310.305(c)(1)(i) by adding the phrase ``whether foreign or domestic''
after the phrase ``that is both serious and unexpected.'' Proposed
Sec. Sec. 314.80(c)(2)(i) and 600.80(c)(2)(i) would amend Sec. Sec.
314.80(c)(1)(i) and 600.80(c)(1)(i) by adding the phrase ``to FDA''
after the word ``report'' and by adding the phrase ``received or
otherwise obtained'' before the phrase ``that is both serious and
unexpected.''
Proposed Sec. Sec. 310.305(c)(2)(i), 314.80(c)(2)(i), and
600.80(c)(2)(i) would amend Sec. Sec. 310.305(c)(1)(i),
314.80(c)(1)(i), and 600.80(c)(1)(i) by removing the phrase ``of
initial receipt of the information by the person whose name appears on
the label (``by the applicant'' for Sec. 314.80(c)(1)(i), and ``by the
licensed manufacturer'' for Sec. 600.80(c)(1)(i)) and replacing it
with the phrase ``after receipt by the manufacturer (``applicant'' for
proposed Sec. Sec. 314.80(c)(2)(i), and 600.80(c)(2)(i)) of the
minimum data set for the serious, unexpected SADR.'' This proposed
amendment is consistent with proposed revisions to the premarketing
expedited safety reporting regulations at proposed Sec.
312.32(c)(1)(i) (see section III.B.2.b of this document). The amendment
would clarify that the 15 calendar day timeframe would begin as soon as
manufacturers and applicants have knowledge of the minimum data set for
an SADR that is serious and unexpected. Manufacturers and applicants
must use due diligence to acquire this information. For this purpose,
they would be required, as described in section III.C.5 of this
document, to use active query to determine the outcome for the SADR
(whether the SADR is serious or nonserious) and acquire at least the
minimum data set for the individual case safety report if they are not
able to immediately obtain this information. Manufacturers and
applicants should include in postmarketing expedited safety reports a
chronological history of their efforts to acquire a minimum data set
and to determine the seriousness and expectedness of an SADR if there
is a delay in obtaining such information.
Proposed Sec. Sec. 310.305(c)(2)(i), 314.80(c)(2)(i) and
600.80(c)(2)(i) state that if a full data set is not available for a
serious and unexpected SADR report at the time of initial submission of
the report to FDA, manufacturers and applicants must submit the
information required under proposed Sec. Sec. 310.305(c)(1)(iv),
314.80(c)(1)(iv) and 600.80(c)(1)(iv) as described in section III.C.5
of this document and also submit a 30-day followup report as described
in section III.D.6 of this document. FDA is proposing this action to
clarify the importance of acquiring complete information for serious
SADRs.
[[Page 12432]]
III.D.2. Information Sufficient To Consider Product Administration
Changes
Proposed Sec. Sec. 310.305(c)(2)(ii), 314.80(c)(2)(ii), and
600.80(c)(2)(ii) would require that manufacturers and applicants submit
to FDA information, received or otherwise obtained, whether foreign or
domestic, that would be sufficient, based upon appropriate medical
judgment, to consider changes in product administration. Manufacturers
and applicants would be required to submit this information to the
agency as soon as possible, but in no case later than 15 calendar days
after the manufacturer or applicant determines that the information
qualifies for expedited reporting. Examples of such information include
any significant unanticipated safety finding or data in the aggregate
from an in vitro, animal, epidemiological, or clinical study, whether
or not conducted under an IND, that suggests a significant human risk,
such as reports of mutagenicity, teratogenicity, or carcinogenicity, or
reports of a lack of efficacy with a drug or biological product used in
treating a life-threatening or serious disease. The proposed rule would
require that manufacturers and applicants maintain records of their
efforts to determine whether information that they have received or
otherwise obtained would qualify for expedited reporting under this
proposed requirement. This proposed requirement is consistent with the
proposed revisions to the premarketing expedited safety reporting
regulations at proposed Sec. 312.32(c)(1)(ii) (see section III.B.2.c
of this document) and with the ICH E2A guidance (60 FR 11284 at 11286).
The proposed amendment would further clarify some of the types of
safety information that must be submitted to FDA in an expedited
manner.
III.D.3. Unexpected SADRs With Unknown Outcome
FDA expects that, in most cases, manufacturers and applicants will
be able to determine the outcome for an SADR (whether the SADR is
serious or nonserious). However, in those few cases where a
determination may not be possible, FDA would require submission of
unexpected SADRs with unknown outcome in an expedited manner (proposed
Sec. Sec. 310.305(c)(2)(iii), 314.80(c)(2)(iii), and
600.80(c)(2)(iii)). Expedited safety reports for unexpected SADRs with
unknown outcome would be submitted to FDA within 45 calendar days after
initial receipt by the manufacturer or applicant of the minimum data
set for the unexpected SADR. FDA is proposing this action to expedite
review of potentially serious SADRs.
The proposed rule would require that manufacturers and applicants
reporting an unexpected SADR with unknown outcome include in the
expedited safety report the reason(s) for their inability to classify
an SADR as either serious or nonserious (i.e., unknown outcome). For
this purpose, manufacturers and applicants should include in the
expedited report a chronological history of their efforts to determine
the outcome of the SADR.
Manufacturers and applicants reporting an unexpected SADR with
unknown outcome must exercise due diligence to determine the
expectedness for the SADR and to acquire at least the minimum data set
for the individual case safety report. For this purpose, these persons
would be required to use active query to acquire this information (see
section III.C.5 of this document). These persons should include in
postmarketing expedited safety reports a chronological history of their
efforts to acquire this information if there is a delay in obtaining
it.
III.D.4. Always Expedited Reports
Proposed Sec. Sec. 310.305(c)(2)(iv), 314.80(c)(2)(iv), and
600.80(c)(2)(iv) would require manufacturers and applicants to submit
to FDA individual case safety reports for SADRs, received or otherwise
obtained, whether foreign or domestic, that are the subject of an
always expedited report. These always expedited reports would be
submitted to the agency as soon as possible, but in no case later than
15 calendar days after receipt by the manufacturer (``applicant'' for
proposed Sec. Sec. 314.80(c)(2)(iv), and 600.80(c)(2)(iv)) of the
minimum data set for the report. The following medically significant
SADRs, which may jeopardize the patient or subject and/or require
medical or surgical intervention to treat the patient or subject, would
be subject to an always expedited report:
[sbull] Congenital anomalies,
[sbull] Acute respiratory failure,
[sbull] Ventricular fibrillation,
[sbull] Torsades de pointe,
[sbull] Malignant hypertension,
[sbull] Seizure,
[sbull] Agranulocytosis,
[sbull] Aplastic anemia,
[sbull] Toxic epidermal necrolysis,
[sbull] Liver necrosis,
[sbull] Acute liver failure,
[sbull] Anaphylaxis,
[sbull] Acute renal failure,
[sbull] Sclerosing syndromes,
[sbull] Pulmonary hypertension,
[sbull] Pulmonary fibrosis,
[sbull] Confirmed or suspected transmission of an infectious agent
by a marketed drug or biological product,
[sbull] Confirmed or suspected endotoxin shock, and
[sbull] Any other medically significant SADR that FDA determines to
be the subject of an always expedited report (i.e., may jeopardize the
patient or subject and/or require medical or surgical intervention to
treat the patient or subject).
These SADRs would be submitted to the agency in an expedited manner
whether unexpected or expected and whether or not the SADR leads to a
serious outcome. The medical gravity of these SADRs requires expedited
reporting.
The agency is proposing that a confirmed or suspected transmission
of an infectious agent by a marketed drug or biological product would
be the subject of an always expedited report. Examples of such
transmissions include human immunodeficiency virus (HIV) transmission
by anti-hemophilic factor, hepatitis C transmission by intravenous
immunoglobulin, bacterial contamination of albumin leading to sepsis,
and parvovirus contamination of anti-hemophilic factor causing an SADR.
These SADRs indicate a public health problem that requires expedited
review by the agency.
The proposal provides that the agency could make a new SADR the
subject of an always expedited report. Such an SADR would only become
the subject of these reports if FDA determines that the SADR is
medically significant (i.e., may jeopardize the patient or subject and/
or require medical or surgical intervention to treat the patient or
subject). New SADRs that become the subject of always expedited reports
would be included in the agency's current guidance for industry on
postmarketing safety reporting for human drugs and licensed biological
products.
Proposed Sec. Sec. 310.305(c)(2)(iv)(B), 314.80(c)(2)(iv)(B), and
600.80(c)(2)(iv)(B) would require that if a full data set is not
available for always expedited reports at the time of initial
submission of the report to FDA, manufacturers and applicants would
submit the information required under proposed Sec. Sec.
310.305(c)(1)(iv), 314.80(c)(1)(iv) and 600.80(c)(1)(iv) as described
in section III.C.5 of this document and also submit a 30-day followup
report as described in section III.D.6 of this document. FDA is
proposing this action to clarify the importance of acquiring complete
information for medically significant SADRs that are the subject of
always expedited reports.
[[Page 12433]]
III.D.5. Medication Errors
Proposed Sec. Sec. 310.305(c)(2)(v)(A), 314.80(c)(2)(v)(A), and
600.80(c)(2)(v)(A) would require that each domestic report of an actual
medication error, received or otherwise obtained, be submitted to the
agency as soon as possible, but in no case later than 15 calendar days
after receipt by the manufacturer (``applicant'' for proposed
Sec. Sec. 314.80(c)(2)(v)(A) and 600.80(c)(2)(v)(A)) of the minimum
data set for a report of an SADR or, if an SADR does not occur, the
minimum information for the report as described in section III.C.5 of
this document (i.e., an identifiable patient, an identifiable reporter,
and a suspect drug or biological product). For postmarketing safety
reporting purposes, all reports of medication errors would be
considered unexpected. FDA is proposing this new type of expedited
report to protect public health.
Proposed Sec. Sec. 310.305(c)(2)(v)(B), 314.80(c)(2)(v)(B), and
600.80(c)(2)(v)(B) would require that reports of potential medication
errors, received or otherwise obtained, be submitted to the agency as
soon as possible, but in no case later than 15 calendar days after
receipt by the manufacturer (``applicant'' for proposed Sec. Sec.
314.80(c)(2)(v)(B) and 600.80(c)(2)(v)(B)) of the minimum information
described in section III.C.5 of this document (i.e., an identifiable
reporter and a suspect drug or biological product). FDA is proposing
submission of this information to the agency in an expedited manner to
attempt to prevent actual medication errors.
Proposed Sec. Sec. 310.305(c)(2)(v)(C), 314.80(c)(2)(v)(C), and
600.80(c)(2)(v)(C) state that if a full data set is not available for
an actual or potential medication error report at the time of initial
submission of the report to FDA, manufacturers and applicants would
submit the information required under proposed Sec. Sec.
310.305(c)(1)(iv), 314.80(c)(1)(iv) and 600.80(c)(1)(iv) as described
in section III.C.5 of this document and also submit a 30-day followup
report as described in section III.D.6 of this document. FDA is
proposing this action to clarify the importance of acquiring complete
information for reports of medication errors.
III.D.6. Followup Reports
Current postmarketing expedited safety reporting regulations at
Sec. Sec. 310.305(c)(2), 314.80(c)(1)(ii), and 600.80(c)(1)(ii)
require persons subject to these regulations to promptly investigate
all serious, unexpected adverse drug experiences that are the subject
of expedited reports and to submit followup reports within 15 calendar
days of receipt of new information or as requested by FDA. If
additional information is not obtainable, records should be maintained
of the unsuccessful steps taken to seek additional information. Thus,
followup reports are currently only required to be submitted to FDA if
requested by the agency or if new information is obtained or otherwise
received by the manufacturer or applicant for an adverse drug
experience previously reported to FDA.
In this rulemaking, FDA continues to require submission of these
followup reports. In addition, as described in the following paragraph,
a 30-day followup report would be required to be submitted in certain
cases (i.e., initial serious and unexpected SADR reports, always
expedited reports and medication error reports that do not contain a
full data set). If a 30-day followup report is required and no new
information is available for the report, then the manufacturer or
applicant would still be required to submit the 30-day followup report,
indicate in the report that no new information was available and
include a description of the reason(s) for its inability to acquire
complete information and its efforts to obtain complete information. In
all other cases, if there is no new information to report to FDA on a
previously submitted SADR no followup report would be required to be
submitted to the agency.
Proposed Sec. Sec. 310.305(c)(2)(vi), 314.80(c)(2)(vi), and
600.80(c)(2)(vi) would require manufacturers and applicants to use
active query to obtain additional information for any serious and
unexpected SADR submitted to FDA in an expedited report under proposed
Sec. Sec. 310.305(c)(2)(i), 314.80(c)(2)(i), and 600.80(c)(2)(i) that
does not contain a full data set. The proposed amendment would also
require these persons to use active query to obtain additional
information for any always expedited report under proposed Sec. Sec.
310.305(c)(2)(iv), 314.80(c)(2)(iv), and 600.80(c)(2)(iv) or any
medication error report under proposed Sec. Sec. 310.305(c)(2)(v),
314.80(c)(2)(v), and 600.80(c)(2)(v) that does not contain a full data
set. This information would be submitted to the agency in a followup
report within 30 calendar days after initial submission of the
expedited report to FDA by the manufacturer or applicant (30-day
followup report). This proposed amendment would provide the agency with
timely acquisition of more complete information for SADRs and
medication errors that are the subject of these reports.
Proposed Sec. Sec. 310.305(c)(2)(vi), 314.80(c)(2)(vi), and
600.80(c)(2)(vi) would also state that:
* * * If a full data set is still not obtainable, the 30-day
followup report must contain the information required under
paragraph (c)(1)(iv) of this section. Any new safety information in
the 30-day followup report must be highlighted. Any new information,
received or otherwise obtained, after submission of a 30-day
followup report must be submitted to FDA as a 15-day followup report
under paragraph (c)(2)(vii) of this section.
This proposed amendment would clarify the information that would be
required in a 30-day followup report if a full data set is still not
available for the report. It would also clarify that FDA would require
a 15-day followup report, as described in the paragraphs that follow,
for any new information obtained or otherwise received for the report
after submission of the 30-day followup report. The proposed amendment
would ensure that manufacturers and applicants would exercise due
diligence to obtain complete information for SADRs that are the subject
of 30-day followup reports.
Proposed Sec. Sec. 310.305(c)(2)(vii), 314.80(c)(2)(vii), and
600.80(c)(2)(vii) would amend Sec. Sec. 310.305(c)(2),
314.80(c)(1)(ii), and 600.80(c)(1)(ii) to clarify that manufacturers
and applicants must submit 15-day followup reports to FDA of any new
information received or otherwise obtained for any expedited or
followup report (except for initial expedited reports under proposed
Sec. Sec. 310.305(c)(2)(i), (c)(2)(iv), and (c)(2)(v), 314.80
(c)(2)(i), (c)(2)(iv), and (c)(2)(v), and 600.80(c)(2)(i), (c)(2)(iv),
and (c)(2)(v) that do not contain a full data set) within 15 calendar
days of initial receipt of new information by the manufacturer or
applicant. Proposed Sec. Sec. 310.305(c)(2)(vii), 314.80(c)(2)(vii),
and 600.80(c)(2)(vii) would also state that:
* * * Expedited reports under paragraphs (c)(2)(i), (c)(2)(iv),
and (c)(2)(v) of this section that do not contain a full data set at
the time of initial submission of the report to FDA are subject to
the 30-day followup reporting requirements under paragraph
(c)(2)(vi) of this section rather than the 15-day followup reporting
requirements under this paragraph.
Thus, 15-day followup reports would be submitted for the following
types of expedited and followup reports:
[sbull] Serious and unexpected SADR reports that contain a full
data set,
[sbull] Information sufficient to consider product administration
changes,
[[Page 12434]]
[sbull] Unexpected SADRs with unknown outcomes,
[sbull] Always expedited reports that contain a full data set,
[sbull] Actual and potential medication error reports that contain
a full data set,
[sbull] 30-day followup reports, and
[sbull] 15-day followup reports.
These proposed revisions clarify the types of expedited reports that
would be subject to the 15-day followup reporting requirements.
FDA notes that a 15-day followup report, rather than a serious and
unexpected SADR report, should be submitted to FDA for an SADR that is
initially reported to the agency as serious and expected or nonserious
and unexpected, but is subsequently determined to be serious and
unexpected. In these cases, manufacturers and applicants should include
in the 15-day followup report a chronological history describing the
events that transpired which resulted in determination of the serious
and unexpected character of the SADR.
FDA is proposing to amend its postmarketing expedited safety
reporting regulations at Sec. Sec. 310.305(c)(2), 314.80(c)(1)(ii),
and 600.80(c)(1)(ii) by removing the second sentence in these
paragraphs regarding maintaining records if additional information is
not obtainable for a serious and unexpected adverse drug experience.
The agency is proposing this amendment because postmarketing safety
reporting requirements for serious and unexpected SADR reports that do
not contain a full data set are now prescribed under proposed
Sec. Sec. 310.305(c)(1)(iv) and (c)(2)(vi), 314.80(c)(1)(iv) and
(c)(2)(vi), and 600.80(c)(1)(iv) and (c)(2)(vi).
III.D.7. Supporting Documentation
Proposed Sec. Sec. 310.305(c)(2)(viii)(A), 314.80(c)(2)(viii)(A),
and 600.80(c)(2)(viii)(A) would require that manufacturers and
applicants submit to FDA, if available, a copy of the autopsy report if
the patient dies. If an autopsy report is not available, the proposed
rule would require that manufacturers and applicants submit a death
certificate to FDA. If an autopsy report becomes available after the
manufacturer or applicant has submitted a death certificate to the
agency, the manufacturer or applicant must submit the autopsy report to
FDA. If the patient was hospitalized, manufacturers and applicants
would be required to submit to FDA, if available, a copy of the
hospital discharge summary. If any of these documents is not in
English, an English translation of the document would be required. FDA
is proposing that manufacturers and applicants submit these documents
to provide the agency with complete information for SADRs that result
in a death or hospitalization.
Proposed Sec. Sec. 310.305(c)(2)(viii)(A), 314.80(c)(2)(viii)(A),
and 600.80(c)(2)(viii)(A) would require that manufacturers and
applicants use active query to obtain the documents required to be
submitted to FDA under this paragraph. These documents would be
required to be submitted to FDA as 15-day followup reports (see section
III.D.6 of this document) within 15 calendar days of initial receipt of
the document by the manufacturer or applicant. In instances when a
document is not submitted to FDA in a 15-day followup report within 3
months after submission of the initial expedited report for the death
or hospitalization, the agency would assume that active query by the
manufacturer or applicant did not result in access to these documents.
In this case, a record of the reason(s) for the lack of documentation
and the effort that was made to obtain the documentation would be
required to be maintained by the manufacturer and applicant.
Proposed Sec. Sec. 310.305(c)(2)(viii)(B), 314.80(c)(2)(viii)(B),
and 600.80(c)(2)(viii)(B) would require that each expedited report
contain in the narrative a list of other relevant documents (e.g.,
medical records, laboratory results, data from studies) regarding the
report that are maintained by manufacturers and applicants. FDA may
require, when appropriate, that copies of one or more of these
documents be submitted to the agency within 5 calendar days after
receipt of the request. FDA would usually request such records in
response to a suspected safety problem associated with the use of a
drug or licensed biological product.
III.D.8. Scientific Literature
Current postmarketing expedited safety reporting regulations at
Sec. Sec. 314.80(d)(1) and 600.80(d)(1) require that expedited reports
based on information from the scientific literature be accompanied by a
copy of the published article. These regulations apply only to reports
found in scientific and medical journals either as case reports or as
the result of a formal clinical trial. Proposed Sec. Sec.
314.80(c)(2)(ix) and 600.80(c)(2)(ix) would amend the current
regulations by removing the phrase ``either as case reports or as the
result of a formal clinical trial'' to clarify that all reports from
the scientific literature, including case reports, and results of a
formal clinical trial, epidemiological study, in vitro study, or animal
study, that qualify for expedited reporting under proposed Sec. Sec.
314.80(c)(2) and 600.80(c)(2) would be required to be submitted to FDA.
The proposed rule would also remove Sec. Sec. 314.80(d)(2) and
600.80(d)(2). These paragraphs provide that reports based on the
scientific literature must be submitted on FDA Form 3500A or comparable
format prescribed by the regulations and that, in cases where persons
subject to the postmarketing safety reporting regulations believe that
preparing the FDA Form 3500A constitutes an undue hardship,
arrangements can be made with the agency for use of an acceptable
alternative reporting format. FDA is proposing to remove these
paragraphs because the reporting format for reports based on
information in the scientific literature would be specified under
proposed Sec. Sec. 314.80(c)(4) and 600.80(c)(4) (see section III.F of
this document).
For organizational purposes, FDA is proposing to move Sec. Sec.
314.80(d) and 600.80(d), as revised by this proposed rule, to proposed
Sec. Sec. 314.80(c)(2)(ix) and 600.80(c)(2)(ix). Proposed Sec.
310.305(c)(2)(ix) would amend Sec. 310.305(c) by adding the paragraph:
Scientific literature. An expedited report based on information
from the scientific literature applies only to reports found in
scientific and medical journals. These expedited reports must be
accompanied by a copy of the published article.
This proposed amendment would clarify for prescription drug products
marketed for human use without an approved application the types of
safety information found in scientific literature that would qualify
for expedited reporting. The proposed amendment would also require that
these reports include a copy of the published article that is the
subject of the expedited report. The proposed amendment would provide
the agency with more complete information for review of safety
information from the scientific literature and would also provide
uniformity between FDA's postmarketing expedited safety reporting
requirements for prescription drugs marketed for human use without an
approved application and marketed drugs with an approved application.
III.D.9. Contractors and Shared Manufacturers
Current regulations at Sec. Sec. 310.305(c)(1)(i) and (c)(3),
314.80(c)(1)(iii), and 600.80(c)(1)(iii) require any person whose name
appears on the label of a marketed drug product or licensed biological
product as a packer or distributor to submit either
[[Page 12435]]
expedited reports of serious and unexpected adverse drug experiences
directly to FDA or reports of all serious adverse drug experiences to
the manufacturer (Sec. 310.305(c)(3) or applicant (Sec. Sec.
314.80(c)(1)(iii) and 600.80(c)(1)(iii)) instead of FDA in 5 calendar
days. This provision also applies to manufacturers for Sec. Sec.
314.80(c)(1)(iii) and 600.80(c)(1)(iii) and to shared manufacturers,
joint manufacturers, and any participants involved in divided
manufacturing for Sec. 600.80(c)(1)(iii). Proposed Sec. Sec.
310.305(c)(2)(xi)(A), 314.80(c)(2)(x)(A), and 600.80(c)(2)(x)(A) would
amend these regulations to require contractors, as defined in proposed
Sec. Sec. 310.305(a), 314.80(a) and 600.80(a) (see section III.A.4 of
this document), to submit to the manufacturer (proposed Sec.
310.305(c)(2)(xi)(A)) or applicant (proposed Sec. Sec.
314.80(c)(2)(x)(A) and 600.80(c)(2)(x)(A)) safety reports of all SADRs
(serious and nonserious) and medication errors for the manufacturer's
(proposed Sec. 310.305(c)(2)(xi)) or applicant's (proposed Sec. Sec.
314.80(c)(2)(x) and 600.80(c)(2)(x)) drug or biological product,
obtained or otherwise received, within 5 calendar days of initial
receipt of the report by the contractor. This provision would also
apply to shared manufacturers of licensed biological products for
proposed Sec. 600.80(c)(2)(x)(A) (i.e., all SARs and medication errors
would be required to be submitted to the applicant within 5 calendar
days). The contractor would be required to submit a report of an SADR
to the manufacturer (proposed Sec. 310.305(c)(2)(xi)(A)) or applicant
(proposed Sec. Sec. 314.80(c)(2)(x)(A) and 600.80(c)(2)(x)(A)) even if
the report does not contain a minimum data set. Contractors and shared
manufacturers would only be required to convey to manufacturers
(proposed Sec. 310.305(c)(2)(xi)(A)) or applicants (proposed
Sec. Sec. 314.80(c)(2)(x)(A) and 600.80(c)(2)(x)(A)) whatever safety
information was obtained or otherwise received. They would not be
required to use active query to acquire safety information, to conduct
followup, or to submit postmarketing safety reports to FDA. Upon
receipt of a safety report from a contractor or shared manufacturer,
the manufacturer (proposed Sec. 310.305(c)(2)(xi)(A)) or applicant
(proposed Sec. Sec. 314.80(c)(2)(x)(A) and 600.80(c)(2)(x)(A)) would
be required to comply with the postmarketing safety reporting
requirements under proposed Sec. Sec. 310.305, 314.80 and 600.80
(e.g., use active query, if necessary, to acquire safety information,
conduct followup, submit postmarketing safety reports to FDA). These
proposed amendments would provide manufacturers and applicants with
complete safety information regarding its products.
Proposed Sec. Sec. 310.305(c)(2)(xi)(B), 314.80(c)(2)(x)(B), and
600.80(c)(2)(x)(B) would require that contracts between manufacturers
and contractors (Sec. 310.305(c)(2)(xi)(B)) and applicants and
contractors (Sec. Sec. 314.80(c)(2)(x)(B) and 600.80(c)(2)(x)(B))
specify the postmarketing safety reporting responsibilities of the
contractor. Although contractors and shared manufacturers have
postmarketing safety reporting responsibilities, the manufacturer
(proposed Sec. 310.305(c)(2)(xi)(B)) or applicant (proposed Sec. Sec.
314.80(c)(2)(x)(B) and 600.80(c)(2)(x)(B)) would be responsible for
ensuring that the contractors and shared manufacturers of its products
comply with these postmarketing safety reporting responsibilities. FDA
believes that, in general, this proposal represents a practice that is
already customary and usual in the pharmaceutical industry because
contractors are typically considered agents of the manufacturer or
applicant.
Proposed Sec. Sec. 310.305(c)(2)(xi)(C), 314.80(c)(2)(x)(C), and
600.80(c)(2)(x)(C) would require that contractors and shared
manufacturers maintain records of SADR reports and medication errors.
This proposal is consistent with current postmarketing safety reporting
requirements.
Proposed Sec. Sec. 310.305(c)(2)(xi)(D), 314.80(c)(2)(x)(D), and
600.80(c)(2)(x)(D) state that the recordkeeping, written procedures,
and disclaimer provisions under proposed Sec. Sec. 310.305, 314.80 and
600.80 would apply to contractors and shared manufacturers. This
proposal clarifies for contractors and shared manufacturers which of
the postmarketing safety reporting provisions would apply to them.
III.D.10. Prescription Drugs Marketed for Human Use Without an Approved
Application
Proposed Sec. 310.305(c)(2)(x) would amend Sec. 310.305(c)(1)(i)
to require that expedited reports for prescription drugs marketed for
human use without an approved application be accompanied by a list of
the current addresses where all safety reports and other safety-related
records for the drug product are maintained by manufacturers and
contractors. In the October 1994 proposal, FDA proposed to include,
under Sec. Sec. 314.80(c)(2) and 600.80(c)(2), a section in its
postmarketing periodic safety reports on location of adverse drug
experience records (59 FR 54046 at 54061). FDA is now reproposing this
amendment for its postmarketing periodic safety reports (see sections
III.E.1.g, III.E.2.k.x, and III.E.3 of this document). The agency is
also proposing to require the list of addresses in expedited reports
for drugs covered under Sec. 310.305 because manufacturers of these
drugs are not required to submit postmarketing periodic safety reports
to FDA. The list of addresses would provide rapid access to safety-
related records for FDA inspections and for requests by FDA for
additional information concerning safety issues.
III.D.11. Class Action Lawsuits
Manufacturers and applicants should not submit SADRs from class
action lawsuits to FDA in an expedited report. The agency believes that
SADRs from class action lawsuits would be submitted to FDA from other
sources (e.g., spontaneous reports) prior to initiation of the class
action lawsuit. Summary tabulations of SADRs from class action lawsuits
would be required in postmarketing periodic safety reports (see
sections III.E.1.e and III.E.2.k.v of this document).
III.D.12. Blood and Blood Component Safety Reports
Current Sec. 606.170(a) requires a blood establishment to
thoroughly investigate any complaint of an adverse reaction arising as
a result of blood collection or transfusion and to prepare and maintain
a written report of the investigation, including followup and
conclusions, as part of the record for that lot or unit of final
product. If appropriate, the report must be forwarded to the
manufacturer of the blood or blood component or the collection
facility. Under Sec. 606.170(b), a complication of a blood collection
or blood transfusion resulting in a fatality must be reported to FDA as
soon as possible by telephone or other rapid means of communication,
and a written report of the investigation must be submitted to FDA
within 7 days of the fatality. Each year, in accordance with Sec.
606.170(b), FDA receives between 50 and 80 reports of fatalities.
Current Sec. 606.171 requires licensed manufacturers of blood and
blood components, unlicensed registered blood establishments and
transfusion services to report biological product deviations. A
biological product deviation is an event that represents either: (1) A
deviation from current good manufacturing practices, applicable
regulations, applicable standards, or established specifications that
may affect the safety, purity, or potency of a product; or (2) an
unexpected or
[[Page 12436]]
unforseeable event that may affect the safety, purity, or potency of a
product. In some cases, a biological product deviation reportable under
Sec. 606.171 may actually result in an adverse reaction in the
transfusion recipient. In many other cases, the biological product
deviation may be discovered before the affected products are
administered or administration of the product may not result in an
adverse reaction.
Although manufacturers of blood and blood components are currently
exempt from the safety reporting requirements under Sec. 600.80, FDA
receives reports of fatal adverse reactions related to blood and blood
components and may receive some additional information through
biological product deviation reporting. However, the agency does not
currently receive adequate information to monitor and assess safety-
related information concerning the collection and transfusion of blood
and blood components. Such information is essential for evaluating the
agency's scientific and regulatory policies and for monitoring industry
practices and their implications on blood safety. For these purposes,
FDA is proposing to amend Sec. 606.170 to require the reporting of all
serious SARs, in addition to fatalities, that are related to the
collection or transfusion of blood and blood components (e.g., red
blood cells, plasma, platelets, and cryoprecipitate). For fatal SARs,
proposed Sec. 606.170(c) would continue the current requirement that a
fatal SAR be reported immediately by telephone, facsimile, express
mail, or electronically transmitted mail and in a written report within
7 calendar days of the fatality. Because blood establishments are
already required to investigate all complaints of an adverse reaction
related to the collection and transfusion of blood and blood components
and many of these reactions are well recognized and understood by blood
establishments and by FDA, the agency is not proposing to require the
submission of postmarketing periodic safety reports (i.e., TPSRs,
PSURs, IPSRs and individual case safety reports--semiannual
submissions).
Specifically, FDA is proposing to amend Sec. 606.170 by revising
the title of the section to read ``Suspected adverse reaction
investigation and reporting''; by making editorial changes to Sec.
606.170(a), which prescribes requirements for the investigation and
recording of any complaint of an SAR related to the collection or
transfusion of blood or blood components; by adding a new requirement
for reporting of serious SARs related to transfusion or collection
procedures (proposed Sec. 606.170(b)); and by redesignating current
Sec. 606.170(b) as Sec. 606.170(c) and revising the paragraph as
discussed below. FDA is also proposing that the terms ``SAR'' and
``serious SAR,'' as used in proposed Sec. 606.170, have the same
meaning as defined in proposed Sec. 600.80(a)(see sections III.A.1 and
III.A.3 of this document).
In general, FDA believes that any SAR related to blood donation or
transfusion that requires immediate medical intervention or followup
medical attention should be reported. For the purpose of reporting
serious SARs related to blood collection, FDA interprets the term to
include:
[sbull] Vasovagal reactions with syncope (hypotension and
bradycardia) requiring medical intervention;
[sbull] Citrate reactions requiring significant medical
intervention;
[sbull] Anaphylaxis or any major allergic reactions;
[sbull] Seizure of any type or duration;
[sbull] Cerebrovascular accidents;
[sbull] Cardiac arrhythmia, angina of any duration, myocardial
infarction, or cardiac arrest;
[sbull] Clinically significant hypotension;
[sbull] Bronchospasm, respiratory insufficiency;
[sbull] Arterial puncture, air embolus;
[sbull] Phlebotomy-related nerve damage; and,
[sbull] Thrombophlebitis, phlebitis, or any procedure-related
infection.
For SARs related to donation, FDA interprets the term ``serious
SAR'' not to include:
[sbull] Self-limited vasovagal reactions (hemodynamically stable);
[sbull] Self-limited citrate reactions;
[sbull] Localized hematoma, uncomplicated; and,
[sbull] Localized skin irritation, uncomplicated.
For the purposes of reporting serious SARs related to receipt of a
blood transfusion, FDA interprets the term to include:
[sbull] Any complication from the use of an unsuitable unit,
including infusion of hemolyzed blood;
[sbull] Any complication from improper blood administration,
including failure to use a standard blood filter (e.g., air embolism);
[sbull] Induced hemolysis, acute or delayed;
[sbull] Transmitted infections, including bacterial infections;
[sbull] Associated graft versus host disease;
[sbull] Related hypersensitivity with respiratory insufficiency
and/or hypotension (e.g., anaphylaxis);
[sbull] Transfusion-related acute lung injury (TRALI);
[sbull] Induced alloimmunization which prevents effective
transfusion therapy (e.g., posttransfusion purpura);
[sbull] Induced congestive heart failure; and
[sbull] Induced cardiac arrhythmias, including those resulting from
metabolic imbalance.
For SARs related to receipt of a blood transfusion, FDA interprets
the term ``SAR'' not to include:
[sbull] Febrile nonhemolytic transfusion reactions;
[sbull] Related hypersensitivity without respiratory insufficiency
nor hypotension;
[sbull] Induced alloimmunization which does not prevent effective
transfusion therapy;
[sbull] Infections not clinically significant to the recipient,
such as cytomegalovirus (CMV) infection in an immunocompetent adult;
and,
[sbull] Induced hemochromatosis.
FDA is proposing to require that for a serious SAR related to blood
collection, the establishment performing the blood collection be
responsible for reporting the serious SAR to FDA, and for a serious SAR
related to transfusion, the establishment responsible for the
compatibility testing be responsible for reporting the serious SAR to
FDA (proposed Sec. 606.170(b)). FDA is proposing to require that
reports of serious SARs, including fatal SARs under proposed Sec.
606.170(c), be reported to FDA using the reporting format described in
proposed Sec. 600.80(c)(4). Thus the reporting facility would be
required to submit a report for each individual patient on FDA Form
3500A or a computer-generated facsimile of FDA Form 3500A using the
appropriate ``preferred term'' in the latest version of MedDRA (see
section III.F of this document).
Current Sec. 606.171 requires reports of biological product
deviations be submitted as soon as possible, but not to exceed 45
calendar days. Because there will be instances when an SAR occurs and a
biological product deviation may have contributed to an SAR, FDA is
proposing to require reporting of serious SARs to the agency within 45
calendar days (for fatal SARs, within 7 calendar days) of the
determination that a serious SAR related to blood collection or
transfusion has occurred. This will permit a blood establishment to
investigate and report both a biological product deviation and an SAR
related to the biological product deviation at the same time and will
limit the reporting burden. In the case of a reported serious SAR that
subsequently results in a fatality, FDA would not require two separate
reports,
[[Page 12437]]
one reporting the serious SAR and the other reporting the fatality.
However, if the fatality occurs after the report of the serious SAR is
submitted to the agency, the blood establishment should update the
initial report to report the fatality.
III.E. Postmarketing Periodic Safety Reporting
The proposed rule would require all applicants to submit to FDA
semiannually on an FDA Form 3500A (VAERS form for vaccines, CIOMS I
Form, if desired, for foreign SADRs) certain spontaneously reported
SADRs (see tables 7 and 9 and section III.E.4 of this document
regarding individual case safety reports--semiannual submissions).
Applicants would also be required to submit other postmarketing
periodic safety reports (i.e., traditional periodic safety reports
(TPSRs), periodic safety update reports (PSURs), or interim periodic
safety reports (IPSRs)) to FDA with a frequency as described in section
III.E.5.a of this document (see tables 7 and 9). PSURs, IPSRs, and
TPSRs would provide FDA with an overview or summary of the safety
profile of a drug or licensed biological product (excluding individual
case safety reports). A TPSR would essentially contain the same format
and content as the periodic safety report currently required by the
agency's postmarketing periodic safety reporting regulations (see table
10 and section III.E.1 of this document). A PSUR would essentially be
consistent with the format and content of the periodic safety report
described in the ICH E2C guidance (see section III.E.2 of this
document), and an IPSR would represent an abbreviated form of a PSUR
(see section III.E.3 of this document). Applicants with drugs and
licensed biological products approved prior to January 1, 1998, would
have the option to submit either a TPSR or PSUR to FDA, whereas
applicants with products approved on or after January 1, 1998, would be
required to submit a PSUR (see tables 7 and 9 and section III.E.5.a of
this document). FDA is proposing to require submission of periodic
safety reports in a PSUR format for products approved on or after
January 1, 1998, to be consistent with the ICH E2C guidance. FDA is not
proposing to require submission of PSURs for products approved prior to
January 1, 1998, because the agency recognizes that the most
significant new safety information on a product is usually acquired in
the first few years after it has been on the market. It is not
necessary for applicants to reformat periodic safety reports for
products approved prior to January 1, 1998. In addition, in some cases,
it will be sufficient for FDA to review an abbreviated form of the PSUR
(i.e., at 7.5 and 12.5 years after U.S. approval of a product). For
these cases, the agency is proposing to require submission of an IPSR
instead of a PSUR (see tables 7 and 9 and sections III.E.3 and
III.E.5.a of this document).
III.E.1. Traditional Periodic Safety Reports (TPSRs)
Current regulations (Sec. Sec. 314.80(c)(2)(ii)(a) through
(c)(2(ii)(c) and 600.80(c)(2)(ii)(A) through (c)(2)(ii)(C)) require the
submission of postmarketing periodic adverse drug experience reports
that contain:
[sbull] A narrative summary and analysis of the information in the
report and an analysis of the 15-day postmarketing Alert reports
submitted during the reporting period (all 15-day Alert reports being
appropriately referenced by the applicant's patient identification
number, adverse reaction term(s), and date of submission to FDA);
[sbull] An FDA Form 3500A describing each adverse drug experience
not previously reported (with an index consisting of a line listing of
the applicant's patient identification number and adverse reaction
term(s)); and
[sbull] A history of actions taken since the last periodic report.
Proposed Sec. Sec. 314.80(c)(3)(i) and 600.80(c)(3)(i) would amend
these regulations by replacing the term ``periodic adverse drug
experience report'' with the term ``traditional periodic safety report
(TPSR).'' FDA is proposing this revision to differentiate the existing
postmarketing periodic safety report from the proposed new
postmarketing periodic safety reports (i.e., PSURs and IPSRs, see
sections III.E.2 and III.E.3 of this document).
III.E.1.a. Narrative summary and analysis of individual case safety
reports. Proposed Sec. Sec. 314.80(c)(3)(i)(A) and 600.80(c)(3)(i)(A)
would amend Sec. Sec. 314.80(c)(2)(ii)(a) and 600.80(c)(2)(ii)(A) by
providing paragraph headings and reorganizing and revising these
paragraphs. Proposed Sec. Sec. 314.80(c)(3)(i)(A)(1) and
600.80(c)(3)(i)(A)(1) would amend Sec. Sec. 314.80(c)(2)(ii)(a) and
600.80(c)(2)(ii)(A) by replacing the phrase ``the information in the
report'' with the following:
serious, expected SADRs and nonserious, unexpected SADRs occurring
in the United States that were submitted to the applicant during the
reporting period from all spontaneous sources (i.e., health care
professionals and other individuals) (with an index consisting of a
line listing of the applicant's manufacturer report number and SADR
term(s)). The narrative summary and analysis would include
spontaneous reports submitted to the applicant by health care
professionals and other individuals (e.g., consumers).
Proposed Sec. Sec. 314.80(c)(3)(i)(A)(2) and 600.80(c)(3)(i)(A)(2)
would amend Sec. Sec. 314.80(c)(2)(ii)(a) and 600.80(c)(2)(ii)(A) by
replacing the phrase ``an analysis of the 15-day Alert reports * * *
date of submission to FDA)'' with the phrase:
An analysis of the expedited reports submitted during the
reporting period under paragraphs (c)(2)(i) through (c)(2)(vii) of
this section (all expedited reports must be appropriately referenced
by the applicant's manufacturer report number, SADR term(s), if
appropriate, and date of submission to FDA),
Current regulations at Sec. Sec. 314.80(c)(2)(iii) and
600.80(c)(2)(iii) state that periodic reporting, except for information
regarding 15-day Alert reports, does not apply to adverse drug
experience information obtained from postmarketing studies (whether or
not conducted under an IND), from reports in the scientific literature,
and from foreign marketing experience. FDA is proposing to remove this
statement because proposed Sec. Sec. 314.80(c)(3)(i)(A)(1) and
600.80(c)(3)(i)(A)(1) specifies the type of information that FDA would
require in a TPSR.
III.E.1.b. Individual case safety reports. FDA is also proposing to
remove Sec. Sec. 314.80(c)(2)(ii)(b) and 600.80(c)(2)(ii)(B) from
these regulations. FDA is proposing this change because the requirement
to submit individual case safety reports to FDA on FDA Form 3500A
(VAERS form for vaccines) would be required in a separate submission on
a semiannual basis (see section III.E.4 of this document).
III.E.1.c. Increased frequency reports. Proposed Sec. Sec.
314.80(c)(3)(i)(A)(3) and 600.80(c)(3)(i)(A)(3) would amend Sec. Sec.
314.80(c)(2)(ii)(a) and 600.80(c)(2)(ii)(A) to require applicants to
include in TPSRs a discussion of any increased reporting frequency of
serious, expected SADRs, including comments on whether it is believed
that the data reflect a meaningful change in SADR occurrence. Even
though the agency has revoked the requirement to submit increased
frequency reports in an expedited manner (62 FR 34166), FDA is
interested in reviewing periodically information on increased
frequencies of serious, expected SADRs and is proposing that this type
of information be submitted to the agency in TPSRs.
[[Page 12438]]
The proposed rule would also require that this section of the TPSR
include an assessment of whether it is believed that the frequency of
lack of efficacy reports, obtained or otherwise received during the
reporting period, is greater than would be predicted by the
premarketing clinical trials for the drug or biological product. This
assessment would be provided whether a serious SADR, nonserious SADR,
or no SADR occurs as a result of a lack of efficacy of the product.
III.E.1.d. Safety-related actions to be taken. Proposed Sec. Sec.
314.80(c)(3)(i)(A)(4) and 600.80(c)(3)(i)(A)(4) would require
applicants to include in TPSRs the applicant's conclusion as to what,
if any, safety-related actions should be taken based on the analysis of
the safety data in the TPSR (e.g., labeling changes, studies
initiated). FDA is proposing this amendment to highlight safety-related
actions that may be necessary.
III.E.1.e. Summary tabulations. Proposed Sec. Sec.
314.80(c)(3)(i)(B), and 600.80(c)(3)(i)(B) would require that a new
section of summary tabulations (i.e., lists of all SADR terms and
counts of occurrences) be included in TPSRs for all serious, expected
SADRs; nonserious, unexpected SADRs; nonserious, expected SADRs; and
expected SADRs with unknown outcome occurring in the United States that
are submitted to the applicant during the reporting period from all
spontaneous sources (i.e., health care professionals and other
individuals). These tabulations would include SADRs that were
previously submitted to FDA in an expedited report (i.e., serious,
unexpected SADRs, unexpected SADRs with unknown outcome, and always
expedited reports) and reports of SADRs not previously submitted to FDA
by applicants (e.g., reports submitted to applicants by FDA; reports
obtained from FDA from freedom of information requests at the
discretion of applicants; reports from class action lawsuits). The
proposed rule would require that cumulative data be provided for SADRs
that are determined to be both serious and unexpected (i.e., all cases
reported to date). These summary tabulations would be presented by body
system or standard organ system classification scheme (e.g.,
cardiovascular, central nervous system, endocrine, renal). The proposed
rule would also require summary tabulations for all domestic reports of
actual medication errors (i.e., serious SADRs, nonserious SADRs, no
SADRs) and potential medication errors (i.e., number of reports for
specific errors) that were previously submitted to the agency as an
expedited report.
In the guidance of 1992, FDA advises applicants to include in their
postmarketing periodic safety reports a listing by body system of all
adverse drug experience terms and counts of occurrences submitted
during the reporting period. FDA is now proposing to clarify and codify
this expectation.
III.E.1.f. History of safety-related actions taken. Proposed
Sec. Sec. 314.80(c)(3)(i)(C), and 600.80(c)(3)(i)(C) would amend
Sec. Sec. 314.80(c)(2)(ii)(c) and 600.80(c)(2)(ii)(C) by adding the
phrase ``safety-related'' before the word ``actions'' and by removing
the phrase ``because of adverse drug experiences.'' FDA is proposing
these changes because actions may be taken for safety-related reasons
other than SADRs. The proposed rule would also amend these regulations
by adding the phrase ``periodic safety'' before the word ``report'' for
clarification.
III.E.1.g. Location of safety records. Proposed Sec. Sec.
314.80(c)(3)(i)(D) and 600.80(c)(3)(i)(D) would require another new
section in TPSRs that would contain a list of the current address(es)
where all safety reports and other safety-related records for the drug
product or licensed biological product are maintained. FDA is proposing
to require a list of these addresses to provide rapid access to safety-
related records for FDA inspections and for requests by FDA for
additional information concerning safety issues.
III.E.1.h. Contact person. Proposed Sec. Sec. 314.80(c)(3)(i)(E)
and 600.80(c)(3)(i)(E) would require another new section in TPSRs that
would contain the name and telephone number of the licensed physician
or licensed physicians responsible for the content and medical
interpretation of the data and information contained within the TPSR.
The fax number and e-mail address for the licensed physician would also
be included, if available. This proposal would provide the agency with
someone to contact with any questions that may arise during review of a
TPSR. FDA is proposing that the contact persons be licensed physicians
because of their crucial knowledge of the medical significance of the
information provided in a TPSR.
Table 10 highlights the differences in content between the
currently required postmarketing periodic adverse drug experience
reports and proposed TPSRs.
Table 10.--Differences Between the Current Requirement for the Content
of Postmarketing Periodic Adverse Drug Experience Reports and the
Proposed Content of TPSRs.
------------------------------------------------------------------------
Proposed revisions to content
Content of periodic adverse drug of periodic adverse drug
experience report experience report (proposed
TPSRs)
------------------------------------------------------------------------
Narrative summary and analysis of the Excludes nonserious expected
information contained in the report. SADRs.
Includes discussion of
increased frequency of serious
expected SADRs and lack of
efficacy reports.
Includes applicant's
recommendations for safety-
related actions to be taken.
Analysis of expedited reports submitted Not revised.
to FDA during the reporting interval.
FDA Form 3500A (VAERS form for Revoked requirement. \1\
vaccines) for each adverse drug
experience not submitted to FDA as an
expedited report.
Index consisting of a line listing of Not revised.
the applicant's patient identification
number and adverse reaction term(s).
History of actions taken since the last Not revised.
report because of adverse drug
experiences.
Require submission summary
tabulations.\2\
New section added for location
of safety records.
New section added for contact
information for licensed
physician responsible for
information in TPSR.
------------------------------------------------------------------------
\1\ Individual case safety reports would be submitted to FDA separately
on a semiannual basis (see section III.E.4 of this document).
\2\ Summary tabulations are currently requested (see the guidance of
1992) but not required for postmarketing periodic adverse drug
experience reports.
[[Page 12439]]
III.E.2. Periodic Safety Update Reports (PSURs)
Proposed Sec. Sec. 314.80(c)(3)(ii) and 600.80(c)(3)(ii) would
amend FDA's postmarketing periodic safety reporting regulations by
adding a new type of postmarketing periodic safety report. This new
report would be identified as a ``periodic safety update report
(PSUR).'' The proposed content and format for the PSUR, as described
below, are consistent with the ICH E2C guidance (62 FR 27470) and would
enable applicants to submit a single core document (PSUR excluding
appendices) to regulatory authorities worldwide. All dosage forms,
formulations, and indications for which applicants hold an approved
application (i.e., NDA, ANDA, BLA) for a given drug substance or
licensed biological product should usually be covered in one PSUR. The
PSUR may include separate presentations of these data as well as other
data (e.g., populations) if such presentations would facilitate review
of the PSUR. FDA is proposing that a PSUR contain the following
information:
III.E.2.a. Title page, table of contents, and introduction. The
title page would include, at a minimum, the following information:
[sbull] Name and international birth date of the drug substance or
licensed biological product that is the subject of the PSUR,
[sbull] Various dosage forms and formulations of the drug substance
or biological product covered by the PSUR,
[sbull] Name and address of the applicant,
[sbull] Reporting period covered by the PSUR, and
[sbull] Date of the PSUR.
The introduction would provide a brief description of how this PSUR
relates to previous reports and circumstances, would reference relevant
drug products, drug substances, or biological products reported in
other periodic safety reports (e.g., a combination product reported in
a separate PSUR), and would indicate any data duplication with other
PSURs. If two or more companies co-market the same drug substance or
licensed biological product, the safety reporting responsibilities of
each of the companies should be specified clearly in the introduction.
III.E.2.b. Worldwide marketing status. This section of the PSUR
would contain a table of the chronological history of the worldwide
marketing status of the drug or biological product(s) covered by the
PSUR from the date the product was first approved (i.e., the
international birth date) through its current status (i.e., cumulative
information). The table would include:
[sbull] Dates of drug or biological product approval and renewal,
[sbull] Safety-related restrictions on product use,
[sbull] Indications for use and special populations covered by the
drug or biological product approval,
[sbull] Lack of approval of the drug substance or biological
product in any dosage form or for any indication for use by any
regulatory authority(ies),
[sbull] Withdrawal of a pending drug or biological product
marketing application by the applicant for safety-or efficacy-related
reasons,
[sbull] Dates of market launches, and
[sbull] Trade name(s).
Drug or biological products that are approved in a country for a
particular indication, population, or dosage form that may result in
different types of patient exposure in that country should be
identified, particularly if there are meaningful differences in the
safety information reported in the PSUR due to the difference in
patient exposures.
III.E.2.c. Actions taken for safety reasons. This section of the
PSUR would contain details on regulatory authority-initiated (e.g.,
FDA) and/or applicant-initiated actions related to safety that were
taken during the period covered by the PSUR and between the data lock
point and PSUR submission (i.e., ``late-breaking'' safety concerns)
including:
[sbull] Withdrawal or suspension of product approval or indication
for use approval,
[sbull] Failure to obtain a marketing authorization renewal or to
obtain an approval for a new indication for use,
[sbull] Restrictions on distribution (e.g., products recalled for
safety reasons),
[sbull] Clinical trial suspension,
[sbull] Dosage modification,
[sbull] Changes in target population or indications, and
[sbull] Formulation changes.
This section of the PSUR would also contain a narrative identifying
the safety-related reasons that led to these actions with relevant
documentation appended when appropriate. Any communication with health
care professionals (e.g., Dear Healthcare Professional letters)
resulting from such actions would also be described with copies
appended.
III.E.2.d. Changes to CCSI. This section of the PSUR would describe
changes to the CCSI (e.g., new contraindications, precautions,
warnings, SADRs, or interactions) made during the period covered by the
PSUR. A copy of any modified section of the CCSI would be included.
Applicants would use the CCSI in effect at the beginning of the
reporting period for the PSUR. The revised CCSI would be used as the
reference document for the next reporting period.
III.E.2.e. Worldwide patient exposure. This section of the PSUR
would include, for the reporting period, an estimate of the worldwide
patient exposure to the drug or biological product(s) covered by the
PSUR (i.e., number of patients, average or median dose received, and
average or median length of treatment). In many cases, accurate patient
exposure data for a reporting period may be difficult to obtain.
However, applicants should exercise due diligence to obtain an estimate
of this exposure. The method used to estimate patient exposure would
always be described. If the patient exposure is impossible to estimate
or is meaningless, an explanation of and justification for such
conclusions would be provided. If patient exposure is impossible to
estimate, other measures of exposure, such as patient-days, number of
prescriptions, or number of dosage units, could be used. If these or
other more precise measures are not available and an adequate
explanation for the lack of such information is provided, bulk sales
could be used with estimates of what such numbers may mean in terms of
patient exposure.
When possible, data broken down by gender and age (especially
pediatric versus adult) would be provided. Data for the pediatric
population would be reported, if possible, by age group (e.g.,
neonates, infants, children, adolescents). If these data are not
available, an explanation for the lack of such information would be
included. In addition, when a pattern of reports indicates a potential
problem, details by country (with locally recommended dosage regimens)
or other segmentation (e.g., indication, dosage form) would also be
presented.
Patient exposure for clinical studies should also be provided when
SADR data from these types of studies are included in the PSUR. For
ongoing or blinded clinical studies, an estimate of patient exposure
should be provided.
III.E.2.f. Individual case safety reports.
III.E.2.f.i. Line listings. Individual line listings of various
data points from individual case safety reports are included as part of
the format for international PSURs agreed to by ICH (ICH E2C guidance,
62 FR 27470 at 27473 and 27474). FDA will not require submission of
such line listings in PSURs because, instead, the agency is proposing
to require a separate
[[Page 12440]]
semiannual submission of certain individual case safety reports on FDA
Form 3500A (VAERS form for vaccines, CIOMS I form, if desired, for
foreign SADRs) (see section III.E.4 of this document). However, FDA is
willing to accept line listings in PSURs as described in the ICH E2C
guidance if applicants wish to include them. FDA believes that such an
approach will help further the goal of harmonizing PSUR generation,
formatting, and submission globally.
III.E.2.f.ii. Summary tabulations. This section of the PSUR would
consist of summary tabulations of individual case safety reports (e.g.,
serious unlisted SADRs, serious listed SADRs, nonserious unlisted
SADRs, nonserious listed SADRs) for the following SADRs obtained or
otherwise received during the reporting period:
[sbull] All serious and nonserious SADRs from spontaneous sources
that were submitted to applicants by a health care professional,
[sbull] All serious SADRs from studies, individual patient INDs,
or, in foreign countries, from named-patient ``compassionate'' use,
[sbull] All serious SADRs and nonserious unlisted SADRs from the
scientific literature,
[sbull] All serious SADRs from regulatory authorities, and
[sbull] Serious SADRs from other sources such as reports created by
poison control centers and epidemiological data bases.
These summary tabulations would be made up of lists by body system
or standard organ system classification scheme (e.g., cardiovascular,
central nervous system, endocrine, renal) of all SADR terms and counts
of occurrences. For SADRs that are determined to be both serious and
unlisted, cumulative data would also be provided (i.e., all cases
reported to date). Applicants may provide information for this section
of the PSUR in a narrative rather than a summary tabulation if the
number of cases is small or the information is inadequate for any of
the tabulations.
As noted previously, FDA would consider ``study'' information to
include the following: safety information from company-sponsored
patient support programs, disease management programs, patient
registries, including pregnancy registries, or any organized data
collection scheme (see section III.A.7 of this document). FDA is
proposing to include summary tabulations for serious listed SADRs from
study information in PSURs to be consistent with the ICH E2C guidance
(62 FR 27470 at 27474), even though the agency indicated in the
clarification guidance of 1997 that only serious and unexpected adverse
drug experiences for which there is a reasonable possibility that the
drug or biological product caused the adverse drug experience should be
reported to FDA from studies.
This section of the PSUR would also contain a brief discussion of
the individual case data in the summary tabulations (e.g., discussion
of medical significance or mechanism). This section of the PSUR should
be used to comment on specific cases rather than to provide an overall
assessment of the cases.
III.E.2.g. Safety studies. This section of the PSUR would contain a
discussion (not just a listing of the studies) of nonclinical,
clinical, and epidemiological studies concerning important safety
information including:
[sbull] All applicant-sponsored studies newly analyzed during the
reporting period;
[sbull] New studies specifically planned, initiated, or continuing
during the reporting period that examine a safety issue, whether actual
or hypothetical; and
[sbull] Published safety studies in the scientific and medical
literature, including relevant published abstracts from meetings
(provide citations for all reports from the literature).
As noted previously, FDA would consider ``study'' information to
include the following: safety information from company-sponsored
patient support programs, disease management programs, patient
registries, including pregnancy registries, or any organized data
collection scheme (see section III.A.7 of this document).
The study design and results of newly analyzed studies should be
clearly and concisely presented with attention to the usual standards
of data analysis and description that are applied to nonclinical and
clinical study reports. Copies of full reports for these studies should
be appended only if new safety issues are raised or confirmed. FDA may
request copies of other studies, if necessary.
For new or ongoing studies, the objective, starting date, projected
completion date, number of subjects (planned and enrolled), and
protocol abstract for each study should be provided. When possible and
relevant, interim results of ongoing studies should be presented.
III.E.2.h. Other information. This section of the PSUR would
contain a discussion of medically relevant lack of efficacy reports
(e.g., might represent a significant hazard to the treated population)
for a product(s) used to treat serious or life-threatening diseases, or
any important new information received after the data lock point (e.g.,
significant new cases).
III.E.2.i. Overall safety evaluation. This section of the PSUR
would contain a concise, yet comprehensive, analysis of all of the
safety information provided in the PSUR, including new information
provided under the section entitled ``Other Information.'' In addition,
the section would include an assessment by applicants of the
significance of the data collected during the reporting period, as well
as from the perspective of cumulative experience. Applicants would
highlight any new information on:
[sbull] Serious, unlisted SADRs;
[sbull] Increased reporting frequencies of listed SADRs, including
comments on whether it is believed that the data reflect a meaningful
change in SADR occurrence;
[sbull] A change in characteristics of listed SADRs (e.g.,
severity, outcome, target population); and
[sbull] Nonserious, unlisted SADRs.
As part of the overall safety evaluation, applicants would also
explicitly address any new safety issue including but not limited to
the following:
[sbull] Drug interactions;
[sbull] Experience with overdose, whether deliberate or accidental,
and its treatment;
[sbull] Drug abuse or intentional misuse;
[sbull] Positive or negative experiences during pregnancy or
lactation;
[sbull] Effects with long-term treatment; and
[sbull] Experience in special patient groups (e.g., pediatric
population evaluated, if possible, by age group; geriatric; organ
impaired).
Applicants would note a lack of significant new information for any of
these categories.
III.E.2.j. Conclusion. This section of the PSUR would indicate new
safety information that is not in accord with previous cumulative
experience and with the CCSI in use at the beginning of the reporting
period (e.g., new evidence that strengthens a possible causal
relationship between the drug or biological product and an SADR, such
as positive rechallenge, an epidemiological association, or new
laboratory studies). This section of the PSUR would also specify and
justify any action recommended or initiated, including changes in the
CCSI.
III.E.2.k. Appendices. This section of the PSUR would include the
following information as appendices:
[[Page 12441]]
III.E.2.k.i. Company core data sheet. A copy of the company core
data sheet covered by the PSUR (i.e., in effect at the beginning of the
period covered by the PSUR) would be provided. The company core data
sheet would be numbered and dated and include the date of last
revision. In addition, a copy of the company core data sheet for the
next reporting period would be provided.
III.E.2.k.ii. U.S. labeling. A copy of the current approved U.S.
labeling would be provided. Any safety information that is included in
the CCSI but not in the U.S. labeling would be identified and an
explanation for the discrepancy provided. Any safety-related changes or
proposed changes to the U.S. labeling made during the reporting period
would be described, including the supplement numbers and dates of
submission for the supplements. Any suggested change or changes in the
U.S. labeling that should be considered based on the safety analysis in
the PSUR would also be described. (If appropriate, a supplemental
application would be filed with FDA concerning those changes as
prescribed under Sec. Sec. 314.70 or 601.12.)
III.E.2.k.iii. Spontaneous reports submitted to the applicant by an
individual other than a health care professional. This appendix would
contain summary tabulations (e.g., serious unlisted SADRs, serious
listed SADRs, nonserious unlisted SADRs, nonserious listed SADRs) for
all spontaneously reported serious SADRs, whether domestic or foreign,
and all spontaneously reported nonserious SADRs occurring in the United
States, obtained or otherwise received during the reporting period by
the applicant from an individual other than a health care professional
(e.g., SADR reports from consumers). These summary tabulations would
consist of lists by body system or by standard organ system
classification scheme (e.g., cardiovascular, central nervous system,
endocrine, renal) of all SADR terms and counts of occurrences. For
those SADRs that are determined to be both serious and unlisted,
cumulative data (i.e., all cases reported to date by individuals other
than a health care professional) would also be provided. The impact of
these spontaneous reports on the overall safety evaluation would be
discussed briefly. FDA may require applicants to submit to the agency,
when appropriate, SADR reports (e.g., FDA Form 3500As), within 5
calendar days after receipt of the request, for any or all of the SADRs
contained within this appendix (see section III.H of this document).
III.E.2.k.iv. SADRs with unknown outcome. This appendix would
contain summary tabulations for unlisted and listed SADRs with unknown
outcome from all spontaneous sources (i.e., health care professionals
and other individuals), obtained or otherwise received by the applicant
during the reporting period. These summary tabulations would consist of
lists by body system or by standard organ system classification scheme
of all SADR terms and counts of occurrences. The impact of these
spontaneous reports on the overall safety evaluation would be discussed
briefly. FDA may require applicants to submit to the agency, when
appropriate, individual case safety reports (e.g., FDA Form 3500As),
within 5 calendar days after receipt of the request, for any or all of
the listed SADRs with unknown outcome contained within this appendix
(see section III.H of this document).
III.E.2.k.v. Class action lawsuits. This appendix would contain
summary tabulations (e.g., serious unlisted SADRs, serious listed
SADRs, nonserious unlisted SADRs, nonserious listed SADRs) for all
SADRs obtained or otherwise received during the reporting period by the
applicant from class action lawsuits. These summary tabulations would
consist of lists by body system or by standard organ system
classification scheme of all SADR terms and counts of occurrences. For
SADRs that are both serious and unlisted, cumulative data would also be
provided. The impact of these reports on the overall safety evaluation
would be discussed briefly. FDA may require applicants to submit to the
agency, when appropriate, individual case safety reports (e.g., FDA
Form 3500As), within 5 calendar days after receipt of the request, for
any or all of the SADRs contained within this appendix (see section
III.H of this document).
III.E.2.k.vi. Lack of efficacy reports. This appendix would contain
an assessment of whether it is believed that the frequency of lack of
efficacy reports, obtained or otherwise received during the reporting
period, is greater than would be predicted by the premarketing clinical
trials for the drug or biological product. This assessment would be
provided whether a serious SADR, nonserious SADR, or no SADR results
from a lack of efficacy of the product.
III.E.2.k.vii. Information on resistance to antimicrobial drug
products. This appendix would contain information, received or
otherwise obtained by the applicant, on resistance to antimicrobial
drug products intended to treat infectious diseases. Information would
include:
[sbull] Changes in U.S. microbial in vitro susceptibility,
[sbull] The relationship of changes in U.S. microbial in vitro
susceptibility and clinical outcomes,
[sbull] Therapeutic failure that may possibly be due to resistance
to the antimicrobial drug product, and
[sbull] Whether the U.S. labeling should be revised because of the
information on antimicrobial resistance learned during the period
covered by the report.
III.E.2.k.viii. Medication errors. This appendix would contain
summary tabulations for all domestic reports of medication errors
submitted during the reporting period as an expedited report. For
actual medication errors, summary tabulations would be provided for
serious SADRs, nonserious SADRs, and no SADRs. For serious SADRs,
cumulative data (i.e., all cases reported to date) would also be
provided. For potential medication errors, the number of reports for
specific errors would be provided. If an SADR occurs, the summary
tabulations would consist of lists by body system or by standard organ
system classification scheme of all SADR terms and counts of
occurrences. The impact of these reports on the overall safety
evaluation would be discussed briefly.
III.E.2.k.ix. U.S. patient exposure. This appendix would contain,
for the reporting period, an estimate of the U.S. patient exposure to
the drug product(s) or biological product(s) covered by the PSUR (i.e.,
number of patients, average or median dose received, and average or
median length of treatment). The method used to estimate patient
exposure would always be described. If the patient exposure is
impossible to estimate or is meaningless, an explanation of and
justification for such conclusions would be provided. If patient
exposure is impossible to estimate, other measures of exposure, such as
patient-days, number of prescriptions, or number of dosage units, may
be used. If these or other more precise measures are not available and
an adequate explanation for the lack of such information is provided,
bulk sales may be used.
III.E.2.k.x. Location of safety records. This appendix would
contain a list of the current address(es) where all safety reports and
other safety-related records for the drug product or licensed
biological product are maintained. The list of addresses would provide
rapid access to safety-related records for FDA inspections and for
requests by FDA for additional information concerning safety issues.
III.E.2.k.xi. Contact person. The name and telephone number of the
licensed
[[Page 12442]]
physician or licensed physicians responsible for the content and
medical interpretation of the data and information contained within the
PSUR would be provided. The fax number and e-mail address of the
licensed physician would also be included, if available. This proposal
would provide the agency with someone to contact with any questions
that may arise during review of a PSUR. FDA is proposing that the
contact persons be licensed physicians because of their crucial
knowledge of the medical significance of the information provided in a
PSUR.
The PSUR excluding appendices, as proposed in this rule, would
represent a harmonized core document for worldwide postmarketing
periodic safety reporting for marketed drugs and licensed biological
products.
III.E.3. Interim Periodic Safety Reports (IPSRs)
Proposed Sec. Sec. 314.80(c)(3)(iii) and 600.80(c)(3)(iii) would
amend FDA's postmarketing periodic safety reporting regulations by
adding another new type of postmarketing periodic safety report. FDA is
proposing that this new report be identified as an ``interim periodic
safety report (IPSR).'' An IPSR would contain the same information as a
PSUR, except that the following information would not be provided:
[sbull] Summary tabulations for individual case safety reports,
obtained or otherwise received during the reporting period and brief
discussion of the data concerning these reports (see section
III.E.2.f.ii of this document),
[sbull] Any important new information received after the data lock
point (e.g., significant new cases) (see section III.E.2.h of this
document),
[sbull] Summary tabulations for spontaneous reports of SADRs
submitted to the applicant by an individual other than a health care
professional (see section III.E.2.k.iii of this document),
[sbull] Summary tabulations for spontaneous reports of SADRs with
unknown outcome submitted to the applicant by health care professionals
and other individuals (see section III.E.2.k.iv of this document),
[sbull] Summary tabulations for reports of SADRs from class action
lawsuits (see section III.E.2.k.v of this document),
[sbull] Summary tabulations of domestic reports of medication
errors (see section III.E.2.k.viii of this document).
The IPSR would provide the agency with an overview of the safety
profile of a drug product containing a drug substance or biological
product without requiring summary information on individual case safety
reports.
III.E.4. Semiannual Submission of Individual Case Safety Reports
Currently, postmarketing periodic safety reporting regulations
(Sec. Sec. 314.80(c)(2)(ii)(b) and 600.80(c)(2)(ii)(B)) require
applicants to submit to FDA in periodic adverse drug experience reports
an FDA Form 3500A (VAERS form for vaccines) for each spontaneously
reported adverse drug experience occurring in the United States that
has not been submitted to the agency as an expedited report (i.e.,
serious, expected adverse drug experiences and all nonserious adverse
drug experiences, whether unexpected or expected). FDA is proposing to
remove this requirement (see section III.E.1.b of this document).
Instead, under proposed Sec. Sec. 314.80(c)(3)(v) and 600.80(c)(3)(v),
the agency would require applicants to submit semiannually a separate
report to FDA consisting of a compilation of FDA Form 3500As (VAERS
forms for vaccines, CIOMS I forms, if desired, for foreign SADRs) for
certain spontaneously reported individual case safety reports as
described in the following explanation. This report would be identified
as ``Individual Case Safety Reports--Semiannual Submission.''
The semiannual submission from applicants that submit TPSRs for a
drug or licensed biological product would include an individual case
safety report for each serious, expected SADR, whether domestic or
foreign, and each nonserious, unexpected SADR occurring in the United
States that is submitted to the applicant during the reporting period
from all spontaneous sources (i.e., health care professionals and other
individuals). The semiannual submission for vaccines would also include
an individual case safety report for each nonserious, expected SADR and
each expected SADR with unknown outcome occurring in the United States
that is submitted to the applicant during the reporting period from all
spontaneous sources. For drugs and licensed biological products that
are not vaccines, nonserious, expected SADRs and expected SADRs with an
unknown outcome would not be submitted as individual case safety
reports in a semiannual submission. Instead, they would be reported as
part of a summary tabulation in a TPSR (see section III.E.1.e of this
document).
The semiannual submission from applicants that submit PSURs for a
drug product containing a drug substance or licensed biological product
would include an individual case safety report for each serious, listed
SADR, whether domestic or foreign, and each nonserious, unlisted SADR
occurring in the United States that is submitted to the applicant
during the reporting period from all spontaneous sources. The
semiannual submission for vaccines would also include an individual
case safety report for each nonserious, listed SADR and each listed
SADR with unknown outcome occurring in the United States that is
submitted to the applicant during the reporting period from all
spontaneous sources. For drugs and licensed biological products that
are not vaccines, nonserious, listed SADRs and listed SADRs with an
unknown outcome would not be submitted as individual case safety
reports in a semiannual submission. Instead, they would be reported as
part of a summary tabulation in a PSUR (see sections III.E.2.f.ii and
III.E.2.k.iii of this document). The semiannual submission should not
include individual case safety reports for serious, listed SADRs that
were previously submitted to FDA as a serious, unexpected SADR in an
expedited report (i.e., the agency does not want to receive duplicative
reports for the same SADR).
FDA needs to continue to receive information on serious, expected/
listed SADRs and nonserious SADRs, whether unexpected/unlisted or
expected/listed, to monitor the safety profile of marketed products to
determine if studies need to be undertaken to evaluate a particular
issue and/or to take appropriate regulatory action (e.g., labeling
change, distribution of Dear Healthcare Professional letter,
restriction on distribution of product, withdrawal of product from the
market). Reports of serious, expected/listed SADRs are used to monitor
changes in the frequency of occurrence or severity of a serious,
expected/listed SADR (e.g., frequency of serious, expected/listed SADR
increases because product interacts with a new approved product that is
frequently used concomitantly with the product). The agency's proposal
to require submission of spontaneously reported serious, expected/
listed SADRs from foreign sources would provide FDA with important
information that the agency currently does not receive (e.g., reports
from foreign countries in which the product is approved for more
indications than in the United States or the product results in
exposure to certain populations that are limited in the United States).
Reports of nonserious, unexpected/unlisted SADRs are used to
identify new nonserious SADRs that are associated with the use of a
product (e.g., sedation, sexual dysfunction, gastrointestinal
distress). This information is valuable
[[Page 12443]]
for individuals taking the product because, if one of these SADRs
occurs, the individual might suspect that it was due to the product and
not due to the onset of a new disorder. These reports may also serve to
signal the emergence of a serious, unexpected/unlisted SADR (e.g., an
aggregate of reports of decreased white blood cell counts may be an
early indicator of a serious condition such as bone marrow suppressive
disorder).
The reports (i.e., individual case safety reports for vaccines or
summary tabulations for drugs and licensed biological products that are
not vaccines) of nonserious, expected/listed SADRs are used to monitor
changes in the frequency of occurrence or severity of a nonserious,
expected/listed SADR. Such information could indicate a potential
safety problem that is worthy of further investigation (e.g., a new
drug or food interaction not previously associated with use of the
product).
Proposed changes to FDA's current reporting requirements for these
types of SADRs include: (1) Different reporting frequencies for the
SADRs, (2) receipt of spontaneously reported serious, expected/listed
SADRs from foreign sources and (3) submission of nonserious, expected/
listed SADRs in a summary tabulation instead of as individual case
safety reports for drugs and licensed biological products that are not
vaccines. With regard to different reporting frequencies, some SADRs
would be reported less frequently (e.g., semiannually rather than every
3 months) and others would be reported more frequently (e.g.,
semiannually rather than annually). FDA seeks comment on these proposed
changes.
The current approved U.S. labeling would be used as the reference
document to determine whether an SADR is unexpected or expected, and
the CCSI would be used to determine whether an SADR is unlisted or
listed.
As described previously, a minimum data set would be required for
all individual case safety reports of an SADR (see section III.C.5 of
this document). In addition, a full data set would be required for
reports of serious, expected SADRs and serious, listed SADRs. If a full
data set is not available for these SADR reports, the information
required under proposed Sec. Sec. 314.80(c)(1)(iv) and
600.80(c)(1)(iv) would be provided. For nonserious SADRs with a minimum
data set, the proposal would require that all safety information
received or otherwise obtained be submitted. The proposal would not
require that information in addition to the minimum data set be
acquired. Thus, followup would not be required for nonserious SADRs
that contain a minimum data set.
Followup information on SADRs submitted in an individual case
safety report--semiannual submission may be submitted in the next
individual case safety report--semiannual submission, unless such
information changes the classification of the SADR to a serious,
unexpected SADR. In these cases, the followup information would be
submitted to FDA as an expedited 15-day followup report (see section
III.D.6 of this document).
Applicants should not submit any reports of lack of efficacy in an
individual case safety report--semiannual submission. As noted
previously, applicants would be required to submit to FDA in an
expedited manner information regarding certain lack of efficacy reports
for the product (i.e., expedited reports of information sufficient to
consider product administration changes) and also to provide in
postmarketing periodic safety reports an assessment of all lack of
efficacy reports for the product as compared to premarketing clinical
trials for the product (see section III.C.7 of this document).
Applicants should not submit SADRs from class action lawsuits to
FDA in an individual case safety report--semiannual submission. The
agency believes, as noted previously, that SADRs from class action
lawsuits would be submitted to FDA from other sources (e.g.,
spontaneous report) prior to initiation of the class action lawsuit
(see section III.D.11 of this document). Summary tabulations of these
SADRs would be required to be included in postmarketing periodic safety
reports (see sections III.E.1.e and III.E.2.k.v of this document).
Applicants should not submit reports of medication errors in an
individual case safety report--semiannual submission. These reports
would be submitted, as previously noted, as an expedited report (see
section III.D.5 of this document).
III.E.5. Reporting Requirements
III.E.5.a. Reporting intervals. Current regulations (Sec. Sec.
314.80(c)(2)(i) and 600.80(c)(2)(i)) require the submission of
postmarketing periodic safety reports at quarterly intervals for 3
years from the date of approval of the application in the United States
and then annually thereafter. Quarterly safety reports must be
submitted within 30 days of the close of the quarter (the first quarter
beginning on the date of U.S. approval of the application); annual
safety reports must be submitted within 60 days of the anniversary date
of U.S. approval of the application. FDA is proposing revisions to
these reporting requirements. The proposals are consistent with the
recommendations of ICH (62 FR 27470 at 27472): ``Therefore, it is
recommended that the preparation of PSUR's for all regulatory
authorities should be based on data sets of 6 months or multiples
thereof.''
Products approved before January 1, 1998. Proposed Sec. Sec.
314.80(c)(3)(i) and 600.80(c)(3)(i) would require applicants holding an
NDA, ANDA, or BLA that was approved for initial marketing of a drug
product containing a drug substance or licensed biological product
before January 1, 1998, to submit either a TPSR or a PSUR every 5 years
after U.S. approval of the application. The proposed rule would also
require these applicants to submit a TPSR or an IPSR 7.5 years and 12.5
years after U.S. approval of the application. Under proposed Sec. Sec.
314.80(c)(3)(iii) and 600.80(c)(3)(iii), the reporting period for an
IPSR would cover the period between the last PSUR or TPSR and the data
lock point for the IPSR (e.g., between years 5 and 7.5 for an IPSR with
a data lock point at 7.5 years after U.S. approval of the application).
Products approved on or after January 1, 1998. Under proposed
Sec. Sec. 314.80(c)(3)(ii) and 600.80(c)(3)(ii), applicants holding an
NDA, ANDA, or BLA that was approved for initial marketing of a drug
product containing a drug substance or licensed biological product on
or after January 1, 1998, would be required to submit a PSUR to FDA
with the following schedule:
[sbull] Semiannually (i.e., every 6 months) for 2 years after U.S.
approval of the application,
[sbull] Annually for the next 3 years, and then
[sbull] Every 5 years thereafter.
The proposed rule would also require applicants to submit an IPSR 7.5
years and 12.5 years after U.S. approval of the application.
Products with approved pediatric use supplements. Proposed
Sec. Sec. 314.80(c)(3)(iv) and 600.80(c)(3)(iv) would require
applicants holding an approved pediatric use supplement to an approved
application (i.e., a supplement for use of the human drug or biological
product in the pediatric population) to submit a PSUR to FDA with the
following schedule:
[sbull] Semiannually (i.e., every 6 months) for 2 years after U.S.
approval of the supplement,
[sbull] Annually for the next 3 years, and
[sbull] Then every 5 years thereafter.
The proposed rule would also require these applicants to submit an IPSR
7.5
[[Page 12444]]
years and 12.5 years after U.S. approval of the supplement. These
applicants would be required to submit PSURs and IPSRs to FDA even if
the pediatric use supplement or original application was approved prior
to January 1, 1998. FDA is proposing this action to harmonize
acquisition of new safety information regarding pediatric populations
for timely review by the agency.
All products. Under proposed Sec. Sec. 314.80(c)(3)(v) and
600.80(c)(3)(v), applicants holding an NDA, ANDA, or BLA would be
required to submit an individual case safety reports--semiannual
submission to FDA every 6 months after U.S. approval of an application.
The 6-month interval for these reports would coincide with the
reporting interval (6-month or multiples of 6 months) for TPSRs, PSURs
or IPSRs.
Alternative reporting frequency. Proposed Sec. Sec. 314.80(c) and
600.80(c) would provide that, when appropriate, FDA may require in
writing that applicants submit postmarketing periodic safety reports at
time intervals other than prescribed by the regulations (see section
III.C.4 of this document). Usually such variations would occur if new
safety concerns arose requiring more timely reporting (e.g., approval
of a new indication or dosage form for the product, approval for use of
the product in a new population, new safety issues in individual case
safety reports submitted to FDA for the product). When anticipated, FDA
would state the revised reporting interval in the approval letter for
the new indication, new population, or new dosage form. In other cases,
such revisions to the reporting interval would be conveyed to
applicants in a written letter from the director of the responsible
review division in FDA with an explanation of why such a new reporting
time interval is required.
III.E.5.b. Submission date. Proposed Sec. Sec. 314.80(c)(3) and
600.80(c)(3) would require that the data lock point for postmarketing
periodic safety reports be the month and day of the international birth
date of the drug product (proposed Sec. Sec. 314.80(c)(3)(i) and
314.80(c)(3)(v)), drug substance (proposed Sec. Sec. 314.80(c)(3)(ii),
314.80(c)(3)(iii), and 314.80(c)(3)(iv)) or licensed biological product
(proposed Sec. Sec. 600.80(c)(3)(i) through 600.80(c)(3)(v)) or any
other month and day agreed on by the applicant and FDA. For example,
applicants that are submitting PSURs on an every 5 year basis may, in
agreement with FDA, change the data lock point to facilitate
international reporting so long as there is never a time period of
greater than 5 years in which FDA has not received a PSUR. Or, the
applicant and FDA may agree to change the data lock point to the month
and day of U.S. approval of the application if this date would result
in better use of the applicant's resources.
Proposed Sec. Sec. 314.80(c)(3) and 600.80(c)(3) would require
that all postmarketing periodic safety reports be submitted to FDA
within 60 calendar days after the data lock point for the report. As
noted previously, the data lock point (i.e., month and day) for
postmarketing periodic safety reports would be based on the month and
day of the international birth date for the product and the frequency
for submission of these reports would be based on the product's date
(i.e., year) of U.S. approval (see section III.A.10 of this document).
III.E.5.c. Cover letter. Proposed Sec. Sec. 314.80(c)(3) and
600.80(c)(3) would require that applicants include a cover letter with
all postmarketing periodic safety reports (i.e., TPSRs, PSURs, IPSRs,
individual case safety reports--semiannual submissions). This cover
letter would contain a list of the NDA and/or ANDA numbers for the
human drug products or BLA numbers for the human biological products
covered by the report.
III.E.5.d. International birth date for combination products.
Proposed Sec. Sec. 314.80(c)(3) and 600.80(c)(3) would also state that
the international birth date for combination products would be the
international birth date of the human drug product containing the drug
substance or licensed biological product that was most recently
approved for marketing. For combination products that are also marketed
individually, applicants may submit either a separate PSUR for the
combination product or include information for the combination product
as a separate presentation in the PSUR for one of the individual
components.
III.F. Reporting Format
Current postmarketing safety reporting regulations at Sec. Sec.
310.305(d)(1), 314.80(f)(1), and 600.80(f)(1) require persons subject
to these requirements to submit an FDA Form 3500A (VAERS form for
vaccines) for each report of an adverse drug experience. Foreign SADRs,
including those associated with the use of vaccines, may be submitted
on an FDA Form 3500A or, if preferred, on a CIOMS I form.
III.F.1. Forms Versus Narrative Format
Proposed Sec. Sec. 310.305(d)(1), 314.80(c)(4)(i), and
600.80(c)(4)(i) would amend the current postmarketing safety reporting
format regulations by reorganizing these regulations and by adding new
information. Proposed Sec. Sec. 310.305(d)(1)(i) would prescribe,
except as provided in the regulations, that:
* * * the manufacturer must complete an FDA Form 3500A for each
individual case safety report of an SADR. Reports based on
information about individual cases or case series in the scientific
literature must be submitted on an FDA Form 3500A(s).
Proposed Sec. Sec. 314.80(c)(4)(i)(A) and 600.80(c)(4)(i)(A) would
prescribe the same requirements for submission of postmarketing
individual case safety reports by applicants. Proposed Sec.
600.80(c)(4)(i)(A) would also describe requirements for use of the
VAERS form for vaccines. Proposed Sec. Sec. 310.305(d)(1)(ii),
314.80(c)(4)(i)(B) and 600.80(c)(4)(i)(B) would prescribe that:
Foreign SADRs may be submitted either on an FDA Form 3500A or,
if preferred, on a CIOMS I form (foreign SARs for vaccines, may be
submitted either on a VAERS form, or, if preferred, on a CIOMS I
form, for proposed Sec. 600.80(c)(4)(i)(B)).
Proposed Sec. Sec. 310.305(d)(1)(iii), 314.80(c)(4)(i)(C) and
600.80(c)(4)(i)(C) would prescribe that:
Each domestic report of an actual or potential medication error
must be submitted on an FDA Form 3500A (or, for vaccines, on a VAERS
form for proposed Sec. 600.80(c)(4)(i)(C)).
Proposed Sec. Sec. 310.305(d)(1)(iv), 314.80(c)(4)(i)(D) and
600.80(c)(4)(i)(D) would prescribe that:
Reports of overall findings or data in the aggregate from
published and unpublished in vitro, animal, epidemiological, or
clinical studies must be submitted in a narrative format.
These proposed amendments would clarify the reporting format that would
be required for individual case safety reports or other safety
information (i.e., overall findings or data in the aggregate). Reports
of actual and potential medication errors would be required to be
submitted on an FDA Form 3500A (or VAERS form, as appropriate) because
these reports describe an individual case even if an SADR does not
occur or a patient is not identifiable. Reports of overall findings or
data in the aggregate would be submitted in a narrative format rather
than on FDA Form 3500A because FDA Form 3500A has been designed for
reporting of data from an individual case.
III.F.2. Medical Dictionary for Regulatory Activities (MedDRA)
ICH has developed an international medical terminology, MedDRA (the
[[Page 12445]]
medical dictionary for regulatory activities), to support the
computerization and transmission of information related to many aspects
of the regulation of medical products (ICH M1). Use of a single medical
terminology internationally would facilitate global communication of
safety information for human drug and biological products (see section
II.B.1 of this document).
Proposed Sec. Sec. 310.305(d)(2), 314.80(c)(4)(ii), and
600.80(c)(4)(ii) would require that each SADR in an individual case
safety report be coded on the FDA Form 3500A, CIOMS I Form, or VAERS
Form using the appropriate ``preferred term'' in the latest version of
MedDRA in use at the time the manufacturer or applicant becomes aware
of the individual case safety report. FDA is proposing to require use
of MedDRA to be consistent with ICH M1.
Proposed Sec. Sec. 310.305(d)(2), 314.80(c)(4)(ii), and
600.80(c)(4)(ii) would also require that each individual case safety
report of a medication error be coded both as a medication error and,
if applicable, with the preferred term for any SADRs associated with
the medication error. The proposal clarifies how actual and potential
medication errors would be coded.
MedDRA must be licensed for a fee from an international MSSO. TRW
was selected as the MSSO by ICH and the International Federation of
Pharmaceutical Manufacturers Associations (IFPMA) through a contract
process that involved bids from companies globally. FDA was involved in
this process. The costs that would be imposed on industry to license
MedDRA was a consideration in the selection of the MSSO.
Companies may license the latest version of MedDRA 5.1 by
contacting TRW in Reston, VA, toll free number 877-258-8280 (703-345-
7799 in Washington, DC area), FAX 703-345-7755, e-mail
subscrib@meddramsso.com, Internet at www.meddramsso.com. Updated
7799 in Washington, DC area), FAX 703-345-7755, e-mail
subscrib@meddramsso.com, Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=www.meddramsso.com. Updated
versions of MedDRA will be provided to subscribers as part of the
annual licensing fee.
MedDRA is a hierarchical system composed of various levels of
terminology (i.e., system organ class, high level group term, high
level term, preferred term, lower level term). The agency is proposing
to require use of the preferred term for reporting to FDA because each
preferred term represents a unique medical concept accepted
internationally, which will aid in the transmission and translation of
reports from various parts of the world. The preferred term provides
medically validated representations of colloquial terms, which will
result in fewer misrepresentations and misunderstandings of colloquial
reports from various parts of the world. The preferred term also
provides medically validated representations of noncurrent terms in
other previously widely used coding terminologies such as COSTART and
WHOART.
FDA believes that use of MedDRA, a standardized medical
terminology, will be welcomed by most of industry. However, for some
manufacturers and applicants, use of MedDRA may result in a significant
economic hardship. Applicants may request, under Sec. Sec. 314.90 or
600.90, that FDA waive the requirement that each SADR in an individual
case safety report be coded using MedDRA. If FDA finds that this
requirement is economically burdensome for a small company, the agency
intends to grant the company a waiver. A large company may also be
granted a waiver if, for instance, it only markets a single product
that generates a few safety reports a year. FDA intends to grant all
reasonable waiver requests. This determination will be made on a case-
by-case basis.
III.F.3. Single Form for Each Identifiable Patient
Current postmarketing safety reporting regulations, at Sec. Sec.
310.305(d)(2), 314.80(f)(2), and 600.80(f)(2), state that each
completed FDA Form 3500A, VAERS Form, or CIOMS I Form should refer only
to an individual patient or a single attached publication. Under
proposed Sec. Sec. 310.305(d)(3), 314.80(c)(4)(iii), and
600.80(c)(4)(iii) FDA would remove the phrase ``or a single attached
publication'' and replace the word ``patient'' with the word ``case.''
This proposed amendment would clarify that an FDA Form 3500A should be
completed for each identifiable patient described in a scientific
article (e.g., six FDA Form 3500As should be completed for an article
describing six patients experiencing a particular SADR). This would
also clarify that an FDA Form 3500A would be used to describe a
potential medication error that does not involve a patient.
III.F.4. Contact Person
Proposed Sec. Sec. 310.305(d)(4), 314.80(c)(4)(iv), and
600.80(c)(4)(iv) would state:
Each completed FDA Form 3500A (VAERS Form for proposed Sec.
600.80(c)(4)(iv)) or CIOMS I Form must include the name and
telephone number (and fax number and e-mail address, if available)
for the licensed physician responsible for the content and medical
interpretation of the data contained within the form (i.e., contact
person for the company).
This information should be provided on FDA Form 3500A under the
``contact office'' box (box G1 on FDA Form 3500A). This proposed
revision would provide FDA with a person to contact with any questions
that may arise during review of an individual case safety report. The
agency believes that the potential medical significance of these safety
reports warrants oversight by a licensed physician.
III.F.5. Computer-Generated Facsimile of FDA Form 3500A or Vaccine
Adverse Event Reporting System (VAERS) Form
Current Sec. Sec. 310.305(d)(3), 314.80(f)(3), and 600.80(f)(3)
state that instead of using an FDA Form 3500A, manufacturers and
applicants may use a computer-generated FDA Form 3500A or other
alternative format provided that the content of the alternative format
is equivalent in all elements to those specified in FDA Form 3500A and
the format is agreed to in advance by MedWatch: The FDA Medical
Products Reporting Program. Alternative formats to the Center for
Biologics Evaluation and Research's VAERS Form must be approved by the
Division of Biostatistics and Epidemiology (Sec. 600.80(f)(3)).
Proposed Sec. Sec. 310.305(d)(5), 314.80(c)(4)(v), and
600.80(c)(4)(v) would remove the use of alternative formats to FDA Form
3500A and the requirement to obtain preapproval by MedWatch for use of
a computer-generated FDA Form 3500A. Proposed Sec. 600.80(c)(4)(v)
would also remove the use of alternative formats to the VAERS Form and
the requirement to obtain preapproval by the Division of Biostatistics
and Epidemiology for use of a computer-generated VAERS Form. Instead,
the proposed rule would permit manufacturers and applicants to use a
computer-generated facsimile of FDA Form 3500A (or VAERS Form for
vaccines) provided that it is readable, includes appropriate
identifying information and contains all the elements (i.e., format,
sections, blocks, titles, descriptors within blocks, text for
disclaimer) of FDA Form 3500A (or the VAERS Form for vaccines) in the
identical enumerated sequence of the form. The proposed rule would also
permit use of a one-page FDA Form 3500A for individual case safety
reports in which no suspect medical device is involved. For one-page
reports, the box, Section D. Suspect Medical Device, on the front page
of FDA Form 3500A would be replaced with the box, Section
[[Page 12446]]
G. All Manufacturers, located on the back page of the form.
To be considered ``readable'' by FDA, the computer-generated
facsimile should be formatted as follows.
[sbull] The facsimile should have at least a \1/4\ inch margin
around the entire form so that information is not lost during scanning,
copying, or faxing of the document. The left-hand margin may be
increased up to \1/2\ inch to permit binding (e.g., hole-punching) of
the form; all other margins should continue to be at least \1/4\ inch.
[sbull] The data and text that is contained within the boxes should
be in a font size of not less than 10 point.
[sbull] The data and text that is contained within the boxes should
be in a font type that is easy to read (e.g., CG Times, Arial) and not
condensed, because the form may be copied or faxed multiple times. For
visual contrast, the font type that is used for the data and text
should, if possible, be different than the font type used to create the
FDA Form 3500A or VAERS Form.
[sbull] All data and text should be contained within each of the
boxes, e.g., an ``x'' mark should be centered within the box, and
narratives should include margins so that letters of the text are not
obscured or made ambiguous by lines defining a box.
FDA would consider ``appropriate identifying information'' to
include:
[sbull] The name of the company centered on the top of the front
page;
[sbull] In the lower left hand corner of the front page, the phrase
``3500A Facsimile'' instead of the phrase ``FDA Form 3500A (date of
form [e.g., 6/93])'' or the phrase ``VAERS facsimile'' instead of the
phrase ``Form VAERS-1'';
[sbull] The phrase ``continued'' at the end of each field that has
additional information continued onto another page; and
[sbull] On each continuation page containing additional
information, the page number identified as Page----of----, the
manufacturer report number in the upper right corner, the name of the
company in the upper right corner, and the section and block number
(e.g., Block B5) for each narrative entry.
This information is included in the draft guidance of 2001. Any
revisions to these parameters would be included in updated versions of
the guidance.
III.F.6. Other Revisions
The proposed rule would remove Sec. Sec. 310.305(d)(4),
314.80(f)(4), and 600.80(f)(4). These paragraphs provide manufacturers
and applicants with addresses for obtaining copies of FDA Form 3500A
and instructions for completing the form. FDA is proposing to remove
these paragraphs because the addresses are provided in the draft
guidance of 2001.
The proposed rule would also remove Sec. Sec. 314.80(e)(2) and
600.80(e)(2). These paragraphs state that persons subject to the
postmarketing safety reporting regulations must separate and clearly
mark reports of adverse drug experiences that occur during a
postmarketing study as being distinct from those experiences that are
being reported spontaneously to the person. FDA is proposing this
revision because this information would be submitted to the agency in a
completed FDA Form 3500A under the box for ``Report source'' (box G3 on
FDA Form 3500A).
III.G. Patient Privacy
Current postmarketing safety reporting regulations at Sec. Sec.
310.305(e), 314.80(h), and 600.80(h) state that persons subject to
these requirements should not include the names and addresses of
individual patients in reports and, instead, should assign a unique
code number to each report, preferably not more than eight characters
in length. Proposed Sec. Sec. 310.305(e), 314.80(e), and 600.80(e)
would amend these regulations by removing the word ``number.'' This
proposed amendment would clarify that the code selected to identify a
patient need not be limited to numbers (i.e., it could contain letters
or a mixture of letters and numbers).
III.H. Recordkeeping
Current postmarketing safety recordkeeping regulations at Sec.
314.80(i) require applicants to maintain for a period of 10 years
records of all adverse drug experiences known to the applicant,
including raw data and any correspondence relating to the adverse drug
experiences. Under proposed Sec. 314.80(f), FDA would amend these
regulations to read:
The applicant must maintain for a period of 10 years records of
all safety information pertaining to its drug product, received or
otherwise obtained, including raw data, any correspondence relating
to the safety information, and any reports of SADRs or medication
errors not submitted to FDA or only provided to FDA in a summary
tabulation. The applicant must also retain for a period of 10 years
any records required to be maintained under this section. When
appropriate, FDA may require an applicant to submit any or all of
these records to the agency within 5 calendar days after receipt of
the request.
This proposed revision clarifies the type of safety records that
applicants would be required to maintain for its drug products. With
regard to a request for these records by FDA, the agency would usually
make such a request either in response to a suspected safety problem
associated with the use of a drug or to determine a company's
compliance with the postmarketing safety reporting requirements. Under
proposed Sec. 600.80(f), the agency is proposing similar revisions to
the recordkeeping requirements for licensed biological products at
Sec. 600.80(i). FDA is proposing these revisions to clarify what types
of postmarketing safety reporting records must be maintained.
Current Sec. 310.305(f)(1) requires manufacturers, packers, and
distributors to maintain for a period of 10 years records of all
adverse drug experiences required under Sec. 310.305, including raw
data, any correspondence relating to adverse drug experiences, and the
records required to be maintained under Sec. 310.305. FDA is proposing
to amend these regulations to be consistent with the postmarketing
safety recordkeeping regulations at proposed Sec. Sec. 314.80(f) and
600.80(f).
III.I. Abbreviated New Drug Application (ANDA) Products
Current Sec. 314.98 requires applicants holding an approved ANDA
to comply with the postmarketing safety reporting requirements under
Sec. 314.80. The proposed amendments to Sec. 314.80 in this rule
would apply to applicants holding an approved ANDA. For postmarketing
periodic safety reporting purposes, proposed Sec. 314.98(a) would
require applicants holding an approved ANDA to determine the data lock
point (i.e., month and day of the international birth date or any other
month and day agreed by the applicant and FDA) for their periodic
safety reports based on the data lock point of postmarketing periodic
safety reports for other drug products containing the same drug
substance (i.e., innovator NDA product that is the same drug product as
the ANDA product or other ANDA products with the same drug substance if
the innovator NDA product is no longer on the market). Thus,
postmarketing periodic safety reports from different applicants for
drug products containing the same drug substance would be submitted to
FDA at the same time. Applicants holding an approved ANDA may contact
FDA, if necessary, for assistance in determining the data lock point
for postmarketing periodic safety reports.
Proposed Sec. 314.98(a) would also state that applicants holding
an approved ANDA would determine the type of postmarketing periodic
safety report that would be required to be submitted to FDA (i.e.,
TPSR, PSUR, or IPSR)
[[Page 12447]]
based on the U.S. approval date of the application for the innovator
NDA product. If the innovator NDA product (even if no longer on the
market) was approved for marketing before January 1, 1998, applicants
holding an approved ANDA for the drug product would have the option of
submitting either TPSRs or PSURs and IPSRs to FDA. In these cases, an
applicant holding an approved ANDA may choose to submit TPSRs to FDA
even though other applicants with approved applications for the drug
product submit PSURs and IPSRs. If the innovator NDA product was
approved for marketing on or after January 1, 1998, applicants holding
an approved ANDA for the drug product would be required to submit PSURs
and IPSRs to FDA.
Proposed Sec. 314.98(a) also provides that applicants holding an
approved ANDA would determine the frequency of submission for
postmarketing periodic safety reports based on the U.S. approval date
of the application for the innovator NDA product. For example, if the
innovator NDA product is the first human drug product containing the
drug substance approved in the world and the application is approved
for marketing on June 15, 1980, applicants of the innovator NDA product
and all ANDA products with the same drug product would either submit a
TPSR or PSUR to FDA every 5 years based on the U.S. approval date of
the innovator NDA product (e.g., data lock point of June 15, 2000, June
15, 2005). In this case, an applicant with an ANDA approved on January
1, 1999, would have a data lock point of June 15, 2000, even though the
reporting period for the drug product is less than 5 years; the next
reporting period for the drug product would cover a 5-year period
(i.e., June 16, 2000 through June 15, 2005). If the first human drug
product containing the drug substance was approved for marketing in
Europe on February 1, 1980, and the same drug product was approved in
the United States on June 15, 1980, applicants of this drug product and
all ANDA products with the same drug product would either submit a TPSR
or PSUR to FDA with a 5-year frequency based on the U.S. approval date
and with a date lock point based on the European approval date (e.g.,
February 1, 2000, February 1, 2005).
All applicants holding an approved NDA or ANDA would be required to
submit postmarketing individual case safety reports--semiannual
submissions to FDA every 6 months (see section III.E.4 in this
document). Thus, even though the agency would not be receiving TPSRs,
PSURs, and IPSRs for drug products with approved ANDAs frequently after
approval of the product, FDA would receive in a timely manner
individual case safety reports for the product (i.e., expedited
reports, individual case safety reports--semiannual submission) that
would identify any potential problems associated with the formulation
of the product. It is not necessary to receive TPSRs, PSURs, or IPSRs
for drugs with approved ANDAs more frequently because the innovator NDA
product has been evaluated for a number of years.
III.J. Postmarketing Approved New Drug Application (NDA) and Biologics
License Application (BLA) Annual Reports
Current Sec. 314.81(b)(2) requires applicants of marketed drug
products subject to an NDA to submit an annual report to FDA within 60
days of the anniversary date of U.S. approval of the application. This
annual report must contain a brief summary of significant new
information from the previous year that might affect the safety,
effectiveness, or labeling of the drug product and a description of
actions the applicant has taken or intends to take as a result of new
information, such as submitting a labeling supplement, adding a warning
to the labeling, or initiating a new study (Sec. 314.81(b)(2)(i)).
This summary section must also contain, in accordance with the 1998
pediatric final rule, a statement of whether labeling supplements for
pediatric use were submitted and whether new studies in the pediatric
population to support appropriate labeling for the pediatric population
were initiated. The 1998 pediatric final rule also requires that the
summary section include, where possible, an estimate of the patient
exposure to the drug product, with special reference to the pediatric
population (neonates, infants, children, and adolescents), including
dosage form. The annual report also must contain a section on
nonclinical laboratory studies that includes copies of unpublished
reports and summaries of published reports of new toxicological
findings in animal studies and in vitro studies (e.g., mutagenicity)
conducted by, or otherwise obtained by, the applicant concerning the
ingredients in the drug product (Sec. 314.81(b)(2)(v)). The applicant
must submit a copy of a published report if requested by FDA. The
annual report also must contain a section on clinical data that
includes, among other data, published clinical trials on safety of the
drug (or abstracts of them) and reports of clinical experience
pertinent to safety (for example, epidemiological studies or analyses
of experience in a monitored series of patients) conducted by or
otherwise obtained by the applicant (Sec. 314.81(b)(2)(vi)). The
clinical data section also must contain, in accordance with the 1998
pediatric final rule, an analysis of available safety and efficacy data
in the pediatric population, changes proposed in the labeling based on
this information, and an assessment of data needed to ensure
appropriate labeling for the pediatric population.
Current Sec. 601.28 requires applicants of licensed biological
products to submit an annual report to FDA within 60 days of the
anniversary date of U.S. approval of the application. This annual
report must contain, among other information, a brief summary stating
whether labeling supplements for pediatric use were submitted and
whether new studies in the pediatric population to support appropriate
labeling for the pediatric population were initiated (Sec. 601.28(a)).
This summary section also must contain, where possible, an estimate of
the patient exposure to the product, with special reference to the
pediatric population (neonates, infants, children, and adolescents),
including dosage form. The annual report also must contain a section on
clinical data that includes an analysis of available safety and
efficacy data in the pediatric population and changes proposed in the
labeling based on this information (Sec. 601.28(b)). This clinical
data section also must contain an assessment of data needed to ensure
appropriate labeling for the pediatric population.
As noted in section I of this document, FDA received comments on
the October 1994 proposal that noted that the proposed amendments to
the agency's postmarketing safety reporting requirements would
duplicate certain information required in postmarketing approved NDA
annual reports. In light of these comments, FDA is proposing to revoke
the requirement for safety-related information in postmarketing
approved NDA and BLA annual reports to eliminate duplicative reporting.
FDA is proposing to remove the requirement in Sec. 314.81(b)(2)(i)
to report safety information or safety-related labeling changes in the
summary section of approved NDA annual reports. FDA is also proposing
to remove the requirement in Sec. Sec. 314.81(b)(2)(i) and 601.28(a)
to submit an estimate of patient exposure to the drug product with
special reference to the pediatric population. FDA is also proposing to
remove the requirement in Sec. 314.81(b)(2)(v) to include the section
on nonclinical laboratory studies in approved NDA annual reports. FDA
is
[[Page 12448]]
also proposing to remove the requirement in Sec. Sec. 314.81(b)(2)(vi)
and 601.28(b) to submit safety-related information in the clinical data
section of approved NDA and BLA annual reports. FDA is proposing these
changes because this safety-related information for a drug or licensed
biological product would be provided to the agency in postmarketing
safety reports (i.e., expedited reports, TPSRs, PSURs, IPSRs,
individual case safety reports--semiannual submissions). For example,
proposed Sec. Sec. 314.80(c)(2)(ii) and 600.80(c)(2)(ii) would require
postmarketing expedited reports for certain information that would be
sufficient, based on appropriate medical judgment, to consider changes
in product administration (e.g., any significant unanticipated safety
finding or data in the aggregate from an in vitro, animal,
epidemiological, or clinical study, whether or not conducted under an
IND, that suggests a significant human risk such as reports of
mutagenicity, teratogenicity, or carcinogenicity, or reports of a lack
of efficacy with a drug or biological product used in treating a life-
threatening or serious disease). Under proposed Sec. Sec.
314.80(c)(3)(ii)(E), 314.80(c)(3)(iii)(E), 600.80(c)(3)(ii)(E), and
600.80(c)(3)(iii)(E), PSURs and IPSRs would contain a section on
worldwide patient exposure that includes, when possible, data broken
down by gender and age (especially pediatric versus adult). Under
proposed Sec. Sec. 314.80(c)(3)(ii)(G), 314.80(c)(3)(iii)(F),
600.80(c)(3)(ii)(G) and 600.80(c)(3)(iii)(F), PSURs and IPSRs would
include a section on safety studies that would contain a discussion of
nonclinical, clinical, and epidemiological studies that contain
important safety information. This safety studies section would include
all applicant-sponsored studies newly analyzed during the reporting
period; new studies specifically planned, initiated, or continuing
during the reporting period; and published safety studies in the
scientific and medical literature.
III.K. Safety Reporting for In Vivo Bioavailability and Bioequivalence
Studies
FDA's existing in vivo bioavailability and bioequivalence study
regulations, under Sec. 320.31(a), require submission of an IND, as
prescribed under part 312, for certain studies in humans (i.e., studies
that involve a new chemical entity, a radioactively labeled drug
product, or a cytotoxic drug product). Section 320.31(b) requires an
IND for certain studies in humans using a drug product that contains an
already approved, non-new chemical entity (i.e., a single-dose study
where either the maximum single or total daily dose exceeds that
specified in the approved labeling for the drug product, a multiple-
dose study where either the single or total daily dose exceeds that
specified in the approved labeling of the drug product, a multiple-dose
study on a controlled release product on which no single-dose study has
been completed). Section 320.31(d) exempts all other in vivo
bioavailability and bioequivalence studies in humans from the
requirements of part 312 if certain conditions are satisfied (i.e.,
samples of any test article and reference standard are reserved by the
person conducting the study and released to FDA upon request, studies
are conducted in compliance with the requirements for institutional
review set forth in 21 CFR part 56 and informed consent set forth in 21
CFR part 50).
FDA believes that drug products that are being investigated in
human bioavailability and bioequivalence studies that are not subject
to an IND are, in general, safe. However, as noted in section II.B.4 of
this document, FDA receives some safety information periodically
regarding drugs in these studies, thus making the agency uncertain
whether it is receiving all necessary safety information regarding the
specificity and severity of SADRs related to these drugs or any new
SADRs that may be related to them. FDA has determined that a more
comprehensive and orderly system for collecting safety information for
these studies is needed. For this purpose, the agency is proposing to
require persons conducting human bioavailability and bioequivalence
studies that are not subject to an IND to submit expedited safety
reports to FDA to alert the agency to potential safety problems
quickly. The proposed rule would not require these persons to submit an
IND to FDA for the studies.
FDA believes that this new proposed safety reporting requirement
will result in submission of minimal reports to the agency ([sim] 200/
year; see table 13 for estimate). FDA seeks comment on the
reasonableness of this estimate and requests that comments provide
information to support any alternative estimates.
The act provides authority to FDA to require safety reports for
human bioavailability and bioequivalence studies that are not subject
to an IND. Section 505(i) of the act provides broad authority for FDA
to issue regulations governing the clinical investigation of new drugs
to protect the rights, safety, and welfare of human subjects and
otherwise to protect the public health. In addition, section 701 of the
act (21 U.S.C. 371) provides that the agency has authority to issue
regulations for the efficient enforcement of the act.
FDA is proposing to amend its regulations at Sec. 320.31(d) to
require persons conducting human bioequivalence and bioavailability
studies that are not subject to an IND to submit safety reports to FDA
as prescribed under Sec. 312.32 for drug products subject to an IND.
Under proposed Sec. 312.32(c)(1), a written safety report must be
submitted within 15 calendar days to FDA and all participating
investigators for any SADR that, based on the opinion of the
investigator or sponsor, is both serious and unexpected and for
information that, based upon appropriate medical judgment, might
materially influence the benefit-risk assessment of an investigational
drug, or that would be sufficient to consider changes in either product
administration or in the overall conduct of a clinical investigation.
Examples of reportable information would include any significant
unanticipated safety finding or data in the aggregate from an in vitro,
animal, epidemiological, or clinical study, whether or not conducted
under an IND, that suggests a significant human risk, such as reports
of mutagenicity, teratogenicity, or carcinogenicity, or reports of a
lack of efficacy with a drug or biological product used in treating a
life-threatening or serious disease. In addition, under proposed Sec.
312.32(c)(2), a telephone or facsimile transmission safety report must
be submitted within 7 calendar days to FDA for any unexpected fatal or
life-threatening SADR.
Proposed Sec. 320.31(d)(3) would require that these safety reports
be transmitted to all participating investigators and the appropriate
FDA division in the Center for Drug Evaluation and Research. Thus,
safety reports for the reference listed drug would be sent to the new
drug review division responsible for that drug; safety reports for the
investigational drug product would be sent to the Director, Division of
Bioequivalence, Office of Generic Drugs. The proposed rule would also
require that each written notification bear prominent identification of
its contents, i.e., ``Bioavailability/Bioequivalence Safety Report.''
Each report should clearly identify the sponsor of the bioavailability
or bioequivalence study and the contract research organization, if
applicable. In each written Bioavailability/Bioequivalence Safety
Report, the sponsor would be required
[[Page 12449]]
to identify all safety reports previously filed for the bioavailability
or bioequivalence study concerning a similar SADR and to analyze the
SADR in light of previous similar reports, as required under proposed
Sec. 312.32(c)(1)(i) for IND safety reports.
An unexpected adverse drug experience is currently defined, under
Sec. 312.32(a), as:
Any adverse drug experience, the specificity or severity of
which is not consistent with the current investigator brochure; or,
if an investigator brochure is not required or available, the
specificity or severity of which is not consistent with the risk
information described in the general investigational plan or
elsewhere in the current application, as amended. * * *
For reporting purposes under proposed Sec. 320.31(d), an
unexpected SADR would be any SADR, the specificity or severity of which
is not consistent with the U.S. labeling for the reference listed drug.
FDA is proposing use of the U.S. labeling for the reference listed drug
for this purpose because studies that are not subject to an IND are
unlikely to have an investigator brochure for use as a reference
document.
Under proposed Sec. 312.32(c)(4), a sponsor of a clinical study
under an IND for a drug marketed in the United States is only required
to submit IND safety reports to FDA (review division that has
responsibility for the IND) for SADRs that occur during the clinical
study itself, whether from domestic or foreign study sites of the IND.
Proposed Sec. 312.32(c)(4) would apply to human bioavailability and
bioequivalence studies that are the subject of proposed Sec.
320.31(d). In these cases, the reference listed drug would be the
marketed drug and persons conducting human bioequivalence and
bioavailability studies that are not subject to an IND would only be
required to submit safety reports to FDA from their studies.
III.L. Proposed Implementation Scheme
FDA proposes that any final rule that may be issued regarding the
proposal to require that SADRs in individual case safety reports be
coded using MedDRA become effective 1 year after its date of
publication in the Federal Register. FDA proposes that any final rule
that may be issued based on all other proposals become effective 180
days after its date of publication in the Federal Register.
IV. Environmental Impact
The agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
V. Analysis of Impacts
V.A. Background and Summary
FDA has examined the impacts of the proposed rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Under the Regulatory
Flexibility Act, if a rule has a significant impact on a substantial
number of small entities, an agency must analyze regulatory options
that would minimize any significant impact of the rule on small
entities. Title II of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written assessment of anticipated costs and
benefits before proposing any rule that may result in an expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100 million in any one year (adjusted annually for
inflation). Section 205 of the Unfunded Mandates Reform Act also
requires that the agency identify and consider a reasonable number of
regulatory alternatives and from those alternatives select the least
costly, most cost-effective, or least burdensome alternative that
achieves the objective of the rule.
The following analysis, in conjunction with the remainder of this
document, demonstrates that this proposed rule is consistent with the
regulatory philosophy and principles identified in Executive Order
12866 and in the other two statutes. The proposed rule would amend
current safety reporting requirements for human drug and biological
products. Based on the analysis below, as summarized in table 11, FDA
projects that the annual benefits would exceed the costs if this
proposed rule resulted in a 2 percent reduction in hospital-related
SADRs. The agency believes that a reduction in hospital related SADRs
of at least 2 percent is a reasonable and likely outcome of this rule.
The agency has determined that the proposed rule is an economically
significant rule as described in the Executive Order. As required by
the Regulatory Flexibility Act, the agency's Initial Regulatory
Flexibility Analysis is included in this section. Because the rule may
impose a mandate on the private sector that will result in a 1-year
expenditure of $110 million or more (the current inflation adjusted
threshold), FDA has conducted a cost-benefit analysis according to the
Unfunded Mandates Reform Act. The relationship of this proposed rule
with other agency rulemaking is described in the background section
(e.g., reproposal of postmarketing periodic safety reporting
requirements) (see section I of this document).
The proposed rule covers a small part of a broader based set of
international initiatives (ICH and CIOMS) that, taken collectively,
have the potential to generate substantial benefits, savings, and
efficiencies for consumers, manufacturers, and regulators. The full
benefits of this proposed rule will accrue when international
regulatory inconsistencies are addressed, safety reporting submission
requirements are harmonized internationally, and electronic information
exchange is uniform and compatible for the major participants involved
in monitoring drug safety. A primary objective of the proposed rule is
the harmonization of FDA's safety reporting requirements with
international initiatives. The proposed rule would also improve the
quality of information contained in postmarketing individual case
safety reports for human drug and biological products. By providing
more complete information for individual case safety reports, the
revised reports would enhance the ability of the drug and biologics
manufacturers and the agency to identify, monitor, and communicate the
risks and benefits of marketed drug and biological products. Monitoring
these risks and benefits is especially critical for newly approved
products introduced to large and diverse patient populations.
Specifically, the proposed rule would clarify and codify the
agency's expectations for timely acquisition, evaluation, and
submission of relevant safety information for marketed human drug and
biological products. The proposed rule would expand postmarketing
expedited safety reporting to include unexpected SADRs that cannot be
classified as either serious or nonserious, information that is
sufficient to consider changes in product administration, certain
medically significant SADRs, and actual and potential medication errors
as specified in the proposal. The proposed rule would require that each
SADR in postmarketing individual case safety reports be coded using a
single medical
[[Page 12450]]
dictionary, MedDRA. The proposed rule would also require applicants to
conduct a more thorough review and analysis of the safety profile of
marketed drug and biological products. Finally, the proposed rule would
codify current best practices in postmarketing safety reporting.
The proposed rule would also amend FDA's regulation on
postmarketing annual reports for human drugs and licensed biological
products to revoke the requirement for submission of safety-related
information. The agency would also require the submission of expedited
safety reports for certain bioavailability and bioequivalence studies
that are exempt from submission of an IND.
The summary of the costs and benefits of this proposed rule are
presented in table 11. The total one-time costs of $144.2 million are
primarily for adopting MedDRA and include planning for implementation
of the MedDRA requirements, purchasing materials, and converting
existing systems to the new dictionary. Firms would also incur annual
operating costs of about $106.6 million for complying with the revised
safety reporting and recordkeeping requirements and $28.5 million for
maintaining the new MedDRA system. Total annualized costs are $155.6
million (assuming a 10-year regulatory period and a 7 percent discount
rate). A 10-year regulatory period for annualizing the costs and
benefits of this proposed rule was selected as a reasonable time frame
to adjust for investments, returns and savings given the potential for
unforseen advances in both medical and information technology. In
addition, by the fourth year savings and costs remain constant.
The expected health benefits of the rule would result from the
improved timeliness and quality of the safety reports and analyses.
Submission of more complete safety information would reduce the number
and duration of hospitalizations due to SADRs. If the proposed rule
reduced the incidence of SADR-related hospitalizations by 2 percent,
these annual savings could be $368.5 million (see table 11). A 1
percent reduction in hospital related events would save $184 million
annually; a 3 percent reduction would save $553 million annually. In
addition, industry will experience economic benefits due to the more
efficient allocation of resources permitted by the international
harmonization of the safety reporting requirements. The annualized
present value of these savings is $28.5 million assuming a 7 percent
discount over 10 years (see table 11). The agency believes this
represents only a partial estimate of future industry savings.
Table 11.--Summary of the Costs and Benefits
[$ million]
------------------------------------------------------------------------
Benefits assuming a 2 percent reduction in
hospital related SADRs Annual
------------------------------------------------------------------------
Reducing hospital costs........................ 368.5
More efficient use of resources................ \1\ 28.5
------------------------
Total benefits........................... 397.0
\1\ This is the annualized present value of the estimated savings
assuming a 7 percent discount over 10 years.
------------------------------------------------------------------------
Costs One-Time Annual Annualized
------------------------------------------------------------------------
Safety Reporting and
Recordkeeping:
Expedited reports (Except ........... 29.0 29.0
medication errors)..........
Expedited reports--medication ........... 68.0 68.0
errors......................
Periodic/other reports....... ........... 9.6 9.6
Implementing MedDRA.............. 144.2 28.5 49.0
--------------
Total.................... 144.2 135.1 155.6
------------------------------------------------------------------------
V.B. Market Failure
The host of international requirements and procedures that
currently govern safety reporting for drugs and biologics creates
substantial economic inefficiencies for firms. Manufacturers of drug
and biological products operating in global markets must meet the
regulatory safety reporting requirements of each country in which the
product is marketed. In many cases, these safety reporting
requirements, in particular submission timeframes for SADR reports,
vary substantially among countries. Thus, drug and biologics
manufacturers must devote considerable resources to reformatting the
data and information pertaining to each SADR according to specific
national requirements. Also, because the timing of report submissions
is typically determined by product approval dates for each country,
manufacturers must submit reports to different countries at different
intervals. Such activities impose substantial costs on both industry
and regulatory authorities. Moreover, product safety can be compromised
due to the difficulty of analyzing SADR reports based on the
inconsistent use of terms derived from multiple dictionaries.
Despite the general recognition that manufacturers could realize
substantial gains if safety reporting and terminologies were
standardized globally, companies currently have limited incentives to
invest capital and resources in standardized reporting systems (e.g.,
MedDRA) unless the standards are required by regulation. This shortfall
in industry incentives occurs because the economic gains of
harmonization cannot be attained by individual firms acting alone.
Although most regulatory authorities have agreed in principal to
implement international standardized reporting procedures, formal
procedures have not yet been established. A few companies have
voluntarily invested in the standardized process, but in the absence of
global standards, these firms are uncertain of potential gains. FDA
believes that the proposed rule is a necessary step toward achieving
the desired international standardization and its corresponding
economic and health benefits.
Industry would benefit from FDA action to reduce uncertainties
associated with investments in harmonization and from the ability to
more efficiently allocate resources associated with safety reporting.
Society would benefit from the improved quality of adverse event
information that is a critical component to reducing health care costs
associated with avoidable SADRs. More timely and
[[Page 12451]]
improved information on SADRs is needed to ensure the safe use of
products and to monitor early warnings and unexpected risks associated
with drugs, drug-drug interactions, drug-food interactions, and risks
to certain patient populations.
V.C. Benefits
The benefits of the proposed rule would result both from the public
health gains attributable to the improved scope, uniformity, and
quality of information and analyses submitted in safety reports and the
economic savings attributable to the more efficient use of industry and
regulatory resources.
This proposed rule would require improved factual and analytic data
underlying safety reporting and analysis, provide for more timely
safety information for certain serious SADRs, and would require a
common medical dictionary, MedDRA.
The timely identification of SADRs is critical to managing risk
information and to the safe prescribing and use of new drugs. Accurate
and timely risk information is especially significant in the early
months after product launch to develop appropriate prescribing and use
behaviors as health care practitioners and consumers are learning about
the product safety and use. Newly approved product use can quickly grow
from a few thousand patients (the population in clinical trials) to
many thousands or millions. Rare but serious SADRs are detected only
after exposure to very large patient populations. Forty percent of SADR
reports are for drugs approved within the last 3 years. Compounding
this need for timely serious SADR information, U.S. patients are
increasingly the first in the world to have access to new medications
(49 percent of new drugs were first approved in the United States
between 1996 and 1998, compared with 31 percent in 1991-1995).
More timely and improved factual information would also enhance the
identification of other important factors associated with the risks of
SADRs. These factors include subpopulations that may differ from
clinical trial participants, patients taking multiple medications or
medications that require therapeutic monitoring, and patients with
concurrent comorbidities.
This rule would require affected entities to complete either a
minimum or full set of data in safety reports, reflecting levels of
risk. That is, more detail is required for higher risk events and
reduced reporting for lower risk events. This rule would also require
the use of MedDRA, a medical dictionary developed by the ICH, in coding
SADR terms. MedDRA will provide a uniform, consistent and specific
presentation of medical terms. By eliminating the use of multiple
dictionaries, MedDRA would facilitate the retrieval, presentation, and
summarization of SADR data and enhance the global communication and
acceptance of safety information and reports. The use of a single
dictionary will substantially upgrade the quality of safety analysis by
incorporating uniformity of terms. MedDRA will aid in more expeditious
and broader international drug use comparisons within a class, and
prescribing and use decisions. Providing more complete information and
more timely safety assessments would enhance the ability of the
manufacturers to more quickly identify, monitor, and communicate the
potential risks and benefits of marketed drugs and biologics.
It is well recognized that drug safety information is a critical
element in the risk management of marketed drugs and biologics. In
addition, the medical literature provides substantial documentation of
avoidable hospitalizations associated with SADRs. Improving the quality
and timeliness of safety information and accelerating the communication
of risk information will enable health care practitioners and consumers
to take appropriate corrective actions (in the case of medication
errors) and to make more informed decisions about treatments. Moreover,
the management of risk information is an essential component of risk-
based decisions that determine the continued marketing or withdrawal of
effective products with newly identified serious SADRs. We discuss
benefits more fully below and show that a small reduction in the number
of hospitalizations due to SADRs (as low as 0.85 percent), due to
improved prescribing and use decisions, would result in the annual
benefits outweighing the total costs.
V.C.1. Expanded Safety Information
New drug approval decisions are based on safety and testing
information derived from clinical trials that typically include several
thousands of patients. However, the number of individuals tested in
preapproval trials is not sufficiently large to reliably detect rare,
serious SADRs. Patient exposure can quickly grow from thousands to
millions after product launch. Thus, especially in the first few years
after product launch, postmarketing surveillance is a critical
component of the overall continuing review and assessment of drug
safety (Ref. 1). Recent studies have identified common factors
associated with increased risks of SADRs. These factors include
subpopulations who differ from the clinical trial participants, e.g.,
the elderly, patients taking multiple medications or medications that
require therapeutic monitoring, and patients with concurrent
comorbidities (Refs. 2 through 5). The proposed rule would require
companies to collect proactively more complete safety information,
improving the factual and analytical data underlying the safety
analyses. This expanded risk information would enable health care
practitioners and consumers to take appropriate corrective actions (in
cases of avoidable medication errors) and to make more informed
decisions about treatments.
V.C.2. Improved Uniformity and Quality of Safety Information
For years, numerous health care organizations, teaching hospitals,
health care professionals, and educators have recognized the importance
to public health of monitoring SADRs. Substantial evidence demonstrates
that effective monitoring and analyzing of SADRs facilitate the
identification of trends and warning signals that result in improved
medication use and patient care (Refs. 6 through 10). Yet, the current
drug and biologics safety reporting system, encompassing raw material
suppliers, manufacturers, health care providers, and consumers, is
fragmented with respect to its oversight and lacks common reporting
procedures and tools for evaluating SADRs. For example, FDA oversees
mandatory safety reporting by manufacturers of drug and biological
products and voluntary reporting from health care providers and
consumers. Health care facilities, on the other hand, may be subject to
safety reporting oversight by individual state regulatory programs,
although not all states have oversight systems. The Joint Commission on
Accreditation of Health Care Organizations (JCAHO), which accredits
health care facilities, has had standards for establishing SADR
reporting systems for hospitalized patients for many years. Hospitals
may establish their own systems independently and almost all conform to
the JCAHO standards (Ref. 11). Despite growing evidence that avoidable
SADRs and serious SADRs are important public health problems and
widespread acknowledgment that monitoring SADRs provides public health
benefits, FDA continues to receive reports of only a small percentage
of the serious and avoidable SADRs that occur in health care facilities
(Ref. 12). This proposed rule would improve safety reporting by drug
[[Page 12452]]
and biologics manufacturers, which may serve to provide a national
framework for improved data collection and analysis of safety reports
from a variety of sources.
The proposed rule would also require the use of MedDRA, a single,
medical terminology developed by ICH that can be used for the coding of
SADR terms. MedDRA is a broad-based dictionary, developed for
international use, that combines both SADR and morbidity terminology to
provide a uniform, consistent, and specific presentation of medical
terms. By eliminating the use of multiple dictionaries, MedDRA would
facilitate the retrieval, presentation, and summarization of SADR data
and enhance the global communication and acceptance of safety
information and reports. In addition, the use of a single comprehensive
medical dictionary by drug safety reporters and reviewers would
substantially upgrade the quality of safety analysis by incorporating
uniformity of terms. Standardizing the terms and improving the quality
of the roughly 250,000 safety reports submitted annually to FDA would
lead to better and more timely safety assessments and to improved
communication of risk information. The widespread use and acceptance of
standardized SADR information by regulators would ultimately enhance
drug comparisons within a class and drug prescribing and use decisions.
V.C.3. Potential Savings From Reduced SADR-Related Hospitalizations
Improved timeliness and analysis of SADR data would lead to a
better understanding and a more rapid communication of the risks of
SADRs. By providing such improvements, the proposed rule would reduce
the incidence of SADRs. An agency estimate of the potential economic
benefits of the rule is presented below and reflects the value of the
expected hospital cost savings and the avoided lost wages that might
result from reduced numbers of SADRs.
V.C.3.a. Reduced rate of SADR-related hospitalizations. Numerous
studies have documented drug-related hospitalizations (60 FR 44182 at
44232, August 24, 1995). A comprehensive review of 36 articles focused
specifically on SADRs as the primary cause of hospitalization. This
study counted the number of reactions attributed to unintended
consequences of drug therapy, excluding admissions due to overdose,
intentional poisoning, attempted suicides, drug abuse, or intoxication.
The percentage of hospitalizations due to SADRs ranged from 0.2 to 22
percent, with a mean of 5.5 percent. FDA adjusted this figure to 5
percent to remove over-the-counter drugs (Ref. 13). Based on 27.8
million hospital admissions reported in 1997, excluding obstetrical
admissions (Ref. 14), the agency estimates the annual number of SADR-
related hospitalizations at about 1.4 million (5 percent x 27.8
million). Absent available data, the agency assumes the costs
associated with SADR-related hospitalizations are similar to the
average cost of a hospital stay, but requests comments and supporting
data on this assumption. Therefore, applying an estimated cost of
$9,177 for an average hospital stay (Ref. 15) implies total annual
SADR-related hospital admission costs of about $12 billion ($9,177 x
1.4 million).
If the improved reporting and analyses of SADRs led to the
avoidance of only 2 percent of these hospitalizations, the economic
savings would amount to $252.2 million annually.
V.C.3.b. Reduced rate of in-hospital SADRs. Bates et al. conducted
a random sample of nonobstetrical admissions to two large tertiary care
hospitals in Massachusetts over a 6-month period (Ref. 16). His
prospective investigation of SADRs included interviews with medical
staff and daily reviews of all medical charts. He estimated the
incidence of all SADRs, including medical errors, at 6.5 percent with
an average increase in hospital costs of $2,595 per case. Extrapolating
these findings, FDA estimated the annual number of in-hospital SADRs at
1.8 million and the total additional hospital cost at $4.7 billion
annually. If this proposed rule led to a 2 percent reduction, the
economic benefits would be $93.6 million annually.
In a comprehensive review of studies that estimated the incidence
of SADRs and/or the magnitude of hospital costs due to SADRs, the U.S.
General Accounting Office cited substantial variation in estimates
(Ref. 17). These differences may be due to inconsistent definitions of
SADRs, different study methodologies (active prospective investigation
versus retrospective review of patient records), representativeness of
the samples, and particular methods used to extrapolate study findings
to a national level. For example, Lazarou et al. and Classen et al.
estimated the incidence of serious SADRs using the WHO definition of
SADR and excluding other factors such as poisonings, intentional
overdoses, and therapeutic failure (Refs. 18 and 19). These two studies
had findings similar to Bates et al. On the other hand, Thomas et al.
reviewed randomly selected hospital discharge records in two states and
found a lower incidence of ``drug injury''. However, he used a
particularly restrictive definition of SADR, one that resulted in
prolonged hospitalization or disability at discharge (Ref. 20). Despite
the uncertainties of estimating the incidence and cost of hospital
related SADRs, FDA believes that the $4.7 billion estimate for in-
hospital SADRs derived above provides a plausible estimate.
V.C.3.c. Indirect benefits of reducing the hospital costs of SADRs.
The indirect benefits of reduced drug-related illnesses are derived
from estimates of the costs of missed work or reduced productivity.
Several studies on SADR-related hospital admissions stratified findings
by patient age. Roughly 58 percent of SADR admissions were for patients
aged 20 to 59. The remaining 42 percent were for patients under 20
years (less than 10 percent) and over 59 years old (Refs. 21 through
23). To calculate productivity losses, the agency assumed 56 hours per
admission for patients aged 20 to 59 years (40 hours of lost work per
hospitalization plus 16 additional hours for recovery and followup
doctor visits) \2\ and 14 hours for the remaining groups (to account
for lost volunteer time or for time away from work for the care givers
of dependent patients). The wage rates used are the average hourly
production workers earnings of $15.96 for patients aged 20 to 59
($12.28 plus 30 percent for benefits), and $12.28 for the remaining
patients or their care givers (Ref. 14). The estimated value of this
lost productivity is $812 million.
---------------------------------------------------------------------------
\2\ The agency used 40 hours to estimate work productivity
losses. This estimate is consistent with current hospital discharge
data and with the length of stay for drug-related hospitalizations
(Ref. 21).
---------------------------------------------------------------------------
To estimate similar indirect benefits for in-hospital SADRs, the
agency assumed the same distribution of patient ages. Related
productivity losses are assumed to be 16 and 6 additional hours
respectively, for patients aged 20 to 59, and for the remaining groups.
The estimated value of this lost productivity is $323 million.
A 2 percent reduction in costs of SADR-related hospitalizations and
prolonged hospitalizations would yield indirect benefit savings of
$22.7 million. These estimates may somewhat overstate the value of lost
productivity for the 20 to 59 age group because all patients are
assumed to be employed. On the other hand, indirect benefits for the
remaining age groups are understated because many of these patients are
in the workforce and for those who are not, data are inadequate to
measure their contribution to society.
[[Page 12453]]
V.C.3.d. Sum of SADR-related costs. Summing these estimates, the
total annual direct and indirect benefits of reducing avoidable SADR-
related hospitalizations and longer hospital stays by 2 percent would
lead to economic benefits of $368.5 million per year. Varying the
assumption of a 2 percent reduction in hospital costs with a 1, 3, and
5 percent reduction, would yield annual benefits of $184 million, $553
million, and $921 million, respectively. A reduction of only 0.85
percent in the hospital costs associated with SADRs would be needed to
outweigh the annualized industry costs of $155 million. Furthermore,
under any of these scenarios, the total SADR-related hospital savings
would outweigh the costs of this rule. With a 2 percent or greater
reduction, the annual benefits would outweigh the costs beginning in
the first year. Nonetheless, the agency seeks comment on our estimates
of expected reductions in hospital-related costs, including the
potential for reducing the incidence and length of stay of hospital-
related SADRs.
In contrast to focusing only on hospital costs of SADRs, one study
estimated the direct costs of drug-related morbidity and mortality for
the ambulatory population at $76.6 billion annually, with the largest
component $47.4 billion for drug-related hospitalizations (Ref. 24).
The remaining cost components included: $14.4 billion for long-term
care, $7.5 billion for physician visits, $5.3 billion for emergency
department visits, and $1.9 billion for additional prescriptions.
Again, assuming a 2 percent reduction, savings are approximately $948
million annually.
V.C.4. Cost Savings and More Efficient Use of Resources
The proposed rule is intended to complement and formalize
international efforts by industry representatives and major
international regulatory bodies to achieve a more uniform and global
approach to safety reporting. The content, analyses, and timing of SADR
report submissions would closely align with international initiatives
and recommendations. To the extent that U.S. requirements become
harmonized within a global context, companies that compete
internationally would benefit from this proposed rule. Multiple
international due dates for safety report submissions and reformatting
of the same information to meet different regulatory requirements
represent opportunity costs that could be allocated elsewhere.
Companies would accrue savings through a substantial reduction or
elimination of the reformatting of postmarketing periodic safety report
information to meet varying international requirements and by
synchronizing report frequencies and due dates internationally. Thus,
as the international community harmonizes, companies would achieve
efficiencies, eliminate duplicative processes, and reallocate those
resources more efficiently.
The agency contracted with the Eastern Research Group, Inc. (ERG),
an economics consulting firm, to estimate the potential benefits that
would accrue to drug and biologics companies in the long run, as
international harmonization efforts align and generate cost savings.
These savings include more efficient regulatory safety reporting, more
efficient sharing of safety information, and a common medical
terminology. ERG estimated the following specific categories of
benefits: More efficient management of drug safety data, more efficient
intercompany agreements, and international harmonization of the
postmarketing periodic safety report format (i.e., use of PSUR format).
ERG applied estimates of savings by category and firm size to the
number of affected firms within each affected industry. The
methodologies and procedures for deriving these estimates are fully
presented in ERG's final report (Ref. 25).
V.C.4.a. Savings related to maintaining and building data bases of
SADRs and intercompany transfers of drug safety data.
Drug and biologics companies maintain safety data bases of all
domestic and foreign SADRs involving their products. The management of
these data bases can be quite complex depending on the individual
circumstances of manufacturing and marketing. Companies may have
foreign subsidiaries, domestic and foreign manufacturing sites, and
varied licensing agreements with other companies for marketing
products. Foreign subsidiaries and licensees generally submit SADR
reports to U.S. companies by fax. U.S. companies then reenter the
reports into their own databases. Use of standardized safety report
formats and content internationally will lend itself to electronic
transmission of safety information. In these cases, intercompany and
intracompany sharing of safety information will be substantially
facilitated. ERG estimated these benefits at $3.1 million annually.
V.C.4.b. Savings related to greater ease in entering into
intercompany agreements. As requirements for drug and biologics safety
reporting become harmonized, drug and biologics companies will find it
easier to coordinate safety reporting efforts when entering into
various agreements with other manufacturers or sales organizations. In
the current organizational structure of the industry, companies are
frequently negotiating licensing agreements, mergers, joint ventures,
and other contractual matters with other companies. For these
arrangements, companies must develop, share, and merge drug safety
reports from around the world. At present, negotiation of drug safety
data sharing is often complicated by reporting formats and requirements
that differ between regions. ERG estimated the potential savings that
would accrue from simplified negotiation of licensing agreements due to
standardized reporting formats and requirements at $4.2 million
annually.
V.C.4.c. Savings related to eventual international harmonization to
the PSUR format. ERG estimated the potential savings to industry of
preparing a single PSUR that would be accepted by regulatory
authorities internationally on the same date. Currently, companies are
faced with many inconsistent requirements and must meet the individual
requirements and timeframes of each country. ERG estimated these
savings at $24.3 million annually.
V.C.4.d. Potential savings in clinical trial management. Some
companies noted that they would convert medical terms from clinical
trials to MedDRA whether or not it was required by FDA. Assuming that
this transition will gradually apply to future clinical trials, a
single medical terminology, internationally developed, accepted, and
applied, would allow companies to more easily transmit, integrate, and
analyze clinical trial data from global sites. Subsequent reductions in
time and resources would contribute to reduced costs during drug
development. Based on input from industry, ERG developed a narrow focus
of savings associated with clinical trial data management valued at
$7.2 million annually.
V.C.4.e. Leveraging specialized knowledge. This proposed rule also
provides the groundwork for establishing focused centers of technical
information on drug safety. Global companies and regulatory agencies
will have the opportunity to create economies of expertise by
concentrating specialized knowledge of global drug use and product
risks and benefits in centralized locations. To the extent that safety
information is better managed, understood, and shared with interested
parties, substantial benefits will accrue. Neither ERG nor FDA could
quantify these benefits.
[[Page 12454]]
V.C.4.f. Total benefits. ERG estimated the total industry savings
from more efficient use of resources to be $38.8 million annually. This
estimate, however, accounts for only a modest portion of the potential
benefits of the broader set of initiatives that enhance electronic
submissions and global harmonization of safety reporting. Table 12
summarizes the estimated annual benefits of this proposed rule. The
agency recognizes, however, that the industry savings component will
not be fully realized until safety reporting requirements are
harmonized internationally. The agency believes that these benefits
could be achieved in a relatively short period after this rule becomes
final. The agency is ready to accept PSUR formats and the use of MedDRA
for coding of individual case safety reports at the present time (see
draft guidance of 2001). In addition, the European Union and Japan
currently accept PSUR formats and the use of MedDRA.
Table 12.--Summary of the Annual Benefits
------------------------------------------------------------------------
$ Million
Savings category (annually)
------------------------------------------------------------------------
Public health benefits for a 2 percent reduction in SADR-
related hospital costs:
Reduced SADR-related hospital admissions............ 252.2
Reduced in-hospital SADRs........................... 93.6
Indirect benefits from reduced hospitalizations..... 22.7
---------------
Total hospital-related savings.................. 368.5
Expanded safety information on product approvals........ (\2\)
Improved risk communication and product selection....... (\2\)
Future Industry Savings:
Efficiencies in database maintenance................ 3.1
Facilitation of PSUR submissions.................... 24.3
Facilitation of intercompany negotiations........... 4.2
Clinical trial management........................... 7.2
---------------
Total Industry Savings.......................... \1\ 38.8
Economies of Managing Drug Expertise.................... (\2\)
------------------------------------------------------------------------
\1\ Assuming \1/3\ of these savings begin in year 2 ($11.6 million), \2/
3\ in year 3 ($23.3 million), and $38.8 million in years 4 through 10,
the annualized present value is $28.5 million, discounted at 7 percent
over 10 years. The 10-year time horizon allows a reasonable projection
of current information given the unforseen progress and impacts of
medical and computer technology.
\2\ Not estimated.
V.D. Costs of Compliance
This section presents the estimated compliance costs of the
proposed requirements. As explained in the following paragraphs, the
proposed rule clarifies and expands existing requirements for
submitting premarketing expedited reports, postmarketing expedited
initial and followup reports, and postmarketing periodic safety reports
to FDA. Drug and biologics manufacturers would be required to use
direct verbal contact to collect information sufficient to determine
the nature, severity, and outcome of SADRs and to evaluate and describe
the safety profile or changes in the safety profile of marketed drugs.
The proposed regulation also specifies criteria for reporting
individual case safety reports and designates data elements that must
be completed as a condition for initial and followup reporting. Each
SADR in a postmarketing individual case safety report for human drugs
and biologics must be coded using the appropriate ``preferred term'' in
the latest version of MedDRA. The proposal also requires a physician to
review the postmarketing expedited and periodic safety reports. The
proposed rule would codify the data elements, analyses, and report
format of the required postmarketing periodic safety report submissions
and harmonize many of these requirements with ICH initiatives.
Applicants holding an approved marketing application would be required
to submit semiannual individual case safety reports and more detailed
postmarketing periodic safety reports that contain cumulative and
comprehensive data, analyses, tabulations, summaries, and other
information. The proposed rule also includes revisions to IND safety
reporting requirements and bioavailability and bioequivalence study
requirements.
V.D.1. Costs of New Recordkeeping and Reporting Requirements
V.D.1.a. Number of reports. In 1998, manufacturers and applicants
of human drug and biological products submitted approximately 230,000
individual case safety reports of SADRs to FDA. Data from about 130,000
of these individual case safety reports in the agency's Adverse Event
Reporting System (AERS) were analyzed to estimate the annual number of
future SADR reports expected to be included as revised expedited and
new semiannual submissions. However, not enough data exists to predict
the number of new expedited reports the agency may expect each year.
For this analysis, estimates of new expedited reports for human drugs
and biological products were based on counts of similar reports
received by the agency during 1998. The estimated number of expedited
reports for blood products is derived from published studies (Refs. 26
and 27).
The agency does not know how many TPSRs, and PSURs and IPSRs would
be submitted annually, because applicants with pre-1998 drug approvals
can submit either format. In addition, applicants with ANDAs approved
on or after January 1, 1998, may choose to submit a TPSR rather than a
PSUR or IPSR if the innovator NDA was approved before January 1, 1998.
Despite this uncertainty, this analysis estimates the number of new
filings of postmarketing periodic safety reports based on average
counts of pre- and post-1998 drug approvals.
The number of affected reports for prescription drugs marketed for
human use without an approved application, IND safety reports,
bioavailability/bioequivalence safety reports, and other reports were
projected from counts of similar reports received by FDA. Estimates for
the total number of reports affected by the proposed rule are shown in
table 13.
[[Page 12455]]
Table 13.--Number of Affected Reports by Regulatory Status
--------------------------------------------------------------------------------------------------------------------------------------------------------
Drugs
marketed Bioavailability
Type of report without an NDA/AND Biologics Blood IND and Total
approved products bioequivalence
application
--------------------------------------------------------------------------------------------------------------------------------------------------------
Expedited:
Serious and unexpected SADRs.......................... 350 50,000 3,000 0 0 0 53,350
Always expedited report............................... 50 1,500 100 0 0 0 1,650
Unexpected SADR with unknown outcome.................. 46 912 25 0 0 0 983
Information sufficient to consider product 5 300 4 0 0 0 309
administration changes...............................
Medication errors..................................... 1,000 100,000 10,000 0 0 0 111,000
30-day followup....................................... 340 43,000 3,000 0 0 0 46,340
Serious SARs--blood products.......................... 0 0 0 7,000 0 0 7,000
IND Safety
Information sufficient to consider product 0 0 0 0 600 0 600
administration changes...............................
Bioavailability/bioequivalence safety report.......... 0 0 0 0 0 200 200
Periodic:
TPSR.................................................. 0 1,400 35 0 0 0 1,435
PSUR.................................................. 0 2,500 35 0 0 0 2,535
ISUR.................................................. 0 350 3 0 0 0 353
Individual case safety reports--semiannual submission. 0 4,726 480 0 0 0 5,206
Other:
Reports to manufacturer or applicant.................. 4 4,548 100 0 0 0 4,652
Submit safety records to FDA upon request............. 2 15 4 0 0 0 21
Annual reports........................................ 0 2,363 69 0 0 0 2,432
--------------------------------------------------------------------------------------------------------------------------------------------------------
V.D.1.b. New time burden. The proposed rule requires manufacturers
and applicants to use active query to acquire the outcome (i.e.,
whether an SADR is serious or nonserious) and required data set for any
spontaneously reported individual case safety report that they receive
pertaining to their marketed human drug or biological product.
Furthermore, the proposed rule requires that every individual case
safety report submitted to the agency be assigned an appropriate MedDRA
code. Although individual case safety reports are currently submitted
for most SADRs, depending on the type of SADR, the proposed rule may
impose an additional burden on health professional personnel if active
query is not already used routinely by a manufacturer or applicant.
Regulatory affairs personnel working with the health professional may
spend additional time assigning the MedDRA code and documenting the
active query. The agency seeks comment on the reasonableness of the
estimates of the time burden and the type of employee anticipated to
fulfill the new requirements detailed in the following paragraphs.
V.D.1.b.i. Expedited reports. The nature of the SADR (i.e., whether
the SADR is expected or unexpected) and whether the outcome is known
(i.e., SADR is serious or nonserious) will determine the data needed
and when and if an individual case safety report should be submitted to
FDA. At present, individual case safety reports of SADRs that are both
serious and unexpected are submitted as 15-day alert reports.
The proposed rule adds conditions for determining expedited reports
(e.g., minimum data set required). In addition, it specifies that an
expedited report for an individual case safety report must contain a
full data set, including MedDRA codes, and that supporting
documentation such as hospital discharge records, autopsy reports, or
death certificates must be submitted, if available. This aspect of the
proposal may impose a new burden estimated at 1 hour each for health
professionals and regulatory affairs personnel (see table 14).
The proposal defines new criteria for determining when expedited
reports should be submitted. Certain medically significant SADRs as
listed in the proposal, whether unexpected or expected, and all
domestic reports of actual and potential medication errors would be
required to be submitted to FDA in an expedited manner. Furthermore,
when the outcome of a spontaneous, unexpected SADR cannot be
determined, an expedited report must be submitted to the agency. In
these circumstances, manufacturers and applicants are assumed to
allocate from 16 to 24 hours more time for health professionals and
regulatory affairs and clerical personnel to prepare and submit these
new reports. Table 14 lists the additional hours each type of employee
may spend complying with these new requirements.
In addition to individual case safety reports, manufacturers and
applicants may receive safety information from domestic or foreign
studies that is judged to be sufficient to consider a change in product
administration. In this case, the proposed rule requires that a
narrative report of these findings be submitted to the agency as an
expedited report. Preparing and submitting this new report may take up
to 8 hours of time from health professionals and regulatory affairs and
clerical personnel as shown in table 14.
V.D.1.b.ii. Followup reports. The proposed rule establishes
timeframes and data elements required for submission of expedited
individual case safety reports. If required data elements were not
submitted with the initial filing of an expedited report of a serious
SADR or a medication error report, then the applicant must continue to
use active query to obtain the additional information. This information
must be submitted to FDA in a followup report
[[Page 12456]]
within 30 calendar days of the previous filing. If the full data set is
still not obtainable, the 30-day followup report must include all
safety information obtained, highlighting new information and stating
the reasons for the inability to obtain complete information. The
agency estimates that 8 additional hours, as shown in table 14, are
needed for these followup reports.
Applicants must also submit any new safety information to FDA for
any other expedited or followup report within 15 days of receipt of the
new information. This provision is currently required; therefore, no
additional hours are allocated to this provision.
V.D.1.b.iii. Blood products. Collection and transfusing facilities
are currently required to investigate, prepare, and maintain written
reports of complaints of SARs arising as a result of blood collection
or transfusion. Furthermore, if a fatality occurs as a complication of
blood collection or transfusion, facilities must notify FDA as soon as
possible and follow up with a written report within 7 calendar days
after the fatality occurs. The proposed rule will require that all
written reports submitted to the agency use the individual case safety
report format. This change in reporting format is not expected to
increase the time needed to prepare and submit reports of fatalities.
In addition, the proposed rule will require that any serious nonfatal
SAR related to collection or transfusion of blood and blood components
be submitted as a expedited report within 45 calendar days. As shown in
table 14, blood facilities may spend up to 16 hours more preparing and
submitting each of these expedited reports.
V.D.1.b.iv. IND and bioavailability/bioequivalence safety reports.
Sponsors of an IND are currently required to submit written and
telephone safety reports. The proposed rule will add some conditions
for reporting and require that reportable SADRs include the minimum
data set. Sponsors of INDs will be required to submit written safety
reports to FDA and all participating investigators of: (1) Any SADR
that, based on the opinion of either the sponsor or investigator, is
both serious and unexpected and (2) any information that might
materially influence the benefit-risk assessment of an investigational
drug or that would be sufficient to consider a change in either product
administration or in the overall conduct of a clinical investigation.
The agency is also expanding the current requirement for telephone and
facsimile transmission of safety reports of unexpected death or life-
threatening SADRs to include those that meet these criteria based on
the opinion of either the sponsor or investigator. In addition, the
agency is making minor changes to align current IND safety reporting
requirements with the proposed changes to postmarketing safety
reporting.
The agency anticipates that very few investigator-initiated reports
would be submitted under the proposed rule. Because the number of new
reports (i.e., approximately 10 per year) would represent less than 0.2
percent of all individual IND safety reports submitted to the agency in
a year, no additional burden is estimated. However, up to 4 hours may
be needed for sponsors to accommodate the new requirements for written
safety reports for information sufficient to consider a change in
product administration (see table 14).
In addition, the agency would require submission of expedited
safety reports for certain bioavailability and bioequivalence studies
that are exempt from submission of an IND. The agency estimates 14
hours per report are needed to comply (see table 14).
V.D.1.b.v. Semiannual submissions of postmarketing individual case
safety reports. The current regulations require that postmarketing
individual case safety reports from domestic marketing experience for
serious expected adverse drug experiences, nonserious unexpected
adverse drug experiences, and nonserious expected adverse drug
experiences be submitted to the agency in postmarketing periodic safety
reports. Under the proposed rule, most individual case safety reports
not submitted to FDA as an expedited report would be submitted as a
separate report twice a year. All reports of actual or potential
medication errors, whether or not an SADR occurs, would be submitted as
expedited reports and not submitted semiannually. Individual case
safety reports of nonserious SADRs that are expected or listed would no
longer be submitted to the agency. Exceptions, for vaccines, would be
reports of nonserious, expected SARs and expected SARs with an unknown
outcome, which would be submitted semiannually. Nevertheless,
applicants would be expected to maintain these reports and include them
in tabular summaries provided in the postmarketing periodic safety
reports (e.g., PSURs).
Whereas the current postmarketing periodic safety reporting
regulations do not apply to foreign reports of SADRs, the proposed rule
would require that foreign individual case safety reports of serious
and expected or listed SADRS be submitted semiannually. The agency is
unable to predict how many foreign reports may be submitted. For the
purpose of this analysis, therefore, the number of nonserious and
expected or listed individual case safety reports is assumed to be
equal to the number of serious and expected or listed foreign reports,
and the overall number of individual case safety reports submitted in a
year would remain unchanged.
Although the number of individual case safety reports submitted
annually as a postmarketing periodic safety report is expected to
remain stable, the timing of these submissions may change. Reports will
be submitted less frequently (semiannually rather than quarterly) for
products that have been on the market for less than 3 years and more
frequently (semiannually rather than annually) for products that have
been on the market for more than 3 years. Furthermore, additional time
may be needed for an active query to obtain a full data set for reports
of serious and expected or listed SADRs and a minimum data set for all
SADRs. Based on reports to AERS in 1998, the agency estimates that, on
average, approximately 35 individual case safety reports may be
submitted semiannually for each drug product. Regulatory affairs
personnel and health professionals might spend up to 10 additional
hours each to obtain and process information for each semiannual
submission (see table 14).
Table 14.--Estimated New Burden for Expedited and Semiannual Reports
----------------------------------------------------------------------------------------------------------------
New burden (hours)
---------------------------------------------------------
Type of report New or revised Health Regulatory
professional affairs Clerical Total
----------------------------------------------------------------------------------------------------------------
Expedited:
Serious and unexpected SADR.. Revised............ 1 1 0 2
Always expedited report...... New................ 2 12 2 16
Unexpected SADR with unknown New................ 3 18 3 24
outcome.
[[Page 12457]]
Information sufficient to New................ 3 3 2 8
consider product
administration changes.
Medication errors............ New................ 2 12 2 16
30-day followup.............. New................ 3 4 1 8
Serious SARs--blood products. Revised............ 2 12 2 16
IND Safety:
Information sufficient to Revised............ 1 2 1 4
consider product
administration changes.
Bioavailability/ New................ 1 11 2 14
bioequivalence safety report.
Individual case safety Revised............ 10 10 0 20
reports--semiannual
submission.
----------------------------------------------------------------------------------------------------------------
V.D.1.b.vi. Postmarketing periodic safety reports (TPSR, PSUR, and
IPSR). Current agency regulations require applicants to submit
postmarketing periodic safety reports at specified intervals. Each
periodic safety report must contain a narrative summary and analysis of
adverse drug experiences received since the last periodic report. The
proposed regulation would require applicants to provide more thorough
review and analysis of the safety profile for certain drugs.
For all applications approved on or after January 1, 1998, these
reports would be in the PSUR format (with some variation) that is
currently accepted by other regulatory authorities. These applications
would be submitted semiannually for 2 years after the U.S. approval
date, annually for the next 3 years, and every 5 years thereafter. In
contrast to current regulations, postmarketing periodic safety reports
would have to contain a more comprehensive analysis of the product's
safety record. Specifically, applicants would be required to submit, as
described in chart 1, summary tabulations of SADRs (i.e., all SADR
terms and counts of occurrences) received since the last periodic
report categorized by body system or standard organ system
classification scheme.
Chart 1.--Required Summary Tabulations of SADRs for PSURs
------------------------------------------------------------------------
Source Outcome
------------------------------------------------------------------------
Spontaneous submissions from All serious and nonserious.
health care professionals.
Studies or individual patient All serious.
INDs.
Scientific literature.......... All serious; all nonserious unlisted.
Regulatory authorities......... All serious.
Other (e.g. poison control All serious.
centers, epidemiological data
bases).
------------------------------------------------------------------------
In addition, applicants would have to submit cumulative summary
tabulations for SADRs that are both serious and unlisted. Applicants
would be required to include a discussion of these data including the
medical significance or mechanism.
Applicants would be required to submit a discussion of safety
information from applicant-sponsored studies (either planned or
initiated) and published safety studies and abstracts. Furthermore,
applicants would be required to include a discussion of certain lack of
efficacy reports and important new information received after the data
lock point. In addition to analysis of individual case safety reports
and studies, applicants would be required to submit a comprehensive
analysis of other safety information specified in the proposal, such as
increased frequencies of listed SADRs, specific populations, and drug
interactions.
Applicants would also be required to provide other relevant safety
and baseline information as specified in the proposal. This information
would include worldwide marketing status, changes to the CCSI, actions
taken for safety reasons, and worldwide patient exposure. Appendices
would include additional safety information as specified in the
proposal including information related to the current (or proposed
changes) in the U.S. labeling and safe use of the product, summary
tabulations of spontaneous individual case safety reports from
individuals other than a health care professional, summary tabulations
of individual case safety reports of SADRs with unknown outcome and
medication errors, summary tabulations of SADRs from class action
lawsuits, U.S. patient exposure, assessments of lack of efficacy
reports and new information on resistance to antimicrobial drug
products. In addition, the name and telephone number of the licensed
physicians responsible for the content and medical interpretation of
the information in the PSUR and the addresses where all safety reports
and other safety related records are maintained would be included.
The proposal also requires IPSRs for approvals on or after January
1, 1998. While following a similar format as the PSUR, the IPSR is less
comprehensive than the PSUR (i.e., does not require submission of
summary tabulation information). This report would be submitted 7.5 and
12.5 years after the U.S. approval date.
Under the proposed regulation, TPSRs would be required for
applications approved before January 1, 1998. Although less
comprehensive than the PSUR, the TPSR would have to contain product
safety information, including summary tabulations and a narrative
summary and analysis of individual case safety reports, and a history
of safety-related actions taken during the
[[Page 12458]]
reporting period. The timing for these report submissions would be at
5, 7.5, 10, 12.5, and 15 years after U.S. approval of the product and
then every 5 years thereafter. Applicants would have the option to file
using the PSUR and IPSR formats.
The additional times required to complete the proposed changes to
postmarketing periodic safety report submissions are shown in table 15.
The agency estimates that the new burdens would be 16 hours for TPSRs,
40 hours for PSURs, and 30 hours for IPSRs. These times represent
estimates of the average time per report, recognizing that preparation
times for each postmarketing periodic safety reports may take as little
as a day for products with few or no SADRs or as much as several months
for other products that are more complex or associated with many SADRs.
Based on reports received by the agency, a few products account for the
majority of the reports of SADRs. For example, 1998 AERS data showed
that approximately 75 percent of the postmarketing periodic safety
reports for drug products included 10 or fewer individual case safety
reports, accounting for only about 5 percent of all of those reports
submitted with postmarketing periodic safety reports. The other 25
percent of postmarketing periodic safety reports included the remaining
95 percent of individual case safety reports submitted in 1998.
Table 15.--Estimated New Burden for Periodic Safety Reports and Other Reports
----------------------------------------------------------------------------------------------------------------
New burden (hours)
---------------------------------------------------------
Type of report New or revised Health Regulatory
professional affairs Clerical Total
----------------------------------------------------------------------------------------------------------------
Periodic:
TPSR--application approved Revised............ 3 9 4 16
before 1/1/95.
PSUR--application approved on New................ 8 24 8 40
or after 1/1/95.
IPSR--application approved on New................ 6 18 6 30
or after 1/1/95.
Other:
Reports of nonserious SADRs New................ 0 1 0 1
and certain medication
errors to manufacturer or
applicant.
Submit safety records to FDA New................ 0 4 4 8
upon request.
Annual reports............... Revised............ \1\ (3) (7.5) (3) (14)
----------------------------------------------------------------------------------------------------------------
\1\ Values in parentheses represent an estimate of the decrease in burden.
V.D.1.b.vii. Other reports. Currently, persons submitting
postmarketing safety reports may elect to submit reports of serious
adverse drug experiences to the manufacturer or applicant rather than
submitting serious unexpected adverse drug experiences directly to FDA.
The proposed rule would require submission of all safety reports (i.e.,
serious and nonserious SADRs and medication errors) to the manufacturer
or applicant within 5 calendar days of initial receipt of the
information. Contractors may need to allocate up to 1 additional hour
to prepare and submit each report of a nonserious SADR or medication
error that does not result in an SADR (see table 15).
Persons maintaining records of SADRs may be asked to submit any or
all records to FDA within 5 calendar days. The agency estimates that 21
such requests for SADR records would be made in a given year. This new
reporting requirement may take regulatory affairs and clerical
personnel up to 4 hours each to fulfill each request (see table 15).
FDA will no longer require that applicants subject to an NDA or BLA
submit certain safety related information with annual reports. This
reduction in reporting requirements will decrease the burden on these
applicants. To prepare and submit each annual report, applicants may
save an estimated 13.5 hours annually (see table 15).
V.D.1.c. Annual cost of the reporting and recordkeeping provisions.
Hourly compensation estimates for personnel implicated in the proposed
changes to safety reports are shown in table 16. The additional cost of
the proposed changes for each type of affected report and the total
annual cost of the proposed rule are summarized in table 17. However,
because the annual costs depend on the actual number and type of
reports submitted to FDA, these costs are uncertain and may fluctuate
from year to year. For example, if there are 50 percent fewer reports
than estimated, annual costs would be approximately $52.2 million
instead of $106.6 million. If the number of reports submitted is 50
percent more than shown in table 17, the annual costs would be about
$159.9 million. The agency seeks comments on the reasonableness of its
estimates of number of reports, burden hours, and costs.
Table 16.--Hourly Compensation
------------------------------------------------------------------------
Regulatory Affairs\2\
Health Practitioner\1\ \3\ Clerical \2\
------------------------------------------------------------------------
$67.31 $36.92 $17.39
------------------------------------------------------------------------
\1\ Hourly compensation derived from the annual salary range for
clinical research physicians in the pharmaceutical industry from http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://careers.yahoo.com.
Hourly compensation includes benefits equal to 40
percent of hourly wage.
\2\ U.S. Department of Labor, BLS, ``Employer Costs for Employee
Compensation, Table 12,'' March 1999.
\3\ Includes biostatisticians.
[[Page 12459]]
Table 17.--Total Annual Cost of New Reporting Burden
----------------------------------------------------------------------------------------------------------------
Number of Per report
Type of report affected cost of new Annual cost
reports burden ($ mil)
----------------------------------------------------------------------------------------------------------------
Expedited:
Serious and unexpected SADRs................................ 53,350 $104.23 $5.6
Always expedited reports........................................ 1,650 612.44 1.0
Unexpected SADR with unknown outcome........................ 983 918.65 0.9
Information sufficient to consider product administration 309 $347.46 0.1
changes....................................................
Medication errors........................................... 111,000 612.44 68.0
30-day followup............................................. 46,340 366.99 17.0
Serious SARs--blood products................................ 7,000 612.44 4.3
IND Safety:
Information sufficient to consider product administration 600 158.54 0.1
changes....................................................
Bioavailability/bioequivalence safety report................ 200 508.21 0.1
Periodic:
TPSR........................................................ 1,435 603.76 0.9
PSUR........................................................ 2,535 1,563.66 4.0
IPSR........................................................ 353 1,172.75 0.4
Individual case safety reports--semiannual submission....... 5,206 1,042.28 5.4
Other:
Reports of nonserious SADRs and certain medication errors to 4,652 36.92 0.2
manufacturer or applicant..................................
Submit safety records to FDA upon request................... 21 217.24 0.0
Annual reports.............................................. 2,432 \1\ (530.99) (1.3)
-----------------
Total Annual Cost of New Reporting Burden............... .............. .............. $106.60
----------------------------------------------------------------------------------------------------------------
\1\ Values in parentheses represent an estimate of cost savings.
V.D.2. Costs of MedDRA
FDA contracted with ERG to estimate the industry cost of using
MedDRA terms to code individual case safety reports. In the fall of
1999, ERG and FDA staff visited three drug companies and conducted
telephone interviews with several more companies and industry
consultants. The purpose of the interviews was to collect information
to assist in estimating the major cost components of implementing
MedDRA. ERG's complete report is on file with the hearing clerk (Ref.
25).
Companies were asked to describe costs incurred or projected based
on company experiences. Companies identified major cost elements that
include one-time implementation costs such as planning and coordination
of the conversion, converting existing data and information systems,
and training. Recurring costs include MedDRA subscription and
maintenance costs.
ERG applied estimates of cost by category and firm size to the
number of affected firms within each industry. Estimates of affected
drug and biologic product manufacturers are derived by applying data
from 1998 FDA Adverse Drug Event Reports and Vaccine Adverse Event
Reports to aggregate firm data from the Small Business Administration,
Census of Manufactures and the National Science Foundation. Estimates
of affected blood facilities are derived from the FDA Center for
Biologics Evaluation and Research database of licensed and/or
registered establishments, the National Blood Data Research Center and
the Census Bureau.
Limitations on ERG cost estimation include the complexities
associated with firms' abilities to separate incremental costs from
factors that substantially influence expenditures, such as integrating
operations of one or more newly merged corporations, isolating U.S.
corporate policies and operations from global corporate policies and
operations, and reaching consensus on the extent and timing of the
conversion of historical SADRs and data.
V.D.2.a. One-time costs
V.D.2.a.i. Planning and coordination. Companies will need to
allocate time to plan and coordinate the conversion of MedDRA across
their affected operations. Planning costs are affected by the extent of
decentralization of coding and pharmacovigilance work within the
corporate structure. Managers for drug and biologics firms are expected
to spend from 240 hours for very small firms to 1,400 hours for very
large firms (greater than 750 or 500 employees respectively for drug
and biologics firms) for planning and coordination. Costs per company
ranged from $10,800 to $64,500 for drug and biologics firms. In
contrast to drug and biologics firms, blood facilities have a limited
range of products, do not need to convert legacy data, and typically
operate only in the United States. Therefore, ERG judged that
compliance costs for blood facilities would be 4 to 5 percent of
equivalent-sized drug and biologics firms. Estimated costs per firm
range from $450 to $2,260 for very small and very large firms,
respectively.
V.D.2.a.ii. Development of information technology support
structure. Companies reported that information technology (IT)
personnel will need to modify existing database systems to:
[sbull] Accommodate adding a new medical dictionary,
[sbull] Allow for MedDRA's complex hierarchical structure and wider
field widths,
[sbull] Reconcile the comparability of existing dictionaries with
MedDRA (in the short term),
[sbull] Integrate a Web browser, and
[sbull] Install or modify an autoencoder system.
IT personnel are estimated to need from 720 hours for very small firms
to 1,920 hours for very large firms to develop and validate computer
data systems that will accommodate MedDRA. Costs are estimated to range
from $25,850 to $68,900 for drug and biologics firms. No costs were
forecast for blood facilities.
V.D.2.a.iii. Purchase or development of an autoencoder. Companies
reported that they currently use an existing database such as COSTART
or WHOART and supplement these dictionaries with their own medical
vocabulary. Autoencoders assist with the automated conversion of
existing medical terms to MedDRA. Companies
[[Page 12460]]
may purchase autoencoders, adapt existing in-house versions, or use
outside contractors. Converting existing terms to MedDRA is estimated
to cost from $20,000 to $100,000 for drug and biologics firms. Costs
are not applicable to blood facilities.
V.D.2.a.iv. Conversion of legacy safety data. Some companies
reported that they would convert virtually all of their legacy data
into MedDRA terms even though it is not required by this proposed rule.
Some companies maintain that this conversion includes information from
clinical trials. Nonetheless, some companies may not convert their
legacy drug safety data into MedDRA or may convert only some of their
products, based on criteria associated with experience and history of
the drug. ERG estimated that 75 percent of companies would incur
conversion costs to allow for the range of company responses. The
number of terms that are converted automatically (with autoencoders) or
manually will affect conversion costs. Estimated costs per company for
converting existing legacy data range from about $16,500 (for
converting 15,000 terms) for very small firms to $275,000 (for
converting roughly 250,000 terms) for very large drug firms. Costs for
biologics firms of corresponding size range from $3,300 (for 3,000
terms) to $55,000 (for about 50,000 terms). Costs are not applicable to
blood facilities.
V.D.2.a.v. Training of personnel. Companies reported that staff
most likely to receive MedDRA training include medical coders,
biostatisticians, and pharmacovigilance, IT, and regulatory affairs
personnel. In addition to formal training, medical data coders will
require several months of experience before they become proficient with
coding in MedDRA. Training costs are dependent on the number of
employees that must be trained in MedDRA and the level of training
needed for their relevant duties. Training costs were estimated to
range from $9,300 to $330,300 for very small to very large drug
manufacturers and from $9,300 to $90,600 for biologics firms of
corresponding size. ERG estimated training costs from $1,300 to $4,300
for very small to very large blood facilities.
V.D.2.a.vi. Revision of standard operating procedures (SOPs).
Companies will revise a substantial group of SOPs in implementing
MedDRA. Affected procedures include dictionary/coding, IT, and drug
safety/pharmacovigilance. Drug and biologics firms are expected to need
from 130 to 1,300 hours for very small to very large firms to revise
their SOPs for MedDRA, with costs ranging from $5,900 to $59,200. ERG
allocated 8 to 50 hours for developing or revising SOPs for blood
facilities. Per firm costs for SOPs are estimated to range from $370 to
$2,260 for very small to very large blood facilities.
V.D.2.b. Recurring costs
V.D.2.b.i. MedDRA core subscription. Companies must pay
subscription costs on an annual basis to the MedDRA MSSO. Core
subscription costs vary with the size of the company and with the level
of services. Estimates of costs range from $5,000 to $40,000 for drug
and biologics firms. ERG judged that blood facilities would incur only
modest annual costs associated with MedDRA subscription and updates
because of the limited range of terminology describing medical
outcomes. ERG assumed that blood facilities would either work through
industry associations to negotiate lower per firm subscription costs
or, alternatively, contract with contract research organizations to
obtain the necessary MedDRA codes.
V.D.2.b.ii. MedDRA versions and quarterly updates. Currently the
MSSO intends to provide quarterly updates as well as periodic new
versions of MedDRA. Companies did not have a sufficient history with
incorporating MedDRA changes to estimate the costs of updates. Cost
components would include senior level reviews of each update,
communicating the changes to affected personnel, and IT support to
upload and reconcile new versions. Costs are estimated to range from
$5,700 to $43,000 for drug and biologics firms. No costs were assigned
to blood facilities.
V.D.2.b.iii. Maintenance of existing dictionaries. Companies
reported that they may need to maintain their existing dictionaries for
an indeterminate time. Conditions that could influence whether and for
how long a company would need to maintain its existing dictionaries
are: (1) The company uses different dictionaries for its postmarketing
safety and clinical study data bases; (2) the company has products in
late-stage clinical trials; and (3) the company has marketed products
near the end of their useful life. ERG estimates the maintenance costs
for existing dictionaries are expected to range from $4,300 to $136,400
annually for drug manufacturers and from $4,300 to $43,400 annually for
biologics manufacturers. No costs were assigned to blood facilities.
Table 18 presents the estimated costs to industry of implementing
MedDRA for each cost category.
Table 18.--Total Compliance Costs of MedDRA by Cost Category
------------------------------------------------------------------------
Total cost \1\ Percent of
Drugs and biologics ($ million) total \1\
------------------------------------------------------------------------
First-Time Costs:
Planning and coordination........... 16.3 9
Purchase or development of auto- 20.5 12
encoder............................
Personnel training.................. 46.0 27
Development of IT structure......... 14.7 9
Legacy safety data conversion....... 31.9 18
Revision of SOPs.................... 14.8 9
Total First-time................ 144.2 83
-----------------
Recurring Costs:
Annual MedDRA core subscription..... 6.6 4
MedDRA versioning................... 6.9 4
Maintenance of additional medical 15.0 9
dictionary.........................
-----------------
Total recurring................. 28.5 16
-----------------
Total first year costs (First- 172.8 100
time + recurring)..............
------------------------------------------------------------------------
\1\ Totals may not add due to rounding.
[[Page 12461]]
V.E. Small Business Analysis
The following analysis along with other sections of this preamble
constitute the agency's regulatory flexibility analysis as required
under the Regulatory Flexibility Act.
V.E.1. Need for and Objectives of the Rule
A primary objective of this proposed rule is the harmonization of
FDA's safety reporting requirements with international initiatives. The
proposed rule would also improve the quality of information contained
in postmarketing safety reports for marketed human drug and biological
products. By providing more complete information for individual case
safety reports, the revised reports would enhance the ability of
manufacturers, applicants, and the agency to identify, monitor, and
communicate the risks and benefits of marketed drug and biological
products. Monitoring these risks and benefits is especially critical
for recently approved products introduced to large and diverse patient
populations following market approval.
V.E.2. Description and Estimate of Small Entities
The proposed rule applies to manufacturers, applicants, and
contractors of drug and biological products, and persons involved in
blood collection and transfusion. The Small Business Administration
(SBA) defines a small business in Standard Industrial Classification
(SIC) 2834 (or North American Industry Classification System (NAICS)
code 325412) as one employing fewer than 750 employees and in SIC 2836
(or NAICS code 325414) as one employing fewer than 500 employees.
According to 1996 U.S. Bureau of the Census statistics, almost 90
percent of the firms under these SIC codes are considered small
businesses. A review of 1998 AERS data, which contain postmarketing 15-
day and periodic safety reports from manufacturers and applicants of
marketed drug and biological products, found that about 200 firms
submitted at least one individual case safety report for a trade name
product and that the majority of these firms were considered large
under the SBA definitions. However, the number of firms submitting
reports vary from year to year. Therefore, using the 1998 AERS data,
estimates of the percentages of reporting firms by size were
distributed to the number of firms in each SIC, suggesting that about
230 drug and 72 biologics firms would be affected by the proposed rule,
of which 190, or about 60 percent, would be considered small.
FDA estimates that about 3,200 blood facilities would be affected
by the proposed regulation. Approximately 3,000 are hospitals with
blood collection and/or compatibility testing operations, classified in
SIC 8062 (or NAICS code 62211), and 200 are blood banks or non-hospital
blood and plasmapheresis centers, classified in SIC 8099 (or NAICS code
621991). The SBA defines businesses in SIC 8062 and 8099 with annual
revenues of $25 million and $7.5 million or less, respectively, as
small. ERG estimated the number of small businesses affected in SIC's
8062 and 8099 at 1,786 and 188, respectively. This is approximately 60
and 94 percent of the blood facilities in SICs 8062 and 8099,
respectively, that will be implementing the MedDRA requirements.
V.E.3. Projected Reporting, Recordkeeping, and Other Compliance
Requirements
V.E.3.a. Reporting and recordkeeping requirements. The proposed
rule may impose an additional burden on manufacturers of human drug
products for which SADRs are reported. In any year, SADRs may be
reported for about half of the products marketed in the United States.
AERS data from 1998 suggest that small firms manufactured less than 12
percent of the products for which SADRs were reported. Moreover, during
this same year, only about 2 percent of the postmarketing 15-day alert
reports submitted to the agency were from small firms. Nevertheless,
the proposed changes to the postmarketing safety reporting requirements
may impose a substantial burden on a significant number of small firms,
especially small startup firms with only one product on the market. The
extent of the impact will depend on the time that has elapsed since the
drug was approved and the number and types of individual case safety
reports received in a reporting period.
To illustrate the impact of the safety reporting and recordkeeping
requirements of the proposed rule, table 19 shows the hypothetical
first-year burden for a drug approved 6 months prior to the effective
date of the final rule. Under this scenario, the first-year burden
incurred for a newly approved product might be as much as $19,600,
assuming 26 expedited and 6 followup reports, two semiannual reports,
and two PSURs had been submitted.
Table 19.--Hypothetical First-Year Reporting and Recordkeeping Burden for Newly Approved Drug Product
--------------------------------------------------------------------------------------------------------------------------------------------------------
Expedited Individual
Expedited Expedited (unexpected Always case safety
(serious, (medication SADR with expedited 30-day follow- report--semi- PSUR Total
unexpected errors) unknown report up annual
SADR) outcome) submission
--------------------------------------------------------------------------------------------------------------------------------------------------------
Per report new burden \1\......... $104 $612 $919 $612 $367 $1,042 $1,564
Number of reports................. 8 16 1 1 6 2 2 36
Totals \2\........................ $834 $9,799 $919 $612 $2,202 $2,084 $3,128 $19,578
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Only whole dollar values are shown.
\2\ Values rounded to the nearest whole number.
V.E.3.b. Implementing MedDRA. Implementing MedDRA would impose
additional significant one-time and recurring costs on drug and
biological product manufacturers. Costs would vary among individual
firms depending on circumstances, including the number of products
manufactured, the frequency of SADRs, and the extent of legacy data
converted. Table 20 displays ERG's estimates per firm of revenues,
annualized compliance costs and costs as a percent of revenues. Costs
for small entities are 0.15 percent and 0.28 percent of revenues for
drug and biological product manufacturers, respectively. Similarly,
average compliance costs for small entities are
[[Page 12462]]
0.01 percent and 0.03 percent of revenue for SICs 8062 and 8099,
respectively.
Table 20.--Compliance Costs as a Percent of Estimated Revenues for Small Entities
----------------------------------------------------------------------------------------------------------------
Compliance
Number of Per firm Per firm cost as a
Industry classification Number of affected estimated annualized percent of
employees firms revenues compliance estimated
($000) costs ($000) revenues
----------------------------------------------------------------------------------------------------------------
SIC 2834 Pharmaceutical < 750 146 44,265 66.9 0.15
preparations...................
SIC 2836 Biological products.... < 500 44 15,752 44.4 0.28
SIC 8062 General medical and < 500 1,786 13,366 0.6 0.01
surgical hospitals.............
SIC 8099 Blood banks (Health and < 500 188 1,320 0.3 0.03
allied services, NEC)..........
----------------------------------------------------------------------------------------------------------------
The reporting, coding, and analysis of SADRs are standard
procedures that manufacturers routinely conduct under current
regulations. No additional professional skills would be necessary to
comply with this rule. However, current safety reviewers, analysts, and
IT personnel would need training to implement MedDRA.
V.E.4. Alternatives and Steps To Minimize the Impact on Small Entities
The major objectives of this proposed rule are to harmonize FDA's
safety reporting requirements with international initiatives and to
improve the quality of safety reports. With these objectives in mind,
the agency considered alternatives to this proposed rule.
V.E.4.a. Do nothing. The agency considered but rejected the option
of not proposing this rule. The proposed rule would align FDA's safety
report terms, formats and requirements for human drugs and biological
products with the recommendations of ICH. With regard to use of a
medical dictionary for safety reporting purposes, at the present time,
major problems exist with comparing safety data globally because
multiple medical dictionaries are being used internationally for coding
of SADRs (see section III.F.2 of this document). In this rule, the
agency proposes to require the use of MedDRA, the medical dictionary
developed by ICH. FDA believes that ``to do nothing'' would be
inconsistent with the agency's efforts to harmonize safety reporting
with international initiatives.
Another objective of this proposed rule is to improve the quality
of safety reports. In this preamble, the agency cited a substantial
number of studies that estimate the number of SADRs that have resulted
in a hospitalization or that occur in a hospital and the hospital costs
related to SADRs. Safety reports that are complete are critical and
necessary to reduce SADRs, medication errors, and hospital costs. This
proposed rule would improve the agency's ability to monitor the safety
of human drugs and biological products. In light of this information,
``to do nothing'' would be inconsistent with the agency's mission of
protecting public health.
V.E.4.b. Do not require a medical dictionary. The agency considered
but rejected the alternative of not requiring the use of MedDRA terms
in individual case safety reports. MedDRA is an integral part of the
postmarket safety reporting system that was developed jointly with
international stakeholders. Requiring MedDRA terms in safety reports
will enhance the analysis of drug safety information. Moreover, MedDRA
is a medical dictionary designed to translate terms in multiple
languages, thus aiding in more expeditious and broader international
drug use comparisons and analysis. Not requiring MedDRA would
compromise the agency objective of improving drug safety reporting and
analysis. In addition, continued use of multiple medical dictionaries
to code SADRs will perpetuate the major problems with comparing safety
data globally that currently exist.
V.E.4.c. Do not require medication errors as expedited reports. The
agency considered but rejected the alternative of not requiring
medication errors as expedited reports. Requiring expedited reports of
medication errors would allow the agency to review critical information
and take appropriate and more timely action on SADRs that are
preventable. Not requiring expedited reports of medication errors would
ignore a key step in reducing medical errors.
V.E.4.d. Do not require blood establishments to submit reports for
all serious SADRs associated with blood collection and transfusion. The
agency considered but rejected the alternative of not requiring blood
establishments to submit reports for all serious SADRs associated with
blood collection and transfusion, in addition to the current
requirement to submit reports of fatalities. Because these
establishments are currently required to conduct investigations and
prepare and maintain reports of serious SADRs, this proposal would
impose minimal costs. However, only some serious SADRs must be reported
in a timely manner. The agency believes it is critical that we receive
all such reports. This would improve the agency's ability to take
appropriate action to protect the blood supply more consistently, to
enhance donor safety and to ensure the safety, purity and potency of
blood and blood components for administration to patients.
V.E.4.e. Do not require certain bioavailability and bioequivalence
reports as expedited reports. The agency considered but rejected the
alternative of not requiring expedited reports of SADRs for
bioavailability and bioequivalence studies not subject to an IND. This
requirement would allow the agency quicker access to information and
would facilitate appropriate action to protect those enrolled in
clinical trials.
V.E.4.f. Waivers for economic hardship. The agency recognizes that
requiring individual case safety reports to be coded using MedDRA will
likely impose significant costs on some small firms (see section
III.F.2 of this document). One alternative would be to consider the
option of allowing companies to request a waiver from MedDRA coding,
based on economic hardship. The agency is seeking comment on ways to
reduce economic hardships of implementing MedDRA while maintaining
adequate procedures to monitor and assess the safety of products.
V.E.4.g Small business outreach, training, and assistance. The
agency has received both written and verbal input from interested
parties, including small businesses, on the recommendations of ICH
regarding safety reporting for human drugs and biological products
(e.g., the ICH E2A guidance, the ICH E2C guidance, and ICH M1). These
public comments addressed published draft versions of the ICH guidances
as well as numerous agency presentations
[[Page 12463]]
at public workshops and forums (e.g., sponsored by the Drug Information
Association (DIA) or the Pharmaceutical Education and Research
Institute (PERI)). The agency has considered these comments in
development of this proposed rule.
Once this proposed rule is finalized, the agency will provide the
public with an overview of the provisions in the rule at workshops and
forums (e.g., DIA meetings, PERI workshops). All firms, including small
firms, would have an opportunity to attend these presentations.
Firms can access AERS-related information on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/aers/index.htm.
The AERS site includes a ``Reporting
/http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=www.fda.gov/cder/aers/index.htm. The AERS site includes a ``Reporting
Regulations and Guidances'' page that provides a summary of the
rulemaking (proposed rules, final rules) and guidances regarding the
agency's safety reporting requirements for human drugs and biological
products. This site is updated as changes to the safety reporting
requirements are made.
V.F. Unfunded Mandates Reform Act of 1995
On the basis of the preceding discussion, under the Unfunded
Mandates Reform Act, FDA concludes that if only .85 percent of the
estimated SADRs are prevented, then the benefits of this proposed rule
will exceed the annualized compliance costs that it imposes on the U.S.
economy. In addition, the agency has considered other alternatives as
discussed in section V.E.4 of this document and determined that the
proposed rule is the best alternative that would meet the objectives of
this rule.
V.G. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Friedman, Michael A. et al., ``The Safety of Newly Approved
Medicines: Do Recent Market Removals Mean There Is a Problem?''
Journal of the American Medical Association, 281:1728-1734, 1999.
2. Murphy, Barbara M., and Lawrence C. Frigo, ``Development,
Implementation, and Results of a Successful Multidisciplinary
Adverse Drug Reaction Reporting Program in a University Teaching
Hospital,'' Hospital Pharmacy, 28:1199-1204, 1993.
3. Beyth, Rebecca J., and Ron Shorr, ``Epidemiology of Adverse Drug
Reactions in the Elderly by Drug Class,'' Drugs & Aging, 14:231-239,
1999.
4. Cooper, James W., ``Adverse Drug Reaction-Related
Hospitalizations of Nursing Facility Patients: A 4-Year Study,''
Southern Medical Journal, 92:485-490, 1999.
5. Gaines, Ann R., and Frederick Varricchio, ``Interferon Beta-1b
Injection Site Reactions and Necroses,'' Multiple Sclerosis, 4:70-
73, 1998.
6. Schumock, Glen T. et al., ``Control Charts to Monitor Rates of
Adverse Drug Reactions,'' Hospital Pharmacy, 30:1088-1096, 1995.
7. Johnston, Philip E., Jason D. Morrow, and R. A. Branch, ``Use of
a Database Computer Program to Identify Trends in Reporting of
Adverse Drug Reactions,'' American Journal of Hospital Pharmacy,
47:1321-1327, 1990.
8. Kennedy, Diane L. et al., ``National Adverse Drug Event
Reporting,'' American Journal of Hospital Pharmacy, 50:1913-1914,
1993.
9. Pierce, L. Ross et al., ``Hemolysis and Renal Failure Associated
With the Use of Sterile Water for Injection to Dilute 25% Human
Albumin Solution,'' American Journal of Health Systems Pharmacy,
55:1057-1070, 1998.
10. Institute of Medicine, edited by Linda T. Kohn et al., ``To Err
is Human: Building a Safer Health System,'' National Academy Press,
1999.
11. Tyler, Linda S., and Nancy A. Nickman, ``Hospital Pharmacy
Compliance with JCAHO Standards and ASHP Guidelines for Reporting
Adverse Drug Reactions,'' American Journal of Hospital Pharmacy,
49:845-850, 1992.
12. U.S. Department of Health and Human Services, Office of the
Inspector General, ``Review of the Food and Drug Administration's
Handling of Adverse Drug Reaction Reports,'' Report No. A-15-98-
50001, 1999.
13. Einarson, Thomas R., ``Drug-Related Hospital Admissions,'' The
Annals of Pharmacotherapy, 27:832-840, 1993.
14. U.S. Department of Commerce, ``Statistical Abstract of the
United States,'' 1999.
15. Agency for Health Care Policy and Research, ``National Medical
Expenditure Survey: Annual Expenses and Sources of Payment for
Health Care Services Research Findings 14,'' p. 7, 1995.
16. Bates, David W. et al., ``The Costs of Adverse Drug Events in
Hospitalized Patients,'' Journal of the American Medical
Association, 277:307-311, 1997.
17. The U.S. General Accounting Office, ``Adverse Drug Events The
Magnitude of Health Risk Is Uncertain Because of Limited Incidence
Data,'' GAO/HEHS-00-21, January, 2000.
18. Lazarou, Jason et al., ``Incidence of Adverse Drug Reactions in
Hospitalized Patients, A Meta-Analysis of Prospective Studies,''
Journal of the American Medical Association, 279:1200-1205, 1998.
19. Classen, David C. et al., ``Adverse Drug Events in Hospitalized
Patients Excess Length of Stay, Extra Costs and Attributable
Mortality,'' Journal of the American Medical Association, 277:301-
306, 1997.
20. Thomas, Eric J. et al., ``Costs of Medical Injuries in Utah
and Colorado,'' Inquiry, 36:255-264.
21. Ives, Timothy J. et al., ``Drug-Related Admissions to a
Family Medicine Inpatient Service'', Archives of Internal Medicine,
147: 1117-1120, 1987.
22. McKinney, James M., and W. L. Harrison, ``Drug-Related
Hospital Admissions,'' American Journal of Hospital Pharmacy,
33:792-795, 1976.
23. Caranasos, George J. et al., ``Drug-Induced Illness Leading
to Hospitalization,'' Journal of the American Medical Association,
228:713-717, 1974.
24. Johnson, Jeffrey A., and J. Lyle Bootman, ``Drug-Related
Morbidity and Mortality, A Cost of Illness Model,'' Archives of
Internal Medicine, 155:1949-1956, 1995.
25. Eastern Research Group, Inc., ``Cost of Implementing MedDRA
Terminology for Pharmaceutical and Biologics Companies,'' 2000.
26. Goodnough, Lawrence T. et al., ``Transfusion Medicine,'' The
New England Journal of Medicine, 340:438-447, 1999.
27. Newman, B.H., ``Donor Reactions and Injuries From Whole
Blood Donation,'' Transfusion Medicine Reviews, 11:64-75, 1997.
28. ``International Reporting of Periodic Drug Safety Update
Summaries,'' Final Report of the CIOMS Working Group II, 1992.
29. ``Current Challenges in Pharmacovigilance: Pragmatic
Approaches,'' Final Report of the CIOMS Working Group V, 2001.
VI. Paperwork Reduction Act of 1995
This proposed rule contains collections of information which are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). ``Collection
of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR 1320.3(c)
and includes agency requests or requirements that members of the public
obtain, maintain, retain, or report information to the agency, or
disclose information to a third party or to the public. The title,
description, and respondent description of the information collection
are shown below with an estimate of the annual reporting burden.
Included in the estimate is the time for reviewing instructions,
gathering and maintaining the data needed, and completing and reviewing
the collection of information.
FDA invites comments on: (1) Whether the proposed collection of
information is necessary for proper performance of FDA's functions,
including whether the information will have practical utility; (2) the
accuracy of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information
[[Page 12464]]
on respondents, including through the use of automated collection
techniques, when appropriate, and other forms of information
technology.
Title: Safety Reporting Requirements for Human Drug and Biological
Products
Description: The proposed rule would amend FDA's safety reporting
regulations for human drug and biological products to implement
definitions, and reporting formats and standards as recommended by the
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) and by the World
Health Organization's Council for International Organizations of
Medical Sciences (CIOMS); codify the agency's expectations for timely
acquisition, evaluation, and submission of relevant safety information
for marketed drugs and licensed biological products; require that
certain information, such as domestic reports of medication errors, be
submitted to the agency in an expedited manner; clarify certain safety
reporting requirements; and make other minor revisions. The proposed
rule would also amend FDA's postmarketing annual reports regulations
for human drugs and licensed biological products by revising the
content for these reports. These changes would further worldwide
consistency in the collection of safety information and submission of
safety reports, increase the quality of safety reports, expedite FDA's
review of critical safety information, and enable the agency to protect
and promote public health. The estimates provided in this section are
not only attributed to the new proposed requirements in this rulemaking
but also include burdens associated with our current safety reporting
requirements.
VI.A. Expedited Safety Reporting
Proposed Sec. Sec. 310.305(c)(2)(i), 314.80(c)(2)(i), and
600.80(c)(2)(i) would require manufacturers and applicants to submit a
report to FDA for each SADR, received or otherwise obtained, that is
both serious and unexpected, whether foreign or domestic, as soon as
possible, but in no case later than 15 calendar days after receipt by
the manufacturer or applicant of the minimum data set for the serious,
unexpected SADR. Based on data concerning the number of expedited
reports currently received by the agency, FDA estimates that
approximately 350 expedited reports of serious and unexpected SADRs
will be submitted annually under proposed Sec. 310.305(c)(2)(i);
approximately 50,000 reports will be submitted annually under proposed
Sec. 314.80(c)(2)(i); and approximately 3,000 reports will be
submitted annually under proposed Sec. 600.80(c)(2)(i). FDA estimates
that approximately 14 manufacturers under proposed Sec.
310.305(c)(2)(i) will submit these reports; approximately 282
applicants under proposed Sec. 314.80(c)(2)(i) will submit these
reports; and approximately 69 applicants under proposed Sec.
600.80(c)(2)(i) will submit these reports. Based on the agency's
familiarity with the content of expedited reports for serious and
unexpected SADRs, FDA estimates that it will take an average of 16
hours for manufacturers and applicants to prepare and submit one of
these reports to FDA. Preparation of an expedited report for a serious
and unexpected SADR would include gathering information (proposed
Sec. Sec. 310.305(b) and (c)(1), 314.80(b) and (c)(1), and 600.80(b)
and (c)(1)), providing attachments, if applicable (proposed Sec. Sec.
310.305(c)(2)(ix) and (c)(2)(x), 314.80(c)(2)(ix), and
600.80(c)(2)(ix)), and formatting information (proposed Sec. Sec.
310.305(c)(2)(xii), (d), and (e), 314.80(c)(2)(xi), (c)(4), and (e),
and 600.80(c)(2)(xi), (c)(4), and (e)).
Proposed Sec. Sec. 310.305(c)(2)(ii), 314.80(c)(2)(ii), and
600.80(c)(2)(ii) would require manufacturers and applicants to submit a
report to FDA concerning information, received or otherwise obtained,
whether foreign or domestic, that would be sufficient, based upon
appropriate medical judgment, to consider product administration
changes (e.g., any significant unanticipated safety finding or data in
the aggregate from an in vitro, animal, epidemiological, or clinical
study, whether or not conducted under an IND, that suggests a
significant human risk, such as reports of mutagenicity,
teratogenicity, or carcinogenicity, or reports of a lack of efficacy
with a drug or biological product used in treating a life-threatening
or serious disease). Manufacturers and applicants would be required to
submit this information to FDA as soon as possible, but in no case
later than 15 calendar days after determination by the manufacturer or
applicant that the information qualifies for expedited reporting.
Expedited reports containing information that would be sufficient to
consider changes in product administration are a new type of safety
report. Based on data concerning voluntary reporting of this type of
information to the agency, FDA estimates that approximately 5 expedited
reports concerning information sufficient to consider product
administration changes will be submitted annually under proposed Sec.
310.305(c)(2)(ii); approximately 300 reports will be submitted annually
under proposed Sec. 314.80(c)(2)(ii); and approximately 4 reports will
be submitted annually under proposed Sec. 600.80(c)(2)(ii). FDA
estimates that approximately 5 manufacturers under proposed Sec.
310.305(c)(2)(ii) will submit these expedited reports; approximately 50
applicants under proposed Sec. 314.80(c)(2)(ii) will submit these
expedited reports; and approximately 4 applicants under proposed Sec.
600.80(c)(2)(ii) will submit these expedited reports. Based on the
content of the voluntary reports submitted to the agency, FDA estimates
that it will take an average of 8 hours for manufacturers and
applicants to prepare and submit an expedited report to FDA concerning
information sufficient to consider product administration changes.
Preparation of these expedited reports would include gathering
information (proposed Sec. Sec. 310.305(b) and (c)(1), 314.80(b) and
(c)(1), and 600.80(b) and (c)(1)), providing attachments, if applicable
(proposed Sec. Sec. 310.305(c)(2)(ix) and (c)(2)(x), 314.80(c)(2)(ix),
and 600.80(c)(2)(ix)), and formatting information (proposed Sec. Sec.
310.305(c)(2)(xii), (d), and (e), 314.80(c)(2)(xi), (c)(4), and (e),
and 600.80(c)(2)(xi), (c)(4), and (e)).
Proposed Sec. Sec. 310.305(c)(2)(iii), 314.80(c)(2)(iii), and
600.80(c)(2)(iii) would require manufacturers and applicants to submit
a report to FDA for each SADR that is unexpected and for which the
determination of an outcome is unattainable (i.e., SADR with unknown
outcome) within 45 calendar days after initial receipt by the
manufacturer or applicant of the minimum data set for an unexpected
SADR. Expedited reports of unexpected SADRs with an unknown outcome are
a new type of safety report. Based on data concerning the number of
unexpected SADR reports with an unknown outcome currently received by
the agency, FDA estimates that approximately 46 expedited reports of an
unexpected SADR with an unknown outcome will be submitted annually
under proposed Sec. 310.305(c)(2)(iii); approximately 912 reports will
be submitted annually under proposed Sec. 314.80(c)(2)(iii); and
approximately 25 reports will be submitted annually under proposed
Sec. 600.80(c)(2)(iii). FDA estimates that approximately 10
manufacturers under proposed Sec. 310.305(c)(2)(iii) will submit these
expedited reports; approximately 109 applicants under proposed
[[Page 12465]]
Sec. 314.80(c)(2)(iii) will submit these expedited reports; and
approximately 12 applicants under proposed Sec. 600.80(c)(2)(iii) will
submit these expedited reports. Based on the agency's familiarity with
the content of expedited reports for serious and unexpected SADRs, FDA
estimates that it will take an average of 24 hours for manufacturers
and applicants to prepare and submit an expedited report for an
unexpected SADR with an unknown outcome to FDA. Preparation of
expedited reports for unexpected SADRs with an unknown outcome would
include gathering information (proposed Sec. Sec. 310.305(b) and
(c)(1), 314.80(b) and (c)(1), and 600.80(b) and (c)(1)), providing
attachments, if applicable (proposed Sec. Sec. 310.305(c)(2)(ix) and
(c)(2)(x), 314.80(c)(2)(ix), and 600.80(c)(2)(ix)), and formatting
information (proposed Sec. Sec. 310.305(c)(2)(xii), (d), and (e),
314.80(c)(2)(xi), (c)(4), and (e), and 600.80(c)(2)(xi), (c)(4), and
(e)).
Proposed Sec. Sec. 310.305(c)(2)(iv), 314.80(c)(2)(iv), and
600.80(c)(2)(iv) would require manufacturers and applicants to submit
to FDA each SADR, received or otherwise obtained, whether foreign or
domestic, that is the subject of an always expedited report. Certain
medically significant SADRs (e.g., ventricular fibrillation, liver
necrosis, confirmed or suspected transmission of an infectious agent by
a marketed drug or biological product) which may jeopardize the patient
or subject and/or require medical or surgical intervention to treat the
patient or subject would be subject to an always expedited report.
These SADRs would be submitted to FDA whether unexpected or expected
and whether or not the SADR leads to a serious outcome. Always
expedited reports would be submitted to the agency within 15 calendar
days after initial receipt by the manufacturer or applicant of the
minimum data set for the report. Always expedited reports are a new
type of safety report. Based on data concerning the number of safety
reports currently received by the agency for the SADRs specified under
proposed Sec. Sec. 310.305(c)(2)(iv), 314.80(c)(2)(iv), and
600.80(c)(2)(iv), FDA estimates that approximately 50 always expedited
reports will be submitted annually under proposed Sec.
310.305(c)(2)(iv); approximately 1,500 reports will be submitted
annually under proposed Sec. 314.80(c)(2)(iv); and approximately 100
reports will be submitted annually under proposed Sec.
600.80(c)(2)(iv). FDA estimates that approximately 10 manufacturers
under proposed Sec. 310.305(c)(2)(iv) will submit these expedited
reports; approximately 100 applicants under proposed Sec.
314.80(c)(2)(iv) will submit these expedited reports; and approximately
10 applicants under proposed Sec. 600.80(c)(2)(iv) will submit these
expedited reports. Based on the agency's familiarity with the content
of expedited reports for serious and unexpected SADRs, FDA estimates
that it will take an average of 16 hours for manufacturers and
applicants to prepare and submit an always expedited report to the
agency. Preparation of always expedited reports would include gathering
information (proposed Sec. Sec. 310.305(b) and (c)(1), 314.80(b) and
(c)(1), and 600.80(b) and (c)(1)), providing attachments, if applicable
(proposed Sec. Sec. 310.305(c)(2)(ix) and (c)(2)(x), 314.80(c)(2)(ix),
and 600.80(c)(2)(ix)), and formatting information (proposed Sec. Sec.
310.305(c)(2)(xii), (d), and (e), 314.80(c)(2)(xi), (c)(4), and (e),
and 600.80(c)(2)(xi), (c)(4), and (e)).
Proposed Sec. Sec. 310.305(c)(2)(v), 314.80(c)(2)(v), and
600.80(c)(2)(v) would require manufacturers and applicants to submit
all domestic reports of medication errors, whether actual or potential.
Expedited reports of medication errors are a new type of safety report.
Based on data concerning the number of domestic reports of medication
errors voluntarily submitted to the agency, FDA estimates that
approximately 1,000 reports of medication errors will be submitted
annually under proposed Sec. 310.305(c)(2)(v); approximately 100,000
reports will be submitted annually under proposed Sec.
314.80(c)(2)(v); and approximately 10,000 reports will be submitted
annually under proposed Sec. 600.80(c)(2)(v). FDA estimates that
approximately 10 manufacturers under proposed Sec. 310.305(c)(2)(v)
will submit these expedited reports; approximately 150 applicants under
proposed Sec. 314.80(c)(2)(v) will submit these expedited reports; and
approximately 30 applicants under proposed Sec. 600.80(c)(2)(v) will
submit these expedited reports. Based on the agency's familiarity with
the content of expedited reports for serious and unexpected SADRs, FDA
estimates that it will take an average of 16 hours for manufacturers
and applicants to prepare and submit an expedited report of a
medication error to the agency. Preparation of medication error reports
would include gathering information (proposed Sec. Sec. 310.305(b) and
(c)(1), 314.80(b) and (c)(1), and 600.80(b) and (c)(1)), providing
attachments, if applicable (proposed Sec. Sec. 310.305(c)(2)(ix) and
(c)(2)(x), 314.80(c)(2)(ix), and 600.80(c)(2)(ix)), and formatting
information (proposed Sec. Sec. 310.305(c)(2)(xii), (d), and (e),
314.80(c)(2)(xi), (c)(4), and (e), and 600.80(c)(2)(xi), (c)(4), and
(e)).
Proposed Sec. Sec. 310.305(c)(2)(vi), 314.80(c)(2)(vi), and
600.80(c)(2)(vi) would require manufacturers and applicants to submit a
30-day followup report to FDA for any expedited report under proposed
Sec. Sec. 310.305(c)(2)(i), (c)(2)(iv), (c)(2)(v), 314.80(c)(2)(i),
(c)(2)(iv), (c)(2)(v), 600.80(c)(2)(i), (c)(2)(iv), and (c)(2)(v) that
does not contain a full data set. These 30-day followup reports would
be submitted within 30 calendar days after submission of the expedited
report. Thirty-day followup reports are a new type of safety report.
Based on data concerning the number of followup reports received by the
agency, FDA estimates that approximately 340 30-day followup reports
will be submitted annually under proposed Sec. 310.305(c)(2)(vi);
approximately 43,000 30-day followup reports will be submitted annually
under proposed Sec. 314.80(c)(2)(vi); and approximately 3,000 30-day
followup reports will be submitted annually under proposed Sec.
600.80(c)(2)(vi). FDA estimates that approximately 7 manufacturers
under proposed Sec. 310.305(c)(2)(vi) will submit 30-day follow up
reports; approximately 140 applicants under proposed Sec.
314.80(c)(2)(vi) will submit 30-day follow up reports; and
approximately 69 applicants under proposed Sec. 600.80(c)(2)(vi) will
submit 30-day followup reports. Based on the agency's familiarity with
the content of followup reports for serious and unexpected SADRs, FDA
estimates that it will take an average of 8 hours for manufacturers and
applicants to prepare and submit a 30-day follow up report to the
agency. Preparation of 30-day follow up reports would include gathering
information (proposed Sec. Sec. 310.305(b) and (c)(1), 314.80(b) and
(c)(1), and 600.80(b) and (c)(1)), providing attachments, if applicable
(proposed Sec. Sec. 310.305(c)(2)(ix) and (c)(2)(x), 314.80(c)(2)(ix),
and 600.80(c)(2)(ix)), and formatting information (proposed Sec. Sec.
310.305(c)(2)(xii), (d), and (e), 314.80(c)(2)(xi), (c)(4), and (e),
and 600.80(c)(2)(xi), (c)(4), and (e)).
Proposed Sec. Sec. 310.305(c)(2)(vii), 314.80(c)(2)(vii), and
600.80(c)(2)(vii) would require manufacturers and applicants to submit
a 15-day followup report to FDA concerning any new information,
received or otherwise obtained, after any initial expedited report or
any followup report, except for
[[Page 12466]]
expedited reports which are subject to the 30-day followup reporting
requirement under proposed Sec. Sec. 310.305(c)(2)(vi),
314.80(c)(2)(vi), and 600.80(c)(2)(vi). Proposed Sec. Sec.
310.305(b)(2), 314.80(b)(2), and 600.80(b)(2) would also require
manufacturers and applicants to submit 15-day followup reports to FDA
with any new information concerning an individual case safety report
forwarded to the manufacturer or applicant by FDA. Proposed Sec. Sec.
310.305(c)(2)(viii)(A), 314.80(c)(2)(viii)(A), and
600.80(c)(2)(viii)(A) would also require manufacturers and applicants
to submit to FDA as 15-day followup reports any documents required
under these paragraphs that become available after submission of an
expedited report. These 15-day followup reports would be submitted
within 15 calendar days of initial receipt of the new information by
the manufacturer or applicant. Based on data concerning the number of
followup reports currently received by the agency, FDA estimates that
approximately 55 15-day followup reports will be submitted annually
under proposed Sec. 310.305(b)(2), (c)(2)(vii), and (c)(2)(viii)(A);
approximately 10,000 15-day followup reports will be submitted annually
under proposed Sec. 314.80(b)(2), (c)(2)(vii), and (c)(2)(viii)(A);
and approximately 1,000 15-day followup reports will be submitted
annually under proposed Sec. 600.80(b)(2), (c)(2)(vii), and
(c)(2)(viii)(A). FDA estimates that approximately 10 manufacturers
under proposed Sec. 310.305 will submit 15-day followup reports;
approximately 184 applicants under proposed Sec. 314.80 will submit
15-day followup reports; and approximately 69 applicants under proposed
Sec. 600.80 will submit 15-day followup reports. Based on the agency's
familiarity with the content of followup reports for serious and
unexpected SADRs, FDA estimates that it will take an average of 4 hours
for manufacturers and applicants to prepare and submit a 15-day
followup report to FDA. Preparation of 15-day followup reports would
include gathering information (proposed Sec. Sec. 310.305(b) and
(c)(1), 314.80(b) and (c)(1), and 600.80(b) and (c)(1)), providing
attachments, if applicable (proposed Sec. Sec. 310.305(c)(2)(ix) and
(c)(2)(x), 314.80(c)(2)(ix), and 600.80(c)(2)(ix)), and formatting
information (proposed Sec. Sec. 310.305(c)(2)(xii), (d), and (e),
314.80(c)(2)(xi), (c)(4), and (e), and 600.80(c)(2)(xi), (c)(4), and
(e)).
Proposed Sec. Sec. 310.305(c)(2)(xi), 314.80(c)(2)(x), and
600.80(c)(2)(x) would require contractors and shared manufacturers to
submit safety reports of any SADRs or medication errors for the product
to the manufacturer (proposed Sec. Sec. 310.305(c)(2)(xi)) or
applicant (proposed Sec. Sec. 314.80(c)(2)(x) and 600.80(c)(2)(x))
within 5 calendar days of its receipt by the contractor or shared
manufacturer. Based on information included in individual case safety
reports currently submitted to the agency, FDA estimates that
approximately 10 safety reports will be submitted to manufacturers
annually under proposed Sec. 310.305(c)(2)(xi); approximately 11,370
safety reports will be submitted to applicants annually under proposed
Sec. 314.80(c)(2)(x); and approximately 250 safety reports will be
submitted to applicants annually under proposed Sec. 600.80(c)(2)(x).
FDA estimates that approximately 5 contractors under proposed Sec.
310.305 will submit safety reports to the manufacturer; approximately
100 contractors under proposed Sec. 314.80 will submit safety reports
to the applicant; and approximately 20 contractors and shared
manufacturers under proposed Sec. 600.80 will submit safety reports to
the applicant. Based on the agency's familiarity with the content of
individual case safety reports, FDA estimates that it will take an
average of 2 hours for contractors and shared manufacturers to prepare
and submit a safety report to a manufacturer or applicant.
Proposed Sec. 312.32(c)(1)(i) would require sponsors to notify FDA
and all participating investigators in a written IND safety report of
any SADR, based on the opinion of the investigator or sponsor, that is
both serious and unexpected, as soon as possible, but in no case later
than 15 calendar days after receipt by the sponsor of the minimum data
set for the serious, unexpected SADR. The sponsor would identify all
safety reports previously filed with the IND concerning a similar SADR
and would analyze the significance of the SADR in light of previous,
similar reports. Based on data concerning the number of written IND
safety reports currently received by the agency, FDA estimates that
approximately 4,860 written IND safety reports of serious and
unexpected SADRs will be submitted annually under proposed Sec.
312.32(c)(1)(i) for human drugs, and approximately 2,980 written IND
safety reports will be submitted annually under proposed Sec.
312.32(c)(1)(i) for human biological products. FDA estimates that
approximately 457 sponsors will submit written IND safety reports for
human drugs, and approximately 602 sponsors will submit written IND
safety reports for human biological products. Based on the agency's
familiarity with the content of written IND safety reports for serious
and unexpected SADRs, FDA estimates that it will take an average of 16
hours for sponsors to prepare and submit one of these reports to FDA.
Preparation of a written IND safety report for a serious and unexpected
SADR would include gathering information (proposed Sec. 312.32(b)) and
formatting information (proposed Sec. 312.32(c)(1)(iii)).
Proposed Sec. 312.32(c)(1)(ii) would require sponsors to notify
FDA and all participating investigators in a written IND safety report
of information, based on appropriate medical judgment, that might
materially influence the benefit-risk assessment of an investigational
drug, or would be sufficient to consider changes in either product
administration or in the overall conduct of a clinical investigation
(e.g., any significant unanticipated safety finding or data in the
aggregate from an in vitro, animal, epidemiological, or clinical study,
whether or not conducted under an IND, that suggests a significant
human risk, such as reports of mutagenicity, teratogenicity, or
carcinogenicity, or reports of a lack of efficacy with a drug or
biological product used in treating a life-threatening or serious
disease). This information would be submitted as soon as possible, but
in no case later than 15 calendar days after determination by the
sponsor that the information qualifies for expedited reporting. Based
on information contained in written IND safety reports that the agency
has received in the past, FDA estimates that approximately 300 written
IND safety reports concerning information that might materially
influence the benefit-risk assessment of an investigational drug, or
that would be sufficient to consider changes in either product
administration or in the overall conduct of a clinical investigation
will be submitted annually under proposed Sec. 312.32(c)(1)(ii) for
human drugs, and approximately 300 reports will be submitted annually
under proposed Sec. 312.32(c)(1)(ii) for human biological products.
FDA estimates that approximately 100 sponsors will submit these written
IND safety reports for human drugs, and approximately 100 sponsors will
submit these reports for human biological products. Based on the
agency's familiarity with the content of written IND safety reports,
FDA estimates that it will take an average of 8 hours for sponsors to
prepare and submit this type of written IND safety
[[Page 12467]]
report to FDA. Preparation of these written IND safety reports would
include gathering information (proposed Sec. 312.32(b)) and formatting
information (proposed Sec. 312.32(c)(1)(iii)).
Proposed Sec. 312.32(c)(2) would require sponsors to notify FDA by
telephone or by facsimile transmission of any unexpected fatal or life-
threatening SADR based on the opinion of the investigator or sponsor as
soon as possible but in no case later than 7 calendar days after
receipt by the sponsor of the minimum data set for an unexpected fatal
or life-threatening SADR. Based on data concerning the number of
telephone IND safety reports currently received by the agency, FDA
estimates that approximately 490 telephone and facsimile IND safety
reports will be submitted annually under proposed Sec. 312.32(c)(2)
for human drugs, and approximately 290 reports will be submitted
annually under proposed Sec. 312.32(c)(2) for human biological
products. FDA estimates that approximately 135 sponsors will submit
these reports for human drugs, and approximately 180 sponsors will
submit these reports for human biological products. Based on the
agency's familiarity with telephone and facsimile IND safety reports,
FDA estimates that it will take an average of 4 hours for sponsors to
prepare and submit one of these reports to FDA. Preparation of a
telephone or facsimile IND safety report would include gathering
information (proposed Sec. 312.32(b)).
Proposed Sec. 312.64(b) would require an investigator to notify
the sponsor of any serious SADR immediately and any other SADR promptly
unless the protocol or investigator's brochure specifies a different
timetable for reporting the SADR. Based on data concerning the number
of sponsors currently conducting clinical investigations under an IND
and the number of written IND safety reports currently received by the
agency, FDA estimates that approximately 100,000 investigator safety
reports will be submitted to sponsors annually under proposed Sec.
312.64(b) for human drugs, and approximately 60,000 investigator safety
reports will be submitted to sponsors annually under proposed Sec.
312.64(b) for human biological products. FDA estimates that
approximately 10,000 investigators will submit safety reports to
sponsors for human drugs, and approximately 6,000 investigators will
submit safety reports to sponsors for human biological products. Based
on the agency's familiarity with the content of IND safety reports, FDA
estimates that it will take an average of 2 hours for an investigator
to prepare and submit one of these reports to the sponsor.
Proposed Sec. 320.31(d)(3) would require persons conducting human
bioavailability and bioequivalence studies that are not subject to an
IND to submit to FDA written safety reports as prescribed under
proposed Sec. 312.32(c)(1) and telephone and facsimile safety reports
as prescribed under proposed Sec. 312.32(c)(2). These persons would
submit these safety reports to all participating investigators and the
appropriate FDA division in the Center for Drug Evaluation and Research
(i.e., safety reports for the reference listed drug would be forwarded
to the new drug review division that has responsibility for that drug;
safety reports for the investigational drug product would be forwarded
to the Director, Division of Bioequivalence, Office of Generic Drugs).
These persons would be required to identify all safety reports
previously filed for the bioavailability or bioequivalence study
concerning a similar SADR, and analyze the SADR in light of previous
similar reports, as required under proposed Sec. 312.32(c)(1)(i).
Written, telephone, and facsimile safety reports for bioavailability
and bioequivalence studies not subject to an IND are a new type of
safety report. Based on data concerning voluntary reporting to the
agency of safety information for these bioavailability and
bioequivalence studies, FDA estimates that approximately 200 safety
reports will be submitted annually under proposed Sec. 320.31(d)(3).
FDA estimates that approximately 10 sponsors will submit these safety
reports. Based on the agency's familiarity with the content of IND
safety reports, FDA estimates that it will take an average of 14 hours
for sponsors to prepare and submit a safety report to FDA.
Proposed Sec. 606.170(b) would require blood establishments to
notify FDA in a written report of any serious SAR, except a fatality,
within 45 calendar days after determination of a serious SAR. These
written reports would be submitted to FDA using the reporting format
provided in proposed Sec. 600.80(c)(4). Based on data from the
scientific literature and reports voluntarily received by the agency,
FDA estimates that approximately 7,000 written reports will be
submitted annually under proposed Sec. 606.170(b). FDA estimates that
approximately 3,062 blood establishments will submit these written
reports. Based on the agency's familiarity with the content of
expedited reports for serious and unexpected SADRs, FDA estimates that
it will take an average of 16 hours to prepare and submit each of these
written reports to FDA.
Proposed Sec. 606.170(c) would require blood establishments to
notify FDA by telephone, facsimile, express mail, or electronically
transmitted mail as soon as possible of an SAR that results in a
fatality. Proposed Sec. 606.170(c) would also require these facilities
to submit a written report to FDA within 7 calendar days after the
fatality. The written reports would be submitted using the reporting
format provided in proposed Sec. 600.80(c)(4). Based on data
concerning the number of reports for fatalities associated with blood
collection and transfusion currently received by the agency, FDA
estimates that approximately 75 reports will be submitted annually
under proposed Sec. 606.170(c). FDA estimates that approximately 75
blood establishments will submit these reports. Based on the agency's
familiarity with the content of written reports for a fatality, FDA
estimates that it will take an average of 20 hours to prepare and
submit each of these reports to FDA.
VI.B. Periodic Safety Reports
Proposed Sec. Sec. 314.80(c)(3)(i) and 600.80(c)(3)(i) would
require persons holding an application (i.e., NDA, ANDA, BLA) approved
before January 1, 1998, to submit a TPSR every 5 years after U.S.
approval of the application. These persons would also be required to
submit a TPSR at 7.5 and 12.5 years after U.S. approval of the
application. Based on data concerning postmarketing periodic safety
reports currently received by the agency, FDA estimates that
approximately 1,400 TPSRs will be submitted annually under proposed
Sec. 314.80(c)(3)(i); approximately 35 TPSRs will be submitted
annually under proposed Sec. 600.80(c)(3)(i). FDA estimates that
approximately 80 applicants under proposed Sec. 314.80(c)(3)(i) will
submit TPSRs, and approximately 20 applicants under proposed Sec.
600.80(c)(3)(i) will submit TPSRs. Based on the agency's familiarity
with the content of postmarketing periodic safety reports, FDA
estimates that it will take an average of 20 hours for applicants to
prepare and submit a TPSR to FDA. Preparation of a TPSR would include
gathering information (proposed Sec. Sec. 314.80(b) and 600.80(b)),
and providing attachments (proposed Sec. Sec. 314.80(c)(3) and
600.80(c)(3)).
Proposed Sec. Sec. 314.80(c)(3)(ii) and 600.80(c)(3)(ii) would
require persons holding an application (i.e., NDA, ANDA, BLA) approved
on or after January 1, 1998, to submit a PSUR to
[[Page 12468]]
FDA according to the following schedule: Semiannually for 2 years after
U.S. approval of the application, annually for the next 3 years, and
then every 5 years thereafter. Proposed Sec. Sec. 314.80(c)(3)(i) and
600.80(c)(3)(i) would permit persons holding an application (i.e., NDA,
ANDA, BLA) approved before January 1, 1998, to submit a PSUR, in lieu
of a TPSR, every 5 years after U.S. approval of the application.
Proposed Sec. Sec. 314.80(c)(3)(iv) and 600.80(c)(3)(iv) would require
persons holding an approved supplement to an approved application for
use of the human drug or biological product in the pediatric population
to submit a PSUR (even if the supplement or application was approved
prior to January 1, 1998) to FDA according to the following schedule:
Semiannually for 2 years after U.S. approval of the supplement,
annually for the next 3 years, and then every 5 years thereafter. Based
on data concerning postmarketing periodic safety reports currently
received by the agency, FDA estimates that approximately 2,500 PSURs
will be submitted annually under proposed Sec. 314.80(c)(3)(i),
(c)(3)(ii), and (c)(3)(iv), and approximately 35 PSURs will be
submitted annually under proposed Sec. 600.80(c)(3)(i), (c)(3)(ii),
and (c)(3)(iv). FDA estimates that approximately 200 applicants under
proposed Sec. 314.80(c)(3) will submit PSURs, and approximately 20
applicants under proposed Sec. 600.80(c)(3) will submit PSURs. Based
on the agency's familiarity with the content of PSURs voluntarily
submitted to the agency, FDA estimates that it will take an average of
40 hours for applicants to prepare and submit a PSUR to the agency.
Preparation of a PSUR would include gathering information (proposed
Sec. Sec. 314.80(b) and 600.80(b)) and providing attachments (proposed
Sec. Sec. 314.80(c)(3) and 600.80(c)(3)).
Proposed Sec. Sec. 314.80(c)(3)(iii) and 600.80(c)(3)(iii) would
require persons holding an application (i.e., NDA, ANDA, BLA) approved
on or after January 1, 1998, to submit an IPSR to FDA 7.5 years and
12.5 years after U.S. approval of the application. Proposed Sec. Sec.
314.80(c)(3)(i) and 600.80(c)(3)(i) would permit persons holding an
application (i.e., NDA, ANDA, BLA) approved before January 1, 1998, to
submit an IPSR at 7.5 and 12.5 years after U.S. approval of the
application. Proposed Sec. Sec. 314.80(c)(3)(iv) and 600.80(c)(3)(iv)
would require persons holding an approved supplement to an approved
application for use of the human drug or biological product in the
pediatric population to submit an IPSR (even if the supplement or
application was approved prior to January 1, 1998) to FDA at 7.5 and
12.5 years after U.S. approval of the supplement. Based on data
concerning postmarketing periodic safety reports currently received by
the agency, FDA estimates that approximately 350 IPSRs will be
submitted annually under proposed Sec. 314.80(c)(3)(i), (c)(3)(iii),
and (c)(3)(iv), and approximately 3 IPSRs will be submitted annually
under proposed Sec. 600.80(c)(3)(i), (c)(3)(iii), and (c)(3)(iv). FDA
estimates that approximately 40 applicants under proposed Sec.
314.80(c)(3) will submit IPSRs, and approximately 3 applicants under
proposed Sec. 600.80(c)(3) will submit IPSRs. Based on the agency's
familiarity with the content of PSURs voluntarily submitted to the
agency, FDA estimates that it will take an average of 30 hours for
applicants to prepare and submit an IPSR to FDA. Preparation of an IPSR
would include gathering information (proposed Sec. Sec. 314.80(b) and
600.80(b)) and providing attachments (proposed Sec. Sec. 314.80(c)(3)
and 600.80(c)(3)).
Proposed Sec. Sec. 314.80(c)(3)(v) and 600.80(c)(3)(v) would
require persons holding an application (i.e., NDA, ANDA, BLA) to submit
to FDA every 6 months after U.S. approval of the application a report
that consists of individual case safety reports (i.e., FDA Form 3500As,
VAERS forms for vaccines, CIOMS I forms, if desired, for foreign SADRs)
for certain spontaneously reported SADRs for marketed human drug and
biological products. Applicants that submit TPSRs to FDA would submit a
report consisting of individual case safety reports for each
spontaneously reported serious, expected SADR, whether domestic or
foreign, and each spontaneously reported nonserious, unexpected SADR
occurring in the United States during the reporting period. Reports for
vaccines would include a VAERS form for each spontaneously reported
nonserious, expected SAR and each expected SAR with unknown outcome
occurring in the United States during the reporting period. Applicants
that submit PSURs or IPSRs to FDA would submit a report consisting of
individual case safety reports for each spontaneously reported serious,
listed SADR, whether domestic or foreign, and each spontaneously
reported nonserious, unlisted SADR occurring in the United States
during the reporting period. Reports for vaccines would include a VAERS
form for each spontaneously reported nonserious, listed SAR and each
listed SAR with unknown outcome occurring in the United States during
the reporting period. If a full data set is not available for a report
of a serious SADR, the reason(s) for the lack of such information would
be provided. Based on data concerning postmarketing periodic safety
reports currently received by the agency, FDA estimates that
approximately 4,726 of these reports will be submitted annually under
proposed Sec. 314.80(c)(3)(v), and approximately 480 of these reports
will be submitted annually under proposed Sec. 600.80(c)(3)(v). FDA
estimates that approximately 285 applicants under proposed Sec.
314.80(c)(3) will submit these reports, and approximately 69 applicants
under proposed Sec. 600.80(c)(3) will submit reports. Based on the
agency's familiarity with the content of postmarketing periodic safety
reports, FDA estimates that it will take an average of 120 hours for
applicants to prepare and submit a report under proposed Sec. Sec.
314.80(c)(3)(v) and 600.80(c)(3)(v) to the agency. Preparation of a
report under proposed Sec. Sec. 314.80(c)(3)(v) and 600.80(c)(3)(v)
would include gathering information (proposed Sec. Sec. 314.80(b) and
(c)(1), and 600.80(b) and (c)(1)), providing attachments, if applicable
(proposed Sec. Sec. 314.80(c)(2)(ix) and (c)(3), and 600.80(c)(2)(ix)
and (c)(3)), and formatting information (proposed Sec. Sec.
314.80(c)(4) and (e), and 600.80(c)(4) and (e)).
VI.C. Other Reports
Proposed Sec. Sec. 310.305(f)(1), 314.80(f), and 600.80(f) would
require manufacturers, applicants, contractors, and shared
manufacturers to submit to FDA, when appropriate, any or all records
required to be maintained by these persons. These records would be
required to be submitted within 5 calendar days after receipt of the
request by the person. Records of all safety information pertaining to
the person's product, received or otherwise obtained, including raw
data, any correspondence relating to the safety information, and any
reports of SADRs or medication errors not submitted to FDA or only
provided to FDA in a summary tabulation would be included, as well as
records required to be maintained under proposed Sec. 310.305 (Sec.
310.305(c)(1)(ii), (c)(1)(iii)(A), (c)(2)(ii), (c)(2)(viii)(A), and
(c)(2)(xi)(C)), proposed Sec. 314.80 (Sec. 314.80(c)(1)(ii),
(c)(1)(iii)(A), (c)(2)(ii), (c)(2)(viii)(A), and (c)(2)(x)(C)), and
proposed Sec. 600.80 (Sec. 600.80(c)(1)(ii), (c)(1)(iii)(A),
(c)(2)(ii), (c)(2)(viii)(A), and (c)(2)(x)(C)). Submission of SADR
records to FDA represents a new reporting requirement. Based on the
agency's requests for voluntary
[[Page 12469]]
submission of safety records, FDA estimates that approximately 2
requests for submission of records will be fulfilled annually under
proposed Sec. 310.305(f)(1), approximately 15 requests for submission
of records will be fulfilled annually under proposed Sec. 314.80(f),
and approximately 4 requests for submission of records will be
fulfilled annually under proposed Sec. 600.80(f). FDA estimates that
approximately 2 manufacturers and contractors under proposed Sec.
310.305 will submit these records, approximately 15 applicants and
contractors under proposed Sec. 314.80 will submit these records, and
approximately 4 applicants, contractors and shared manufacturers under
proposed Sec. 600.80 will submit these records. Based on the volume of
safety information voluntarily submitted to FDA in response to an
agency request for such information, FDA estimates that it will take an
average of 8 hours for manufacturers, applicants, contractors, and
shared manufacturers to fulfill each request for submission of records
to the agency.
Proposed Sec. 314.81(b)(2) would require applicants of marketed
drug products subject to an NDA to submit an annual report to FDA
within 60 days of the anniversary date of U.S. approval of the
application. This report would contain summary information;
distribution data; chemistry, manufacturing, and controls changes;
clinical data; and a status report of any postmarketing studies
performed by, or on behalf of, the applicant. Based on data concerning
the number of approved NDA annual reports received by the agency, FDA
estimates that approximately 2,363 reports will be submitted under
proposed Sec. 314.81(b)(2). FDA estimates that approximately 286
applicants will submit these reports. Based on the agency's familiarity
with the content of approved NDA annual reports, FDA estimates that it
will take an average of 35.5 hours for applicants to prepare and submit
one of these annual reports to FDA.
Proposed Sec. 601.28 would require applicants of licensed
biological products to submit an annual report of postmarketing
pediatric studies to FDA within 60 days of the anniversary date of
approval of the application. This report would contain summary
information, clinical data in the pediatric population, and a status
report of any postmarketing studies in the pediatric population. Based
on data concerning the number of approved BLA annual reports received
by the agency, FDA estimates that approximately 69 reports will be
submitted under proposed Sec. 601.28. FDA estimates that approximately
69 applicants will submit these reports. Based on the agency's
familiarity with the content of approved BLA annual reports, FDA
estimates that it will take an average of 25 hours for applicants to
prepare and submit an annual report to the agency.
VI.D. Recordkeeping
Proposed Sec. Sec. 310.305(c)(2)(xi)(B), 314.80(c)(2)(x)(B), and
600.80(c)(2)(x)(B) would require that contracts between manufacturers
and contractors (proposed Sec. 310.305(c)(2)(xi)(B)) and applicants
and contractors (proposed Sec. Sec. 314.80(c)(2)(x)(B) and
600.80(c)(2)(x)(B)) specify the safety reporting responsibilities of
the contractor. For purposes of this section, a record represents a
contract. Based on information contained in individual case safety
reports submitted to the agency in the past (i.e., report source), FDA
estimates that approximately 4 records will be maintained annually
under proposed Sec. 310.305(c)(2)(xi)(B), approximately 480 records
will be maintained annually under proposed Sec. 314.80(c)(2)(x)(B),
and approximately 2 records will be maintained annually under proposed
Sec. 600.80(c)(2)(x)(B). FDA estimates that approximately 2
manufacturers under proposed Sec. 310.305 will maintain these records,
approximately 160 applicants under proposed Sec. 314.80 will maintain
these records, and approximately 2 applicants under proposed Sec.
600.80 will maintain these records. Based on the agency's familiarity
with recordkeeping processes, FDA estimates that it will take an
average of 1 hour for manufacturers and applicants to maintain each
record annually under proposed Sec. Sec. 310.305(c)(2)(xi)(B),
314.80(c)(2)(x)(B), and 600.80(c)(2)(x)(B).
Proposed Sec. Sec. 310.305(f), 314.80(f), and 600.80(f) would
require manufacturers, applicants, contractors, and shared
manufacturers to maintain for a period of 10 years records of all
safety information, received or otherwise obtained, including raw data;
any correspondence relating to the safety information; and any reports
of SADRs or medication errors not submitted to FDA or only provided to
FDA in a summary tabulation. These persons would also be required to
retain for a period of 10 years any records required to be maintained
under proposed Sec. 310.305 (Sec. 310.305(c)(1)(ii), (c)(1)(iii)(A),
(c)(2)(ii), (c)(2)(viii)(A), and (c)(2)(xi)(C)), proposed Sec. 314.80
(Sec. 314.80(c)(1)(ii), (c)(1)(iii)(A), (c)(2)(ii), (c)(2)(viii)(A),
and (c)(2)(x)(C)), and proposed Sec. 600.80 (Sec. 600.80(c)(1)(ii),
(c)(1)(iii)(A), (c)(2)(ii), (c)(2)(viii)(A), and (c)(2)(x)(C)). For the
purposes of this section, a record includes any and all documentation
regarding an individual SADR or medication error. Based on data
concerning the number of SADRs currently reported to the agency, FDA
estimates that approximately 500 records will be maintained annually
under proposed Sec. 310.305(f), approximately 220,000 records will be
maintained annually under proposed Sec. 314.80(f), and approximately
20,000 records will be maintained annually under proposed Sec.
600.80(f). FDA estimates that approximately 25 manufacturers and
contractors under proposed Sec. 310.305 will maintain these records,
approximately 700 applicants and contractors under proposed Sec.
314.80 will maintain these records, and approximately 69 applicants,
contractors, and shared manufacturers under proposed Sec. 600.80 will
maintain these records. Based on the agency's familiarity with
recordkeeping processes, FDA estimates that it will take an average of
5 hours for manufacturers, applicants, contractors, and shared
manufacturers to maintain each record annually under proposed
Sec. Sec. 310.305, 314.80, and 600.80.
Proposed Sec. Sec. 310.305(g), 314.80(g), and 600.80(g) would
require manufacturers, applicants, contractors, and shared
manufacturers to maintain written procedures for the surveillance,
receipt, evaluation, and reporting of safety information to FDA. Based
on the number of persons subject to the postmarketing safety reporting
regulations, FDA estimates that approximately 25 records will be
maintained annually under proposed Sec. 310.305(g), approximately 700
records will be maintained annually under proposed Sec. 314.80(g), and
approximately 69 records will be maintained annually under proposed
Sec. 600.80(g). FDA estimates that approximately 25 manufacturers and
contractors under proposed Sec. 310.305 will maintain these records,
approximately 700 applicants and contractors under proposed Sec.
314.80 will maintain these records, and approximately 69 applicants,
contractors, and shared manufacturers under proposed Sec. 600.80 will
maintain these records. Based on the agency's familiarity with
recordkeeping processes, FDA estimates that it will take an average of
1 hour for manufacturers, applicants, contractors, and shared
manufacturers to maintain a record of the written procedures
[[Page 12470]]
annually under proposed Sec. Sec. 310.305(g), 314.80(g), and
600.80(g).
Proposed Sec. 312.32(c) would require sponsors to maintain records
for reports of SADRs that do not contain a minimum data set. This would
include any information received or otherwise obtained for the SADR
along with a record of their efforts to obtain a minimum data set for
the report. For the purposes of this section, a record includes any and
all documentation regarding an individual SADR. Maintaining records of
SADRs that do not contain a minimum data set represents a new
recordkeeping requirement. Based on information contained in IND safety
reports, FDA estimates that approximately 200 records will be
maintained annually under proposed Sec. 312.32(c) for human drugs;
approximately 240 records will be maintained annually under proposed
Sec. 312.32(c) for human biological products. FDA estimates that
approximately 50 sponsors will maintain these records for human drugs
and approximately 60 sponsors will maintain these records for human
biological products. Based on the agency's familiarity with
recordkeeping processes, FDA estimates that it will take an average of
1 hour for sponsors to maintain each record annually under proposed
Sec. 312.32(c).
Proposed Sec. 606.170(a) would require blood collection and
transfusing facilities to maintain records for complaints of SARs
regarding each unit of blood or blood product. These facilities must
prepare a written report of the investigation of SARs, including
followup and conclusions. Based on data for records currently
maintained by blood collection and transfusing facilities, FDA
estimates that approximately 4,512 records will be maintained annually
under proposed Sec. 606.170(a). FDA estimates that approximately 376
facilities will maintain these records. Based on the agency's
familiarity with recordkeeping processes, FDA estimates that it will
take an average of 12 hours for facilities to maintain each record
annually under proposed Sec. 606.170(a).
Description of Respondents: Business or other for-profit
organizations.
In compliance with section 3507(d) of the Paperwork Reduction Act
of 1995 (44 U.S.C. 3507(d)), the agency has submitted a copy of this
proposed rule to OMB for its review and approval of these information
collections. Interested persons are requested to send comments
regarding this information collection, including suggestions for
reducing this burden, to the Office of Information and Regulatory
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., rm. 10235,
Washington, DC 20503, OMB, Attn: Stuart Shapiro, Desk Officer for FDA,
FAX: 202-395-6974. Submit written comments on the information
collection by April 14, 2003.
Table 21.--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of
21 CFR section Number of responses per Total annual Hours per Total hours
respondents respondent responses response
----------------------------------------------------------------------------------------------------------------
310.305(c)(2)(i) \2\........... 14 25 350 16 5,600
310.305(c)(2)(ii).............. 5 1 5 8 40
310.305(c)(2)(iii)............. 10 4.6 46 24 1,104
310.305(c)(2)(iv).............. 10 5 50 16 800
310.305(c)(2)(v)............... 10 100 1,000 16 16,000
310.305(c)(2)(vi).............. 7 48.6 340 8 2,720
310.305(b)(2), (c)(2)(vii), and 10 5.5 55 4 220
(c)(2)(viii)(A)...............
310.305(c)(2)(xi).............. 5 2 10 2 20
310.305(f)(1).................. 2 1 2 8 16
312.32(c)(1)(i) \3\--human 457 10.6 4,860 16 77,760
drugs.........................
312.32(c)(1)(ii)--human drugs.. 100 3 300 8 2,400
312.32(c)(2)--human drugs...... 135 3.6 490 4 1,960
312.32(c)(1)(i)--human 602 4.9 2,980 16 47,680
biological products...........
312.32(c)(1)(ii)--human 100 3 300 8 2,400
biological products...........
312.32(c)(2)--human biological 180 1.6 290 4 1,160
products......................
312.64(b)--human drugs......... 10,000 10 100,000 2 200,000
312.64(b)--human biological 6,000 10 60,000 2 120,000
products......................
314.80(c)(2)(i) \4\............ 282 177.3 50,000 16 800,000
314.80(c)(2)(ii)............... 50 6 300 8 2,400
314.80(c)(2)(iii).............. 109 8.4 912 24 21,888
314.80(c)(2)(iv)............... 100 15 1,500 16 24,000
314.80(c)(2)(v)................ 150 666.7 100,000 16 1,600,000
314.80(c)(2)(vi)............... 140 307.1 43,000 8 344,000
314.80(b)(2), (c)(2)(vii), and 184 54.3 10,000 4 40,000
(c)(2)(viii)(A)...............
314.80(c)(2)(x)................ 100 113.7 11,370 2 22,740
314.80(c)(3)(i)................ 80 17.5 1,400 20 28,000
314.80(c)(3)(i), (c)(3)(ii), 200 12.5 2,500 40 100,000
and (c)(3)(iv)................
314.80(c)(3)(i), (c)(3)(iii), 40 8.7 350 30 10,500
and (c)(3)(iv)................
314.80(c)(3)(v)................ 285 16.6 4,726 120 567,120
314.80(f)...................... 15 1 15 8 120
314.81(b)(2)................... 286 8.3 2,363 35.5 83,886
320.31(d)(3)................... 10 20 200 14 2,800
600.80(c)(2)(i) \5\............ 69 43.5 3,000 16 48,000
600.80(c)(2)(ii)............... 4 1 4 8 32
600.80(c)(2)(iii).............. 12 2.1 25 24 600
600.80(c)(2)(iv)............... 10 10 100 16 1,600
600.80(c)(2)(v)................ 30 333.3 10,000 16 160,000
600.80(c)(2)(vi)............... 69 43.5 3,000 8 24,000
600.80(b)(2), (c)(2)(vii), and 69 14.5 1,000 4 4,000
(c)(2)(viii)(A)...............
600.80(c)(2)(x)................ 20 12.5 250 2 500
600.80(c)(3)(i)................ 20 1.8 35 20 700
600.80(c)(3)(i), (c)(3)(ii), 20 1.8 35 40 1,400
and (c)(3)(iv)................
[[Page 12471]]
600.80(c)(3)(i), (c)(3)(iii), 3 1 3 30 90
and (c)(3)(iv)................
600.80(c)(3)(v)................ 69 6.9 480 120 57,600
600.80(f)...................... 4 1 4 8 32
601.28......................... 69 1 69 25 1,725
606.170(b)..................... 3,062 2.3 7,000 16 112,000
606.170(c)..................... 75 1 75 20 1,500
-----------------
Total...................... 23,283 2,149.7 424,794 896.5 4,541,113
----------------------------------------------------------------------------------------------------------------
\1\ The estimates provided in this table are not only attributed to the new proposed requirements in this
rulemaking but also include burdens associated with our current safety reporting requirements. There are no
capital costs or operating and maintainence costs associated with this collection of information.
\2\ The paragraphs of Sec. 310.305 cited in the table include burdens associated with gathering information
under Sec. 310.305(b) and (c)(1), providing attachments, if applicable, under Sec. 310.305(c)(2)(ix) and
(c)(2)(x), and formatting information under Sec. 310.305(c)(2)(xii), (d), and (e).
\3\ The paragraphs of Sec. 312.32 cited in the table include burdens associated with gathering information
under Sec. 312.32(b) and formatting information under Sec. 312.32(c)(1)(iii).
\4\ The paragraphs of Sec. 314.80 cited in the table include burdens associated with gathering information
under Sec. 314.80(b) and (c)(1), providing attachments, if applicable, under Sec. 314.80(c)(2)(ix) and
(c)(3), and formatting information under Sec. 314.80(c)(2)(xi), (c)(4), and (e).
\5\ The paragraphs of Sec. 600.80 cited in the table include burdens associated with gathering information
under Sec. 600.80(b) and (c)(1), providing attachments, if applicable, under Sec. 600.80(c)(2)(ix) and
(c)(3), and formatting information under Sec. 600.80(c)(2)(xi), (c)(4), and (e).
Table 22.--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR section Number of frequency of Total annual Hours per Total hours
recordkeepers recordkeeping records record
----------------------------------------------------------------------------------------------------------------
310.305(c)(2)(xi)(B).......... 2 2 4 1 4
310.305(f) \2\................ 25 20 500 5 2,500
310.305(g).................... 25 1 25 1 25
312.32(c)--human drugs........ 50 4 200 1 200
312.32(c)--human biological 60 4 240 1 240
products.....................
314.80(c)(2)(x)(B)............ 160 3 480 1 480
314.80(f) \3\................. 700 314.3 220,000 5 1,100,000
314.80(g)..................... 700 1 700 1 700
600.80(c)(2)(x)(B)............ 2 1 2 1 2
600.80(f) \4\................. 69 289.8 20,000 5 100,000
600.80(g)..................... 69 1 69 1 69
606.170(a).................... 376 12 4,512 12 54,144
Total..................... 2,238 653.1 246,732 35 1,258,364
----------------------------------------------------------------------------------------------------------------
\1\ The estimates provided in this table are not only attributed to the new proposed requirements in this
rulemaking but also include burdens associated with our current safety reporting requirements. There are no
capital costs or operating costs associated with this collection of information. There are maintenance costs
of $2,025 annually per recordkeeper ($2,000 annually per recordkeeper for existing recordkeeping requirements
(see 67 FR 47821) and $25 annually per recordkeeper for new proposed requirements in this rulemaking).
\2\ Includes records required to be maintained under Sec. 310.305(c)(1)(ii), (c)(1)(iii)(A), (c)(2)(ii),
(c)(2)(viii)(A), and (c)(2)(xi)(C).
\3\ Includes records required to be maintained under Sec. 314.80(c)(1)(ii), (c)(1)(iii)(A), (c)(2)(ii),
(c)(2)(viii)(A), and (c)(2)(x)(C).
\4\ Includes records required to be maintained under Sec. 600.80(c)(1)(ii), (c)(1)(iii)(A), (c)(2)(ii),
(c)(2)(viii)(A), and (c)(2)(x)(C).
VII. Executive Order 13132: Federalism
Executive Order 13132 requires Federal agencies to carefully
examine regulatory actions to determine if they would have a
significant impact on federalism. Using the criteria and principles set
forth in the Executive order, the agency has considered the impact of
this proposed rule on the States, on their relationship with the
Federal Government, and on the distribution of power and
responsibilities among the various levels of government.
FDA is publishing this proposed rule to revise its regulations
governing the format, content, and submission of safety reports to the
agency for human drugs and biological products. The proposal would
revise current regulations to implement definitions and reporting
formats and standards recommended by ICH and CIOMS. The proposal would
codify the agency's expectations for timely acquisition, evaluation,
and submission of relevant safety information for marketed drugs and
biological products. The proposal would require that postmarketing
individual case safety reports of unexpected SADRs that cannot be
classified as either serious or nonserious be submitted to the agency
in an expedited manner. The proposal would also require that certain
medically significant SADRs always be submitted to FDA in an expedited
manner whether the SADR is unexpected or expected. The proposal would
also require that all domestic reports of medication errors, whether
actual or potential, be submitted to FDA in an expedited manner. The
proposal would clarify certain safety reporting requirements and make
other minor revisions. The proposal would also amend the agency's
postmarketing annual reports regulations for applicants of human drugs
and licensed biological products to revise the content for these
reports. The proposal would also amend the agency's bioavailability and
bioequivalence study regulations for sponsors of human drugs to require
expedited safety reports for certain studies which are exempt from
submission of an IND. Because enforcement of these safety reporting
requirements would be a Federal responsibility, there would be little,
if
[[Page 12472]]
any, impact on the States from this rule if finalized.
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the rule does not contain policies that have substantial direct effects
on the States, on the relationship between National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, the agency has concluded
that the rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.
List of Subjects
21 CFR Part 310
Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.
21 CFR Part 312
Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.
21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
21 CFR Part 320
Drugs, Reporting and recordkeeping requirements.
21 CFR Part 600
Biologics, Reporting and recordkeeping requirements.
21 CFR Part 601
Administrative practice and procedure, Biologics, Confidential
business information.
21 CFR Part 606
Blood, Labeling, Laboratories, Reporting and recordkeeping
requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, it is proposed that 21 CFR parts 310,
312, 314, 320, 600, 601, and 606 be amended as follows:
PART 310--NEW DRUGS
1. The authority citation for 21 CFR part 310 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f,
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262,
263b-263n.
2. Section 310.305 is revised to read as follows:
Sec. 310.305 Safety reporting and recordkeeping for manufacturers of
prescription drugs marketed for human use without an approved
application.
(a) Definitions. The following definitions of terms apply to this
section:
Active query means direct verbal contact (i.e., in person or by
telephone or other interactive means such as a video conference) with
the initial reporter of a suspected adverse drug reaction (SADR) or a
medication error by a health care professional (e.g., physician,
physician assistant, pharmacist, dentist, nurse, any individual with
some form of health care training) representing the manufacturer. For
SADRs, active query entails, at a minimum, a focused line of
questioning designed to capture clinically relevant information
associated with the drug product and the SADR, including, but not
limited to, information such as baseline data, patient history,
physical exam, diagnostic results, and supportive lab results.
Actual medication error means a medication error that involves an
identifiable patient whether the error was prevented prior to
administration of the product or, if the product was administered,
whether the error results in a serious SADR, nonserious SADR, or no
SADR.
Contractor means any person (e.g., packer or distributor whether or
not its name appears on the label of the product; licensee; contract
research organization) that has entered into a contract with the
manufacturer to manufacture, pack, sell, distribute, or develop the
drug or to maintain, create, or submit records regarding SADRs or
medication errors.
Disability means a substantial disruption of a person's ability to
conduct normal life functions.
Full data set means completion of all the applicable elements on
FDA Form 3500A (or on a Council for International Organizations of
Medical Sciences (CIOMS) I form for reports of foreign SADRs),
including a concise medical narrative of the case (i.e., an accurate
summary of the relevant data and information pertaining to an SADR or
medication error).
Life-threatening SADR means any SADR that, in the view of the
initial reporter, places the patient at immediate risk of death from
the SADR as it occurred. It does not include an SADR that, had it
occurred in a more severe form, might have caused death.
Medication error means any preventable event that may cause or lead
to inappropriate medication use or patient harm while the medication is
in the control of the health care professional, patient, or consumer.
Such events may be related to professional practice, health care
products, procedures, and systems including: Prescribing; order
communication; product labeling, packaging, and nomenclature;
compounding; dispensing; distribution; administration; education;
monitoring; and use.
Minimum data set means the report includes an identifiable patient,
an identifiable reporter, a suspect drug product, and an SADR.
Nonserious SADR means any SADR that is determined not to be a
serious SADR.
Potential medication error means an individual case safety report
of information or complaint about product name, labeling, or packaging
similarities that does not involve a patient.
SADR with unknown outcome means an SADR that cannot be classified,
after active query, as either serious or nonserious.
Serious SADR means any SADR that results in any of the following
outcomes: Death, a life-threatening SADR, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant
disability/incapacity, or a congenital anomaly/birth defect. Important
medical events that may not result in death, be life-threatening, or
require hospitalization may be considered a serious SADR when, based
upon appropriate medical judgment, they may jeopardize the patient or
subject and may require medical or surgical intervention to prevent one
of the outcomes listed in this definition. Examples of such medical
events include allergic bronchospasm requiring intensive treatment in
an emergency room or at home, blood dyscrasias or convulsions that do
not result in inpatient hospitalization, or the development of drug
dependency or drug abuse.
Spontaneous report means a communication from an individual (e.g.,
health care professional, consumer) to a company or regulatory
authority that describes an SADR or medication error. It does not
include cases identified from information solicited by the manufacturer
or contractor, such as individual case safety reports or findings
derived from a study, company-sponsored patient support program,
disease management program, patient registry, including pregnancy
[[Page 12473]]
registries, or any organized data collection scheme. It also does not
include information compiled in support of class action lawsuits.
Suspected adverse drug reaction (SADR) means a noxious and
unintended response to any dose of a drug product for which there is a
reasonable possibility that the product caused the response. In this
definition, the phrase ``a reasonable possibility'' means that the
relationship cannot be ruled out.
Unexpected SADR means any SADR that is not included in the current
U.S. labeling for the drug product. Reactions that may be
symptomatically and pathophysiologically related to a reaction included
in the U.S. labeling, but differ from the labeled reaction because of
greater severity or specificity, would be unexpected. For example,
under this definition, hepatic necrosis would be unexpected (by virtue
of greater severity) if the U.S. labeling only referred to elevated
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and
cerebral vasculitis would be unexpected (by virtue of greater
specificity) if the U.S. labeling only included cerebral vascular
accidents. ``Unexpected,'' as used in this definition, refers to an
SADR that has not been previously observed (i.e., included in the U.S.
labeling); it does not refer to an SADR that might be anticipated from
the pharmacological properties of the drug product. SADRs that are
mentioned in the U.S. labeling as occurring with a class of drugs but
not specifically mentioned as occurring with the particular drug are
considered unexpected.
(b) Review of safety information. (1) Each manufacturer of a
prescription drug product marketed for human use without an approved
application must promptly review all safety information pertaining to
its product obtained or otherwise received by the manufacturer from any
source, foreign or domestic, including information derived from
commercial marketing experience, postmarketing clinical investigations,
postmarketing epidemiology/surveillance studies, animal or in vitro
studies, electronic communications with manufacturers via the Internet
(e.g., e-mail), reports in the scientific literature, and unpublished
scientific papers, as well as reports from foreign regulatory
authorities that have not been previously reported to the Food and Drug
Administration (FDA) by the manufacturer.
(2) Individual case safety reports that are forwarded to the
manufacturer by FDA must not be resubmitted to the agency by the
manufacturer; however, manufacturers must submit to FDA all followup
information for these reports.
(c) Reporting requirements. The manufacturer must submit to FDA one
copy of each expedited report (described under paragraphs (c)(2)(i)
through (c)(2)(vii) of this section) pertaining to its drug product.
Upon written notice, FDA may require, when appropriate, that the
manufacturer submit reports under this section to FDA at times other
than those stated.
(1) Determination of outcome, minimum data set, and full data set--
(i)(A) Initial determinations. Upon initial receipt of an SADR report,
the manufacturer must immediately determine, the outcome for the SADR
(whether the SADR is serious or nonserious) and at least the minimum
data set for the individual case safety report. For reports of actual
medication errors that do not result in an SADR and potential
medication errors, the manufacturer must immediately determine the
minimum information for the individual case safety report (minimum
information described under paragraphs (c)(1)(iii)(B) and
(c)(1)(iii)(C) of this section). If the manufacturer is not able to
immediately determine the information in this paragraph, active query
must be used to obtain it as soon as possible.
(B) Spontaneous reports. For spontaneous reports, the manufacturer
must always assume, for safety reporting purposes under this section,
that there is at least a reasonable possibility, in the opinion of the
initial reporter, that the drug product caused the spontaneously
reported event.
(C) Clinical trials. For a clinical trial, the possibility that the
drug product caused the SADR or that a medication error has occurred
must be assumed if either the investigator or the manufacturer believes
that such a reasonable possibility exists.
(ii) SADRs with unknown outcome. For an SADR with unknown outcome
that cannot be immediately determined, the manufacturer must continue
to use active query to attempt to determine the outcome of the SADR
within 30 calendar days after initial receipt of the SADR report by the
manufacturer. The manufacturer must maintain a record of its efforts to
determine the outcome for an SADR with unknown outcome.
(iii)(A) Minimum data set for SADR reports. The manufacturer must
not submit an individual case safety report for an SADR to FDA if the
report does not contain a minimum data set; instead, the manufacturer
must maintain records of any information received or otherwise obtained
for the SADR along with a record of its efforts to obtain a minimum
data set.
(B) Minimum information for reports of actual medication errors
that do not result in an SADR. For reports of actual medication errors
that do not result in an SADR, an individual case safety report must be
submitted to FDA even though the report does not contain a minimum data
set (i.e., does not have an SADR). These reports must contain at least
an identifiable patient, an identifiable reporter, and a suspect drug
product.
(C) Minimum information for potential medication error reports. For
reports of potential medication errors, an individual case safety
report must be submitted to FDA even though the report does not contain
a minimum data set (i.e., does not have an identifiable patient or an
SADR). These reports must contain at least an identifiable reporter and
a suspect drug product.
(iv) Full data set. For reports of serious SADRs, always expedited
reports (see paragraph (c)(2)(iv) of this section), and medication
error reports (see paragraph (c)(2)(v) of this section), the
manufacturer must submit a full data set. If a full data set is not
available for the report, the manufacturer must use active query to
obtain this information. If a full data set is not obtainable, after
active query, the manufacturer must:
(A) Submit all safety information, received or otherwise obtained,
for the report;
(B) Indicate the reason(s) for its inability to acquire a full data
set; and
(C) Document its efforts to obtain a full data set (i.e.,
description of unsuccessful steps taken to obtain this information).
(v) Serious SADRs not initially reported by health care
professional. For a serious SADR that was not initially reported to the
manufacturer by a health care professional (e.g., report from a
consumer), the manufacturer must contact the health care professional
associated with the care of the patient using active query to gather
further medical perspective on the case and to acquire a full data set
for the report. If the manufacturer is unable to contact the health
care professional, it must include in the report for the serious SADR:
(A) The reason(s) for its inability to contact the health care
professional; and
(B) A description of its efforts to contact the health care
professional.
(2) Postmarketing ``expedited reports''--(i) Serious and unexpected
SADR. The manufacturer must report to FDA each SADR, received or
otherwise obtained, that is both serious and
[[Page 12474]]
unexpected, whether foreign or domestic, as soon as possible, but in no
case later than 15 calendar days after receipt by the manufacturer of
the minimum data set for the serious, unexpected SADR. If a full data
set is not available for the serious and unexpected SADR report at the
time of initial submission of the report to FDA, the manufacturer must
submit the information required under paragraph (c)(1)(iv) of this
section and also submit a 30-day followup report as required by
paragraph (c)(2)(vi) of this section.
(ii) Information sufficient to consider product administration
changes. The manufacturer must also report to FDA information, received
or otherwise obtained, whether foreign or domestic, that would be
sufficient, based upon appropriate medical judgment, to consider
changes in product administration. The manufacturer must submit this
information to FDA, as soon as possible, but in no case later than 15
calendar days after determination by the manufacturer that the
information qualifies for expedited reporting. Examples of such
information include any significant unanticipated safety finding or
data in the aggregate from an in vitro, animal, epidemiological, or
clinical study, whether or not conducted under an investigational new
drug application (IND), that suggests a significant human risk, such as
reports of mutagenicity, teratogenicity, or carcinogenicity, or reports
of a lack of efficacy with a drug product used in treating a life-
threatening or serious disease. The manufacturer must maintain a record
of its efforts to determine whether the information required to be
reported under this paragraph qualifies for expedited reporting.
(iii) Unexpected SADR with unknown outcome. The manufacturer must
also report to FDA each SADR that is unexpected and for which the
determination of an outcome is unattainable (i.e., SADR with unknown
outcome) within 45 calendar days after initial receipt by the
manufacturer of the minimum data set for the unexpected SADR. The
manufacturer must document in the expedited report the reason(s) for
the inability to determine the outcome.
(iv) Always expedited report. (A) The manufacturer must also report
to FDA each SADR, received or otherwise obtained, whether foreign or
domestic, that is the subject of an always expedited report. These
reports must be submitted to FDA as soon as possible, but in no case
later than 15 calendar days after receipt by the manufacturer of the
minimum data set for the report. The following medically significant
SADRs, which may jeopardize the patient or subject and/or require
medical or surgical intervention to treat the patient or subject, are
subject to an always expedited report:
(1) Congenital anomalies,
(2) Acute respiratory failure,
(3) Ventricular fibrillation,
(4) Torsades de pointe,
(5) Malignant hypertension,
(6) Seizure,
(7) Agranulocytosis,
(8) Aplastic anemia,
(9) Toxic epidermal necrolysis,
(10) Liver necrosis,
(11) Acute liver failure,
(12) Anaphylaxis,
(13) Acute renal failure,
(14) Sclerosing syndromes,
(15) Pulmonary hypertension,
(16) Pulmonary fibrosis,
(17) Confirmed or suspected transmission of an infectious agent by
a marketed drug or biological product,
(18) Confirmed or suspected endotoxin shock, and
(19) Any other medically significant SADR that FDA determines to be
the subject of an always expedited report (i.e., may jeopardize the
patient or subject and/or require medical or surgical intervention to
treat the patient or subject).
(B) SADRs that are the subject of an always expedited report must
be submitted to FDA whether unexpected or expected and whether or not
the SADR leads to a serious outcome. If a full data set is not
available for an always expedited report at the time of initial
submission of the report to FDA, the manufacturer must submit the
information required under paragraph (c)(1)(iv) of this section and
also submit a 30-day followup report as required by paragraph
(c)(2)(vi) of this section.
(v) Medication errors--(A) Actual medication error. The
manufacturer must also submit to FDA each domestic report of an actual
medication error, received or otherwise obtained, as soon as possible,
but in no case later than 15 calendar days after receipt by the
manufacturer of the minimum data set for a report of an SADR or, if an
SADR does not occur, the minimum information described under paragraph
(c)(1)(iii)(B) of this section (i.e., identifiable patient,
identifiable reporter, and suspect drug product).
(B) Potential medication error. The manufacturer must also submit
to FDA each domestic report of a potential medication error, received
or otherwise obtained, as soon as possible, but in no case later than
15 calendar days after receipt by the manufacturer of the minimum
information described under paragraph (c)(1)(iii)(C) of this section
(i.e., identifiable reporter and suspect drug product).
(C) Full data set. If a full data set is not available for an
actual or potential medication error report at the time of initial
submission of the report to FDA, the manufacturer must submit the
information required under paragraph (c)(1)(iv) of this section and
also submit a 30-day followup report as required by paragraph
(c)(2)(vi) of this section.
(vi) The 30-day followup report. The manufacturer must use active
query to obtain additional information for any expedited report under
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that
does not contain a full data set and must submit a followup report to
FDA within 30 calendar days after initial submission of the expedited
report to FDA by the manufacturer. If a full data set is still not
obtainable, the 30-day followup report must contain the information
required under paragraph (c)(1)(iv) of this section. Any new safety
information in the 30-day followup report must be highlighted. Any new
information, received or otherwise obtained, after submission of a 30-
day followup report must be submitted to FDA as a 15-day followup
report under paragraph (c)(2)(vii) of this section.
(vii) The 15-day followup report. The manufacturer must report to
FDA any new information, received or otherwise obtained, for any
expedited or followup report (except for initial expedited reports
under paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section
that do not contain a full data set) within 15 calendar days of initial
receipt of the new information by the manufacturer. Expedited reports
under paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section
that do not contain a full data set at the time of initial submission
of the report to FDA are subject to the 30-day followup reporting
requirements under paragraph (c)(2)(vi) of this section rather than the
15-day followup reporting requirements under this paragraph.
(viii) Supporting documentation. (A) If the patient dies, the
manufacturer must submit a copy of the autopsy report to FDA, if it is
available. If an autopsy report is not available, the manufacturer must
submit a death certificate to FDA. If an autopsy report becomes
available after the manufacturer has submitted a death certificate to
the agency, the autopsy report must be submitted to FDA. If the patient
was hospitalized, the manufacturer must submit a copy of the hospital
discharge summary to FDA, if it is available. If any of these documents
is not in English, the document must be
[[Page 12475]]
accompanied by an English translation. Manufacturers must use active
query to obtain these documents. These documents must be submitted to
FDA as 15-day followup reports (see paragraph (c)(2)(vii) in this
section) within 15 calendar days of initial receipt of the document by
the manufacturer. If these documents are not submitted to FDA in a 15-
day followup report within 3 months after submission of the initial
expedited report for the death or hospitalization, the agency will
assume that active query by the manufacturer has not resulted in access
to these documents. In this case, a record of the reason(s) for the
lack of such documentation and the effort that was made to obtain the
documentation must be maintained by the manufacturer.
(B) Each expedited report must contain in the narrative a list of
other relevant documents (e.g., medical records, laboratory results,
data from studies) for the report that are maintained by the
manufacturer. When appropriate, FDA may require a manufacturer to
submit copies of one or more of these documents to the agency within 5
calendar days after receipt of the request.
(ix) Scientific literature. An expedited report based on
information from the scientific literature applies only to reports
found in scientific and medical journals. These expedited reports must
be accompanied by a copy of the published article.
(x) Attachments. Each expedited report must be accompanied by a
copy of the current U.S. labeling for the drug product and a list of
current addresses where all safety reports and other safety-related
records for the drug product are maintained by manufacturers and
contractors.
(xi) Submission of safety reports by contractors. (A) Contractors
must submit to the manufacturer safety reports of any SADRs or
medication errors for the manufacturer's drug product, obtained or
otherwise received, within 5 calendar days of initial receipt of the
report by the contractor. The contractor must submit a safety report
for an SADR to the manufacturer even if the report does not contain a
minimum data set. Upon receipt of the safety report from a contractor,
the manufacturer must comply with the postmarketing safety reporting
requirements of this section.
(B) A contract between the manufacturer and a contractor must
specify the postmarketing safety reporting responsibilities of the
contractor. The manufacturer is responsible for ensuring that the
contractors of its drug products comply with these postmarketing safety
reporting responsibilities.
(C) The contractor must maintain a record of each submission to the
manufacturer under paragraph (c)(2)(xi)(A) of this section that
includes:
(1) A copy of each safety report;
(2) The date the report was initially received by the contractor;
(3) The date the report was submitted to the manufacturer; and
(4) The name and address of the manufacturer.
(D) The recordkeeping, written procedures, and disclaimer
provisions under paragraphs (f) through (h) of this section apply to
contractors.
(xii) Report identification. Each expedited report submitted to FDA
under paragraphs (c)(2)(i) through (c)(2)(vii) of this section must
bear prominent identification as to its contents, e.g., ``expedited
report--Sec. 310.305--serious and unexpected SADR,'' ``expedited
report--Sec. 310.305--30-day followup report.'' Each type of report
(e.g., serious and unexpected SADR reports, 30-day followup reports)
must be submitted to FDA under separate cover. Reports of medication
errors must indicate whether the error is actual or potential and if
actual, whether a serious SADR, nonserious SADR, or no SADR occurred,
e.g., ``expedited report--Sec. 310.305--actual medication error--
nonserious SADR,'' ``expedited report--Sec. 310.305--potential
medication error.''
(d) Reporting format. (1)(i) Except as provided in paragraphs
(d)(1)(ii), (d)(1)(iv), and (d)(5) of this section, the manufacturer
must complete an FDA Form 3500A for each individual case safety report
of an SADR. Reports based on information about individual cases or case
series in the scientific literature must be submitted on an FDA Form
3500A(s).
(ii) Foreign SADRs may be submitted either on an FDA Form 3500A or,
if preferred, on a CIOMS I form.
(iii) Each domestic report of an actual or potential medication
error must be submitted on an FDA Form 3500A.
(iv) Reports of overall findings or data in the aggregate from
published and unpublished in vitro, animal, epidemiological, or
clinical studies must be submitted in a narrative format.
(2) Each SADR in an individual case safety report must be coded on
the FDA Form 3500A or CIOMS I form using the appropriate ``preferred
term'' in the latest version of MedDRA (the medical dictionary for
regulatory activities) in use at the time the manufacturer becomes
aware of the individual case safety report. For individual case safety
reports of medication errors, the report must be coded both as a
medication error and, if applicable, with the preferred term for any
SADRs associated with the medication error.
(3) Each completed FDA Form 3500A or CIOMS I form should refer only
to an individual case.
(4) Each completed FDA Form 3500A or CIOMS I form must include the
name and telephone number (and fax number and e-mail address, if
available) for the licensed physician responsible for the content and
medical interpretation of the data contained within the form (i.e.,
contact person for the company).
(5) Instead of using FDA Form 3500A, the manufacturer may use a
computer-generated facsimile of FDA Form 3500A provided that it is
readable, includes appropriate identifying information, and contains
all the elements (i.e., format, sections, blocks, titles, descriptors
within blocks, text for disclaimer) of FDA Form 3500A in the identical
enumerated sequence of the form. For individual case safety reports in
which no suspect medical device is involved, a one-page FDA Form 3500A
is acceptable.
(e) Patient privacy. The names and addresses of individual patients
should not be included in reports under this section; instead, the
manufacturer and its contractors should assign a unique code to each
report, preferably not more than eight characters (i.e., numbers/
letters) in length. The name of the reporter from whom the information
was received should be included. Names of patients, individual
reporters, health care professionals, hospitals, and geographic
identifiers in safety reports are not releasable to the public under
FDA's public information regulations in part 20 of this chapter.
(f) Recordkeeping. (1) Each manufacturer must maintain for a period
of 10 years records of all safety information pertaining to its drug
product, received or otherwise obtained, including raw data, any
correspondence relating to the safety information, and any reports of
SADRs or medication errors not submitted to FDA. The manufacturer must
also retain for a period of 10 years any records required to be
maintained under this section. When appropriate, FDA may require a
manufacturer to submit any or all of these records to the agency within
5 calendar days after receipt of the request.
(2) Manufacturers and packers may retain the records required in
paragraph (f)(1) of this section as part of its complaint files
maintained under Sec. 211.198 of this chapter.
(3) Manufacturers must permit any authorized FDA employee, at all
[[Page 12476]]
reasonable times, to have access to and copy and verify the records
established and maintained under this section.
(g) Written procedures. Each manufacturer must develop and maintain
written procedures for the surveillance, receipt, evaluation, and
reporting of postmarketing safety information to FDA.
(h) Disclaimer. A report or information submitted by a manufacturer
under this section (and any release by FDA of that report or
information) does not necessarily reflect a conclusion by the
manufacturer or by FDA, that the report or information constitutes an
admission that the drug caused or contributed to an SADR. The
manufacturer need not admit, and may deny, that the report or
information submitted under this section constitutes an admission that
the drug caused or contributed to an SADR.
PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
3. The authority citation for 21 CFR part 312 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371; 42
U.S.C. 262.
4. Section 312.32 is amended by revising paragraphs (a), (b), the
introductory text of paragraph (c), paragraphs (c)(1) and (c)(4), and
the first sentence of paragraph (c)(2); in paragraph (d)(3) by removing
the phrase ``adverse drug experience'' and by adding in its place the
abbreviation ``SADR'' and by removing the phrase ``such experience''
and by adding in its place the phrase ``such reaction''; and in
paragraph (e) by removing the phrase ``adverse experience'' both times
it appears and by adding in its place the abbreviation ``SADR'' to read
as follows:
Sec. 312.32 IND safety reports.
(a) Definitions. The following definitions of terms apply to this
section:
Disability means a substantial disruption of a person's ability to
conduct normal life functions.
Life-threatening suspected adverse drug reaction (SADR) means any
SADR that, in the view of the investigator or sponsor, places the
patient or subject at immediate risk of death from the SADR as it
occurred. It does not include an SADR that, had it occurred in a more
severe form, might have caused death.
Minimum data set means the report includes an identifiable patient,
an identifiable reporter, a suspect drug product, and an SADR.
Serious SADR means any SADR that results in any of the following
outcomes: Death, a life-threatening SADR, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant
disability/incapacity, or a congenital anomaly/birth defect. Important
medical events that may not result in death, be life-threatening, or
require hospitalization may be considered a serious SADR when, based
upon appropriate medical judgment, they may jeopardize the patient or
subject and may require medical or surgical intervention to prevent one
of the outcomes listed in this definition. Examples of such medical
events include allergic bronchospasm requiring intensive treatment in
an emergency room or at home, blood dyscrasias or convulsions that do
not result in inpatient hospitalization, or the development of drug
dependency or drug abuse.
Suspected adverse drug reaction (SADR) means a noxious and
unintended response to any dose of a drug product for which there is a
reasonable possibility that the product caused the response. In this
definition, the phrase ``a reasonable possibility'' means that the
relationship cannot be ruled out.
Unexpected SADR means any SADR, the specificity or severity of
which is not consistent with the current investigator brochure; or, if
an investigator brochure is not required or available, the specificity
or severity of which is not consistent with the risk information
described in the general investigational plan or elsewhere in the
current application, as amended. For example, under this definition,
hepatic necrosis would be unexpected (by virtue of greater severity) if
the investigator brochure only referred to elevated hepatic enzymes or
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis
would be unexpected (by virtue of greater specificity) if the
investigator brochure only included cerebral vascular accidents.
``Unexpected,'' as used in this definition, refers to an SADR that has
not been previously observed (e.g., included in the investigator
brochure); it does not refer to an SADR that might be anticipated from
the pharmacological properties of the drug product. SADRs that are
mentioned in the investigator's brochure as occurring with a class of
drugs but not specifically mentioned as occurring with the particular
drug are considered unexpected.
(b) Review of safety information. The sponsor must promptly review
all information relevant to the safety of the drug obtained or
otherwise received by the sponsor from any source, foreign or domestic,
including information derived from any clinical or epidemiological
investigations, animal or in vitro studies, reports in the scientific
literature, and unpublished scientific papers, as well as reports from
foreign regulatory authorities that have not been previously reported
to FDA by the sponsor and reports of foreign commercial marketing
experience for drugs that are not marketed in the United States.
(c) IND safety reports. The sponsor must not submit an individual
case safety report for an SADR to FDA if the report does not contain a
minimum data set; instead, the sponsor must maintain records of any
information received or otherwise obtained for the SADR along with a
record of its efforts to obtain a minimum data set.
(1) Written reports--(i) Serious and unexpected SADR. The sponsor
must notify FDA and all participating investigators in a written IND
safety report of any SADR that, based on the opinion of the
investigator or sponsor, is both serious and unexpected, as soon as
possible, but in no case later than 15 calendar days after receipt by
the sponsor of the minimum data set for the serious, unexpected SADR.
The sponsor must identify all safety reports previously filed with the
IND concerning a similar SADR, and must analyze the significance of the
SADR in light of previous, similar reports.
(ii) Information sufficient to consider product administration
changes. The sponsor must also notify FDA and all participating
investigators in a written IND safety report of information that, based
upon appropriate medical judgment, might materially influence the
benefit-risk assessment of an investigational drug or that would be
sufficient to consider changes in either product administration or in
the overall conduct of a clinical investigation. The sponsor must
submit this information to FDA and all participating investigators as
soon as possible, but in no case later than 15 calendar days after the
determination by the sponsor that the information qualifies for
reporting under this paragraph. Examples of such information include
any significant unanticipated safety finding or data in the aggregate
from an in vitro, animal, epidemiological, or clinical study, whether
or not conducted under an IND, that suggests a significant human risk,
such as reports of mutagenicity, teratogenicity, or carcinogenicity or
reports of a lack of efficacy with a drug product used in treating a
life-threatening or serious disease.
(iii) Submission of written reports. Each written report may be
submitted on an FDA Form 3500A or in a narrative format. Foreign SADRs
may be
[[Page 12477]]
submitted either on an FDA Form 3500A or, if preferred, on a Council
for International Organizations of Medical Sciences (CIOMS) I form.
Reports of overall findings or data in the aggregate from published and
unpublished in vitro, animal, epidemiological, or clinical studies must
be submitted in a narrative format. Each written notice must bear
prominent identification of its contents, i.e., ``IND safety report.''
Each written notification to FDA must be transmitted to the FDA review
division that has responsibility for the review of the IND. If FDA
determines that additional data are needed, the agency may require
further data to be submitted.
(2) Telephone and facsimile transmission safety reports. The
sponsor must also notify FDA by telephone or by facsimile transmission
of any unexpected fatal or life-threatening SADR based on the opinion
of the investigator or sponsor as soon as possible but in no case later
than 7 calendar days after receipt by the sponsor of the minimum data
set for the unexpected fatal or life-threatening SADR. * * *
* * * * *
(4) Investigations of marketed drugs. A sponsor of a clinical study
under an IND for a drug marketed in the United States is only required
to submit IND safety reports to FDA (review division that has
responsibility for the IND) for SADRs from the clinical study itself,
whether from domestic or foreign study sites of the IND. The sponsor
must also submit to FDA safety information from these clinical studies
as prescribed by the postmarketing safety reporting requirements under
Sec. Sec. 310.305, 314.80, and 600.80 of this chapter.
* * * * *
5. Section 312.64 is amended by revising paragraph (b) to read as
follows:
Sec. 312.64 Investigator reports.
* * * * *
(b) Safety reports. An investigator must report to the sponsor any
serious SADR (as defined in Sec. 312.32(a)) immediately and any other
SADR (as defined in Sec. 312.32(a)) promptly unless the protocol or
investigator's brochure specifies a different timetable for reporting
the SADR.
* * * * *
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
6. The authority citation for 21 CFR part 314 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356,
356a, 356b, 356c, 371, 374, 379e.
7. Section 314.80 is revised to read as follows:
Sec. 314.80 Postmarketing safety reporting and recordkeeping.
(a) Definitions. The following definitions of terms apply to this
section:
Active query means direct verbal contact (i.e., in person or by
telephone or other interactive means such as a video conference) with
the initial reporter of a suspected adverse drug reaction (SADR) or
medication error by a health care professional (e.g., physician,
physician assistant, pharmacist, dentist, nurse, any individual with
some form of health care training) representing the applicant. For
SADRs, active query entails, at a minimum, a focused line of
questioning designed to capture clinically relevant information
associated with the drug product and the SADR, including, but not
limited to, information such as baseline data, patient history,
physical exam, diagnostic results, and supportive lab results.
Actual medication error means a medication error that involves an
identifiable patient whether the error was prevented prior to
administration of the product or, if the product was administered,
whether the error results in a serious SADR, nonserious SADR, or no
SADR.
Company core data sheet means a document prepared by the applicant
containing, in addition to safety information, material relating to
indications, dosing, pharmacology, and other information concerning the
drug substance. The only purpose of this document is to provide the
company core safety information (CCSI) for periodic safety update
reports (PSURs), interim periodic safety reports (IPSRs), and certain
individual case safety reports--semiannual submissions (i.e., if PSURs
are submitted for the product).
Company core safety information (CCSI) means all relevant safety
information contained in the company core data sheet that the applicant
proposes to include in the approved product labeling in all countries
where the applicant markets the drug substance. It is the reference
information by which an SADR is determined to be ``listed'' or
``unlisted'' for PSURs, IPSRs, and certain individual case safety
reports-semiannual submissions (i.e., if PSURs are submitted for the
product).
Contractor means any person (e.g., manufacturer, packer or
distributor whether its name appears on the label of the product;
licensee; contract research organization) that has entered into a
contract with the applicant to manufacture, pack, sell, distribute, or
develop the drug or to maintain, create, or submit records regarding
SADRs or medication errors.
Data lock point means the date designated as the cut-off date for
data to be included in a postmarketing periodic safety report.
Disability means a substantial disruption of a person's ability to
conduct normal life functions.
Full data set means completion of all the applicable elements on
FDA Form 3500A (or on a Council for International Organizations of
Medical Sciences (CIOMS) I form for reports of foreign SADRs),
including a concise medical narrative of the case (i.e., an accurate
summary of the relevant data and information pertaining to an SADR or
medication error).
International birth date means the date the first regulatory
authority in the world approved the first marketing application for a
human drug product containing the drug substance.
Life-threatening SADR means any SADR that, in the view of the
initial reporter, places the patient at immediate risk of death from
the SADR as it occurred. It does not include an SADR that, had it
occurred in a more severe form, might have caused death.
Listed SADR means an SADR whose nature, specificity, severity, and
outcome are consistent with the information in the CCSI.
Medication error means any preventable event that may cause or lead
to inappropriate medication use or patient harm, while the medication
is in the control of the health care professional, patient or consumer.
Such events may be related to professional practice, health care
products, procedures, and systems including: Prescribing; order
communication; product labeling, packaging, and nomenclature;
compounding; dispensing; distribution; administration; education;
monitoring; and use.
Minimum data set means the report includes an identifiable patient,
an identifiable reporter, a suspect drug product, and an SADR.
Nonserious SADR means any SADR that is determined not to be a
serious SADR.
Potential medication error means an individual case safety report
of information or complaint about product name, labeling, or packaging
similarities that does not involve a patient.
SADR with unknown outcome means an SADR that cannot be classified,
after active query, as either serious or nonserious.
[[Page 12478]]
Serious SADR means any SADR that results in any of the following
outcomes: Death, a life-threatening SADR, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant
disability/incapacity, or a congenital anomaly/birth defect. Important
medical events that may not result in death, be life-threatening, or
require hospitalization may be considered a serious SADR when, based
upon appropriate medical judgment, they may jeopardize the patient or
subject and may require medical or surgical intervention to prevent one
of the outcomes listed in this definition. Examples of such medical
events include allergic bronchospasm requiring intensive treatment in
an emergency room or at home, blood dyscrasias or convulsions that do
not result in inpatient hospitalization, or the development of drug
dependency or drug abuse.
Spontaneous report means a communication from an individual (e.g.,
health care professional, consumer) to a company or regulatory
authority that describes an SADR or medication error. It does not
include cases identified from information solicited by the applicant or
contractor, such as individual case safety reports or findings derived
from a study, company-sponsored patient support program, disease
management program, patient registry, including pregnancy registries,
or any organized data collection scheme. It also does not include
information compiled in support of class action lawsuits.
Suspected adverse drug reaction (SADR) means a noxious and
unintended response to any dose of a drug product for which there is a
reasonable possibility that the product caused the response. In this
definition, the phrase ``a reasonable possibility'' means that the
relationship cannot be ruled out.
Unexpected SADR means any SADR that is not included in the current
U.S. labeling for the drug product. Reactions that may be
symptomatically and pathophysiologically related to a reaction included
in the U.S. labeling, but differ from the labeled reaction because of
greater severity or specificity, would be unexpected. For example,
under this definition, hepatic necrosis would be unexpected (by virtue
of greater severity) if the U.S. labeling only referred to elevated
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and
cerebral vasculitis would be unexpected (by virtue of greater
specificity) if the U.S. labeling only included cerebral vascular
accidents. ``Unexpected,'' as used in this definition, refers to an
SADR that has not been previously observed (i.e., included in the U.S.
labeling); it does not refer to an SADR that might be anticipated from
the pharmacological properties of the drug product. SADRs that are
mentioned in the U.S. labeling as occurring with a class of drugs but
not specifically mentioned as occurring with the particular drug are
considered unexpected.
Unlisted SADR means an SADR whose nature, specificity, severity, or
outcome is not consistent with the information included in the CCSI.
(b) Review of safety information. (1) Each applicant having an
approved application for a drug product under section 505(c) of the act
must promptly review all safety information pertaining to its product
obtained or otherwise received by the applicant from any source,
foreign or domestic, including information derived from commercial
marketing experience, postmarketing clinical investigations,
postmarketing epidemiology/surveillance studies, animal or in vitro
studies, electronic communications with applicants via the Internet
(e.g., e-mail), reports in the scientific literature, and unpublished
scientific papers, as well as reports from foreign regulatory
authorities that have not been previously reported to FDA by the
applicant.
(2) Individual case safety reports that are forwarded to the
applicant by FDA must not be resubmitted to the agency by the
applicant; however, applicants must include information from these
individual case safety reports in any comprehensive safety analysis
subsequently submitted to FDA. In addition, applicants must submit to
FDA all followup information for these individual case safety reports.
(c) Reporting requirements. The applicant must submit to FDA two
copies of each postmarketing expedited report (described under
paragraphs (c)(2)(i) through (c)(2)(vii) of this section) and one copy
of each postmarketing periodic safety report of an individual case
safety reports--semiannual submission (described under paragraph
(c)(3)(v) of this section) pertaining to its drug product. The
applicant must also submit to FDA one copy of a PSUR, IPSR, or
traditional periodic safety report (TPSR)) along with one copy for each
approved application for a human drug product covered by the report.
FDA may waive the requirement for multiple copies in appropriate
instances. Upon written notice, FDA may require, when appropriate, that
the applicant submit reports under this section to FDA at times other
than those stated. An applicant that wishes to submit reports under
this section at different intervals must submit to FDA a request for a
waiver under Sec. 314.90.
(1) Determination of outcome, minimum data set, and full data set--
(i)(A) Initial determinations. Upon initial receipt of an SADR report,
the applicant must immediately determine the outcome for the SADR
(whether the SADR is serious or nonserious) and at least the minimum
data set for the individual case safety report. For reports of actual
medication errors that do not result in an SADR and potential
medication errors the applicant must immediately determine the minimum
information for the individual case safety report (minimum information
described under paragraphs (c)(1)(iii)(B) and (c)(1)(iii)(C) of this
section). If the applicant is not able to immediately determine the
information in this paragraph, active query must be used to obtain it
as soon as possible.
(B) Spontaneous reports. For spontaneous reports, the applicant
must always assume, for safety reporting purposes under this section,
that there is at least a reasonable possibility, in the opinion of the
initial reporter, that the drug product caused the spontaneously
reported event.
(C) Clinical trials. For a clinical trial, the possibility that the
drug product caused the SADR or that a medication error has occurred
must be assumed if either the investigator or the applicant believes
that such a reasonable possibility exists.
(ii) SADRs with unknown outcome. For an SADR with unknown outcome
that cannot be immediately determined, the applicant must continue to
use active query to attempt to determine the outcome of the SADR within
30 calendar days after initial receipt of the SADR report by the
applicant. The applicant must maintain a record of its efforts to
determine the outcome for an SADR with unknown outcome.
(iii)(A) Minimum data set for SADR reports. The applicant must not
submit an individual case safety report for an SADR to FDA if the
report does not contain a minimum data set; instead, the applicant must
maintain records of any information received or otherwise obtained for
the SADR along with a record of its efforts to obtain a minimum data
set.
(B) Minimum information for reports of actual medication errors
that do not result in an SADR. For reports of actual medication errors
that do not result in an SADR, an individual case safety report must be
submitted to FDA even though the report does not contain a minimum data
set (i.e., does not have an SADR). These reports must contain at
[[Page 12479]]
least an identifiable patient, an identifiable reporter, and a suspect
drug product.
(C) Minimum information for potential medication error reports. For
reports of potential medication errors, an individual case safety
report must be submitted to FDA even though the report does not contain
a minimum data set (i.e., does not have an identifiable patient or an
SADR). These reports must contain at least an identifiable reporter and
a suspect drug product.
(iv) Full data set. For reports of serious SADRs, always expedited
reports (see paragraph (c)(2)(iv) of this section), and medication
error reports (see paragraph (c)(2)(v) of this section), the applicant
must submit a full data set. If a full data set is not available for
the report, the applicant must use active query to obtain this
information. If a full data set is not obtainable, after active query,
the applicant must:
(A) Submit all safety information, received or otherwise obtained,
for the report;
(B) Indicate the reason(s) for its inability to acquire a full data
set; and
(C) Document its efforts to obtain a full data set (i.e.,
description of unsuccessful steps taken to obtain this information).
(v) Serious SADRs not initially reported by a health care
professional. For a serious SADR that was not initially reported to the
applicant by a health care professional (e.g., report from a consumer),
the applicant must contact the health care professional associated with
the care of the patient using active query to gather further medical
perspective on the case and to acquire a full data set for the report.
If the applicant is unable to contact the health care professional, it
must include in the report for the serious SADR:
(A) The reason(s) for its inability to contact the health care
professional; and
(B) A description of its efforts to contact the health care
professional.
(vi) Nonserious SADRs. For reports of nonserious SADRs with a
minimum data set, except for those resulting from a medication error,
all safety information received or otherwise obtained by the applicant
must be submitted to FDA even though information in addition to the
minimum data set is not required to be acquired. Reports of nonserious
SADRs resulting from a medication error require a full data set under
paragraph (c)(1)(iv) of this section.
(2) Postmarketing ``expedited reports''--(i) Serious and unexpected
SADR. The applicant must report to FDA each SADR, received or otherwise
obtained, that is both serious and unexpected, whether foreign or
domestic, as soon as possible, but in no case later than 15 calendar
days after receipt by the applicant of the minimum data set for the
serious unexpected SADR. If a full data set is not available for the
serious and unexpected SADR at the time of initial submission of the
expedited report to FDA, the applicant must submit the information
required under paragraph (c)(1)(iv) of this section and also submit a
30-day followup report as required by paragraph (c)(2)(vi) of this
section.
(ii) Information sufficient to consider product administration
changes. The applicant must also report to FDA information, received or
otherwise obtained, whether foreign or domestic, that would be
sufficient, based upon appropriate medical judgment, to consider
changes in product administration. The applicant must submit this
information to FDA as soon as possible, but in no case later than 15
calendar days after determination by the applicant that the information
qualifies for expedited reporting. Examples of such information include
any significant unanticipated safety finding or data in the aggregate
from an in vitro, animal, epidemiological, or clinical study, whether
or not conducted under an investigational new drug application (IND),
that suggests a significant human risk, such as reports of
mutagenicity, teratogenicity, or carcinogenicity, or reports of a lack
of efficacy with a drug product used in treating a life-threatening or
serious disease. The applicant must maintain a record of its efforts to
determine whether the information required to be reported under this
paragraph qualifies for expedited reporting.
(iii) Unexpected SADR with unknown outcome. The applicant must also
report to FDA each SADR that is unexpected and for which the
determination of an outcome is unattainable (i.e., SADR with unknown
outcome) within 45 calendar days after initial receipt by the applicant
of the minimum data set for the unexpected SADR. The applicant must
document in the expedited report the reason(s) for the inability to
determine the outcome.
(iv) Always expedited report. (A) The applicant must also report to
FDA each SADR, received or otherwise obtained, whether foreign or
domestic, that is the subject of an always expedited report. These
reports must be submitted to FDA as soon as possible, but in no case
later than 15 calendar days after receipt by the applicant of the
minimum data set for the report. The following medically significant
SADRs, which may jeopardize the patient or subject and/or require
medical or surgical intervention to treat the patient or subject are
subject to an always expedited report:
(1) Congenital anomalies,
(2) Acute respiratory failure,
(3) Ventricular fibrillation,
(4) Torsades de pointe,
(5) Malignant hypertension,
(6) Seizure,
(7) Agranulocytosis,
(8) Aplastic anemia,
(9) Toxic epidermal necrolysis,
(10) Liver necrosis,
(11) Acute liver failure,
(12) Anaphylaxis,
(13) Acute renal failure,
(14) Sclerosing syndromes,
(15) Pulmonary hypertension,
(16) Pulmonary fibrosis,
(17) Confirmed or suspected transmission of an infectious agent by
a marketed drug or biological product,
(18) Confirmed or suspected endotoxin shock, and
(19) Any other medically significant SADR that FDA determines to be
the subject of an always expedited report (i.e., may jeopardize the
patient or subject and/or require medical or surgical intervention to
treat the patient or subject).
(B) SADRs that are the subject of an always expedited report must
be submitted to FDA whether unexpected or expected and whether the SADR
leads to a serious outcome or not. If a full data set is not available
for an always expedited report at the time of initial submission of the
report to FDA, the applicant must submit the information required under
paragraph (c)(1)(iv) of this section and also submit a 30-day followup
report as required by paragraph (c)(2)(vi) of this section.
(v) Medication errors--(A) Actual medication error. The applicant
must also submit to FDA each domestic report of an actual medication
error, received or otherwise obtained, as soon as possible, but in no
case later than 15 calendar days after receipt by the applicant of the
minimum data set for a report of an SADR or, if an SADR does not occur,
the minimum information described under paragraph (c)(1)(iii)(B) of
this section (i.e., identifiable patient, identifiable reporter, and
suspect drug product).
(B) Potential medication error. The applicant must also submit to
FDA each domestic report of a potential medication error, received or
otherwise obtained, as soon as possible, but in no case later than 15
calendar days after receipt by the applicant of the minimum information
described under paragraph (c)(1)(iii)(C) of this section (i.e.,
identifiable reporter and suspect drug product).
[[Page 12480]]
(C) Full data set. If a full data set is not available for an
actual or potential medication error report at the time of initial
submission of the report to FDA, the applicant must submit the
information required under paragraph (c)(1)(iv) of this section and
also submit a 30-day followup report as required by paragraph
(c)(2)(vi) of this section.
(vi) The 30-day followup report. The applicant must use active
query to obtain additional information for any expedited report under
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that
does not contain a full data set and must submit a followup report to
FDA within 30 calendar days after initial submission of the expedited
report to FDA by the applicant. If a full data set is still not
obtainable, the 30-day followup report must contain the information
required under paragraph (c)(1)(iv) of this section. Any new safety
information in the 30-day followup report must be highlighted. Any new
information, received or otherwise obtained, after submission of a 30-
day followup report must be submitted to FDA as a 15-day followup
report under paragraph (c)(2)(vii) of this section.
(vii) The 15-day followup report. The applicant must report to FDA
any new information, received or otherwise obtained, for any expedited
or followup report (except for initial expedited reports under
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that do
not contain a full data set) within 15 calendar days of initial receipt
of the new information by the applicant. Expedited reports under
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that do
not contain a full data set at the time of initial submission of the
report to FDA are subject to the 30-day followup reporting requirements
under paragraph (c)(2)(vi) of this section rather than the 15-day
followup reporting requirements under this paragraph.
(viii) Supporting documentation. (A) If the patient dies, the
applicant must submit a copy of the autopsy report to FDA, if it is
available. If an autopsy report is not available, the applicant must
submit a death certificate to FDA. If an autopsy report becomes
available after the applicant has submitted a death certificate to the
agency, the autopsy report must be submitted to FDA. If the patient was
hospitalized, the applicant must submit a copy of the hospital
discharge summary to FDA, if it is available. If any of these documents
is not in English, the document must be accompanied by an English
translation. Applicants must use active query to obtain these
documents. These documents must be submitted to FDA as 15-day followup
reports (see paragraph (c)(2)(vii) of this section) within 15 calendar
days of initial receipt of the document by the applicant. If these
documents are not submitted to FDA in a 15-day followup report within 3
months after submission of the initial expedited report for the death
or hospitalization, the agency will assume that active query by the
applicant has not resulted in access to these documents. In this case,
a record of the reason(s) for the lack of such documentation and the
effort that was made to obtain the documentation must be maintained by
the applicant.
(B) Each expedited report must contain in the narrative a list of
other relevant documents (e.g., medical records, laboratory results,
data from studies) for the report that are maintained by the applicant.
When appropriate, FDA may require an applicant to submit copies of one
or more of these documents to the agency within 5 calendar days after
receipt of the request.
(ix) Scientific literature. An expedited report based on
information from the scientific literature applies only to reports
found in scientific and medical journals. These expedited reports must
be accompanied by a copy of the published article.
(x) Submission of safety reports by contractors. (A) Contractors
must submit to the applicant safety reports of any SADRs or medication
errors for the applicant's drug product, obtained or otherwise
received, within 5 calendar days of initial receipt of the report by
the contractor. The contractor must submit a safety report for an SADR
to the applicant even if the report does not contain a minimum data
set. Upon receipt of the safety report from the contractor, the
applicant must comply with the postmarketing safety reporting
requirements of this section.
(B) A contract between the applicant and a contractor must specify
the postmarketing safety reporting responsibilities of the contractor.
The applicant is responsible for assuring that the contractors of its
drug products comply with these postmarketing safety reporting
responsibilities.
(C) The contractor must maintain a record of each submission to the
applicant under paragraph (c)(2)(x)(A) of this section that includes:
(1) A copy of each safety report;
(2) The date the report was initially received by the contractor;
(3) The date the report was submitted to the applicant; and
(4) The name and address of the applicant.
(D) The recordkeeping, written procedures and disclaimer provisions
under paragraphs (f), (g), and (i) of this section apply to
contractors.
(xi) Report identification. Each expedited report submitted to FDA
under paragraphs (c)(2)(i) through (c)(2)(vii) of this section must
bear prominent identification as to its contents, e.g., ``expedited
report--serious and unexpected SADR,'' ``expedited report--30-day
followup.'' Each type of report (e.g., serious and unexpected SADR
reports, 30-day followup reports) must be submitted to FDA under
separate cover. Reports of medication errors must indicate whether the
error is actual or potential and, if actual, whether a serious SADR,
nonserious SADR, or no SADR occurred, e.g., ``expedited report--actual
medication error--nonserious SADR,'' ``Expedited report--potential
medication error.''
(3) Postmarketing periodic safety reports. The applicant must
submit postmarketing periodic safety reports under this section (i.e.,
TPSRs, PSURs, IPSRs, individual case safety reports-semiannual
submission) to FDA within 60 calendar days after the data lock point
for the report. The applicant must include a cover letter containing a
list of the new drug application number(s) (i.e., NDA number(s)) for
the human drug product(s) covered by the postmarketing periodic safety
report. The international birth date for combination products is the
international birth date of the human drug product containing the drug
substance most recently approved for marketing.
(i) Traditional periodic safety reports (TPSRs). An applicant
holding an application for a human drug product approved under section
505(c) of the act before January 1, 1998, must submit either a PSUR as
prescribed under paragraph (c)(3)(ii) of this section or a TPSR as
described under this paragraph every 5 years after U.S. approval of the
application. In addition, these applicants must submit either an IPSR
as described under paragraph (c)(3)(iii) of this section or a TPSR as
described under this paragraph 7.5 years and 12.5 years after U.S.
approval of the application. The data lock point for the TPSR, PSUR, or
IPSR is the month and day of the international birth date of the drug
product or any other month and day agreed on by the applicant and FDA.
Each TPSR must contain:
(A) Summary. This section of the TPSR includes:
(1) A narrative summary and analysis of serious, expected SADRs and
nonserious, unexpected SADRs
[[Page 12481]]
occurring in the United States that were submitted to the applicant
during the reporting period from all spontaneous sources (i.e., health
care professionals and other individuals) (with an index consisting of
a line listing of the applicant's manufacturer report number and SADR
term(s));
(2) An analysis of the expedited reports submitted during the
reporting period under paragraphs (c)(2)(i) through (c)(2)(vii) of this
section (all expedited reports must be appropriately referenced by the
applicant's manufacturer report number, SADR term(s), if appropriate,
and date of submission to FDA);
(3) A discussion of any increased reporting frequency of serious,
expected SADRs, including comments on whether it is believed that the
data reflect a meaningful change in SADR occurrence, and an assessment
of whether it is believed that the frequency of lack of efficacy
reports, obtained or otherwise received during the reporting period, is
greater than would be predicted by the premarketing clinical trials for
the drug product; and
(4) The applicants' conclusion as to what, if any, safety-related
actions should be taken based on the analysis of the safety data in the
TPSR (e.g., labeling changes, studies initiated);
(B) Summary tabulations. This section of the TPSR includes summary
tabulations (i.e., lists of all SADR terms and counts of occurrences)
presented by body system or by standard organ system classification
scheme for:
(1) All serious expected SADRs, nonserious unexpected SADRs,
nonserious expected SADRs, and expected SADRs with unknown outcome
occurring in the United States that are submitted to the applicant
during the reporting period from all spontaneous sources (i.e., health
care professionals and other individuals);
(2) All serious unexpected SADRs, unexpected SADRs with unknown
outcome, and always expedited reports that were previously submitted to
FDA in an expedited report under paragraphs (c)(2)(i), (c)(2)(iii), and
(c)(2)(iv) of this section (include cumulative data for serious
unexpected SADRs, i.e., all cases reported to date);
(3) All reports of SADRs not previously submitted to FDA by the
applicant (e.g., reports submitted to applicants by FDA, reports
obtained from FDA from freedom of information requests at the
discretion of the applicant, reports from class action lawsuits); and
(4) All domestic reports of medication errors previously submitted
to FDA under paragraph (c)(2)(v) of this section. For actual medication
errors, provide summary tabulations of serious SADRs, nonserious SADRs,
and no SADRs. For potential medication errors, provide the number of
reports for specific errors;
(C) History of safety-related actions taken. This section of the
TPSR includes a history of safety-related actions taken since the last
periodic safety report (e.g., labeling changes, studies initiated);
(D) Location of safety records. This section of the TPSR includes a
list of the current address(es) where all safety reports and other
safety-related records for the drug product are maintained; and
(E) Contact person. This section of the TPSR includes the name and
telephone number for the licensed physician(s) responsible for the
content and medical interpretation of the information contained within
the TPSR. Include, if available, the fax number and e-mail address for
the licensed physician(s).
(ii) Periodic safety update report (PSUR). An applicant holding an
application for a human drug product approved under section 505(c) of
the act on or after January 1, 1998, must submit a PSUR to FDA
according to the following schedule: Semiannually (i.e., every 6
months) for 2 years after U.S. approval of the application, annually
for the next 3 years and then every 5 years thereafter. The data lock
point for the PSUR is the month and day of the international birth date
of the drug substance or any other month and day agreed on by the
applicant and FDA. Each PSUR must contain:
(A) Title page, table of contents, and introduction. (1) The title
page includes, at a minimum, the following information:
(i) Name and international birth date of the drug substance that is
the subject of the PSUR,
(ii) Various dosage forms and formulations of the drug substance
covered by the PSUR,
(iii) Name and address of the applicant,
(iv) Reporting period covered by the PSUR, and
(v) Date of the PSUR.
(2) The introduction:
(i) Provides a brief description of how the PSUR relates to
previous reports and circumstances;
(ii) References relevant drug products or substances reported in
other periodic safety reports (e.g., a combination product reported in
a separate PSUR); and
(iii) Indicates any data duplication with other PSURs.
(B) Worldwide marketing status. This section of the PSUR contains a
table of the chronological history of the worldwide marketing status of
the drug product(s) covered by the PSUR from the date the product(s)
was first approved (i.e., the international birth date) through its
current status (i.e., cumulative information). The table consists of:
(1) Dates of drug approval and renewal;
(2) Safety-related restrictions on product use;
(3) Indications for use and special populations covered by the drug
approval;
(4) Lack of approval of the drug substance in any dosage form or
for any indication for use by any regulatory authority(ies);
(5) Withdrawal of a pending marketing application for the drug
product by the applicant for safety- or efficacy-related reasons;
(6) Dates of market launches; and
(7) Trade name(s).
(C) Actions taken for safety reasons. (1) This section of the PSUR
includes details on the following types of regulatory authority-
initiated (e.g., by FDA) and/or applicant-initiated actions related to
safety that were taken during the period covered by the PSUR and
between the data lock point and PSUR submission (i.e., ``late-
breaking'' safety concerns):
(i) Withdrawal or suspension of drug product approval or indication
for use approval;
(ii) Failure to obtain a marketing authorization renewal or to
obtain an approval for a new indication for use;
(iii) Restrictions on distribution (e.g., products recalled for
safety reasons);
(iv) Clinical trial suspension;
(v) Dosage modification;
(vi) Changes in target population or indications; and
(vii) Formulation changes.
(2) This section of the PSUR also contains a narrative identifying
the safety-related reasons that led to these actions with relevant
documentation appended when appropriate.
(3) Any communication with health care professionals (e.g., Dear
Healthcare Professional letters) resulting from such actions must also
be described with copies appended.
(D) Changes to CCSI. This section of the PSUR describes changes to
the CCSI (e.g., new contraindications, precautions, warnings, SADRs, or
interactions) made during the period covered by the PSUR. A copy of any
modified section of the CCSI must be included. The applicant must use
the CCSI in effect at the beginning of the reporting period for the
PSUR. The revised CCSI is to be used as the reference document for the
next reporting period.
[[Page 12482]]
(E) Worldwide patient exposure. (1) This section of the PSUR
includes, for the reporting period, an estimate of the worldwide
patient exposure to the drug product(s) covered by the PSUR (i.e.,
number of patients, average or median dose received, and average or
median length of treatment). The method used to estimate patient
exposure must always be described. If the patient exposure is
impossible to estimate or is meaningless, an explanation of and
justification for such conclusions must be provided. If patient
exposure is impossible to estimate, other measures of exposure, such as
patient-days, number of prescriptions, or number of dosage units, may
be used. If these or other more precise measures are not available and
an adequate explanation for the lack of such information is provided,
bulk sales may be used.
(2) When possible, data broken down by gender and age (especially
pediatric versus adult) must be provided. For the pediatric population,
data must be reported, if possible, by age group (e.g., neonates,
infants, children, adolescents). If these data are not available, an
explanation must be included.
(3) When a pattern of reports indicates a potential problem,
details by country (with locally recommended dosage regimens) or other
segmentation (e.g., indication, dosage form) must be presented.
(F) Individual case safety reports. (1) This section of the PSUR
includes summary tabulations of individual case safety reports (e.g.,
serious unlisted SADRs, serious listed SADRs, nonserious unlisted
SADRs, nonserious listed SADRs) for the following SADRs obtained or
otherwise received during the reporting period:
(i) All serious and nonserious SADRs from spontaneous sources that
were submitted to applicants by a health care professional;
(ii) All serious SADRs from studies, individual patient INDs, or,
in foreign countries, from named-patient ``compassionate'' use;
(iii) All serious SADRs and nonserious unlisted SADRs from the
scientific literature;
(iv) All serious SADRs from regulatory authorities; and
(v) Serious SADRs from other sources such as reports created by
poison control centers and epidemiological data bases.
(2) The summary tabulations must be made up of lists by body system
or by standard organ system classification scheme of all SADR terms and
counts of occurrences. For SADRs that are determined to be both serious
and unlisted, include cumulative data (i.e., all cases reported to
date).
(3) The applicant must conclude this section with a brief
discussion of the data concerning the individual case safety reports in
the PSUR (e.g., discussion of medical significance or mechanism).
(G) Safety studies. This section of the PSUR contains a discussion
of nonclinical, clinical, and epidemiological studies that contain
important safety information, as follows:
(1) All applicant-sponsored studies newly analyzed during the
reporting period (copies of full reports should be appended only if new
safety issues are raised or confirmed; FDA may request copies of other
studies, if necessary);
(2) New studies specifically planned, initiated, or continuing
during the reporting period that examine a safety issue, whether actual
or hypothetical; and
(3) Published safety studies in the scientific and medical
literature, including relevant published abstracts from meetings
(provide literature citation).
(H) Other information. This section of the PSUR includes:
(1) A discussion of medically relevant lack of efficacy reports
(e.g., might represent a significant hazard to the treated population)
for a product(s) used to treat serious or life-threatening diseases;
and
(2) Any important new information received after the data lock
point (e.g., significant new cases).
(I) Overall safety evaluation. This section of the PSUR contains a
concise, yet comprehensive, analysis of all of the safety information
provided in the PSUR, including new information provided under
paragraph (c)(3)(ii)(H)(2) of this section. In addition, this section
of the PSUR includes an assessment by the applicant of the significance
of the data collected during the reporting period, as well as from the
perspective of cumulative experience.
(1) The applicant must highlight any new information on:
(i) Serious, unlisted SADRs;
(ii) Increased reporting frequencies of listed SADRs, including
comments on whether it is believed that the data reflect a meaningful
change in SADR occurrence;
(iii) A change in characteristics of listed SADRs (e.g., severity,
outcome, target population); and
(iv) Nonserious, unlisted SADRs.
(2) As part of the overall safety evaluation, the applicant must
also explicitly address any new safety issue including but not limited
to the following (lack of significant new information for each of the
following must be mentioned):
(i) Drug interactions;
(ii) Experience with overdose, whether deliberate or accidental,
and its treatment;
(iii) Drug abuse or intentional misuse;
(iv) Positive or negative experiences during pregnancy or
lactation;
(v) Effects with long-term treatment; and
(vi) Experience in special patient groups (e.g., pediatric,
geriatric, organ impaired). For the pediatric population, data must be
evaluated, if possible, by age group (e.g., neonates, infants,
children, adolescents).
(J) Conclusion. This section of the PSUR:
(1) Indicates new safety information that is not in accord with
previous cumulative experience and with the CCSI in use at the
beginning of the reporting period (e.g., new evidence that strengthens
a possible causal relationship between the drug product and an SADR
such as positive rechallenge, an epidemiological association, or new
laboratory studies); and
(2) Specifies and justifies any action recommended or initiated,
including changes in the CCSI.
(K) Appendices. This section of the PSUR includes:
(1) Company core data sheet. Provide a copy of the company core
data sheet covered by this PSUR (i.e., in effect at the beginning of
the period covered by the PSUR) as well as the company core data sheet
for the next reporting period. Company core data sheets must be
numbered and dated and include the date of last revision.
(2) U.S. labeling. Provide a copy of the current approved U.S.
labeling. Specify any safety information that is included in the CCSI
but not in the U.S. labeling and provide an explanation for the
discrepancy. Describe any safety-related changes or proposed changes to
the U.S. labeling made during the reporting period (include the
supplement number(s) and date(s) of submission for the supplement(s))
and any suggested change(s) that should be considered based on the
safety analysis in the PSUR.
(3) Spontaneous reports submitted to the applicant by an individual
other than a health care professional. Provide summary tabulations
(e.g., serious unlisted SADRs, serious listed SADRs, nonserious
unlisted SADRs, nonserious listed SADRs) for all spontaneously reported
serious SADRs, whether domestic or foreign, and all spontaneously
reported nonserious
[[Page 12483]]
SADRs occurring in the United States, obtained or otherwise received
during the reporting period by the applicant from an individual other
than a health care professional (e.g., reports from consumers). These
summary tabulations must consist of lists by body system or by standard
organ system classification scheme of all SADR terms and counts of
occurrences. For those SADRs that are determined to be both serious and
unlisted, include cumulative data (i.e., all cases reported to date by
individuals other than a health care professional). Include a brief
discussion of the impact of the spontaneous reports described in this
appendix on the overall safety evaluation.
(4) SADRs with unknown outcome. Provide summary tabulations for
unlisted and listed SADRs with unknown outcome from all spontaneous
sources (i.e., health care professionals and other individuals),
obtained or otherwise received by the applicant during the reporting
period. These summary tabulations must consist of lists by body system
or by standard organ system classification scheme of all SADR terms and
counts of occurrences. Include a brief discussion of the impact of the
spontaneous reports described in this appendix on the overall safety
evaluation.
(5) Class action lawsuits. Provide summary tabulations (e.g.,
serious unlisted SADRs, serious listed SADRs, nonserious unlisted
SADRs, nonserious listed SADRs) for all SADRs obtained or otherwise
received during the reporting period by the applicant from class action
lawsuits. These summary tabulations must consist of lists by body
system or by standard organ system classification scheme of all SADR
terms and counts of occurrences. For those SADRs that are determined to
be both serious and unlisted, include cumulative data. Include a brief
discussion of the impact of the reports described in this appendix on
the overall safety evaluation.
(6) Lack of efficacy reports. Provide an assessment of whether it
is believed that the frequency of lack of efficacy reports, obtained or
otherwise received during the reporting period, is greater than would
be predicted by the premarketing clinical trials for the drug product.
(7) Information on resistance to antimicrobial drug products.
Provide information, received or otherwise obtained by the applicant,
on resistance to antimicrobial drug products intended to treat
infectious diseases. Include information on changes in U.S. microbial
in vitro susceptibility, the relationship of changes in U.S. microbial
in vitro susceptibility and clinical outcomes, therapeutic failure that
may possibly be due to resistance to the antimicrobial drug product,
and whether the U.S. labeling should be revised because of the
information on antimicrobial resistance learned during the period
covered by this PSUR.
(8) Medication errors. Provide summary tabulations of all domestic
reports of medication errors submitted during the reporting period
under paragraph (c)(2)(v) of this section. For actual medication
errors, provide summary tabulations for serious SADRs, nonserious
SADRs, and no SADRs (for serious SADRs include cumulative data, i.e.,
all cases reported to date). For potential medication errors, provide
the number of reports for specific errors. If an SADR occurs, the
summary tabulations must consist of lists by body system or by standard
organ system classification scheme of all SADR terms and counts of
occurrences. Include a brief discussion of the impact on the overall
safety evaluation of these reports.
(9) U.S. patient exposure. Provide, for the reporting period, an
estimate of the U.S. patient exposure to the drug product(s) covered by
the PSUR (i.e., number of patients, average or median dose received,
and average or median length of treatment). The method used to estimate
patient exposure must always be described. If the patient exposure is
impossible to estimate or is meaningless, an explanation of and
justification for such conclusions must be provided. If patient
exposure is impossible to estimate, other measures of exposure, such as
patient-days, number of prescriptions, or number of dosage units, may
be used. If these or other more precise measures are not available and
an adequate explanation for the lack of such information is provided,
bulk sales may be used.
(10) Location of safety records. Provide a list of the current
address(es) where all safety reports and other safety-related records
for the drug product(s) are maintained.
(11) Contact person. Provide the name and telephone number of the
licensed physician(s) responsible for the content and medical
interpretation of the data and information contained within the PSUR.
Include, if available, the fax number and e-mail address of the
licensed physician(s).
(iii) Interim periodic safety report (IPSR). An applicant holding
an application for a human drug product approved under section 505(c)
of the act on or after January 1, 1998, must submit an IPSR to FDA 7.5
years and 12.5 years after U.S. approval of the application. The data
lock point for the IPSR is the month and day of the international birth
date of the drug substance or any other month and day agreed on by the
applicant and FDA. The reporting period for the IPSR covers the period
between the last PSUR or TPSR and the data lock point for the IPSR
(e.g., between years 5 and 7.5 for an IPSR with a data lock point 7.5
years after U.S. approval of the application). Each IPSR must contain:
(A) Title page, table of contents, and introduction. (1) The title
page includes, at a minimum, the following information:
(i) Name and international birth date of the drug substance that is
the subject of the IPSR,
(ii) Various dosage forms and formulations of the drug substance
covered by the IPSR,
(iii) Name and address of the applicant,
(iv) Reporting period covered by the IPSR, and
(v) Date of the IPSR.
(2) The introduction:
(i) Provides a brief description of how the IPSR relates to
previous reports and circumstances,
(ii) References relevant drug products or substances reported in
other periodic safety reports (e.g., a combination product reported in
a separate IPSR), and
(iii) Indicates any data duplication with other IPSRs.
(B) Worldwide marketing status. This section of the IPSR contains a
table of the chronological history of the worldwide marketing status of
the drug product(s) covered by the IPSR from the date the product(s)
was first approved (i.e., the international birth date) through its
current status (i.e., cumulative information). The table consists of:
(1) Dates of drug approval and renewal;
(2) Safety-related restrictions on product use;
(3) Indications for use and special populations covered by the drug
approval;
(4) Lack of approval of the drug substance in any dosage form or
for any indication for use by any regulatory authority(ies);
(5) Withdrawal of a pending marketing application for a drug
product by the applicant for safety or efficacy related reasons;
(6) Dates of market launches; and
(7) Trade name(s).
(C) Actions taken for safety reasons. (1) This section of the IPSR
includes details on the following types of regulatory authority-
initiated (e.g., by FDA) and/or applicant-initiated actions
[[Page 12484]]
related to safety that were taken during the period covered by the IPSR
and between the data lock point and IPSR submission (i.e., ``late-
breaking'' safety concerns):
(i) Withdrawal or suspension of drug product approval or indication
for use approval;
(ii) Failure to obtain a marketing authorization renewal or to
obtain an approval for a new indication for use;
(iii) Restrictions on distribution (e.g., products recalled for
safety reasons);
(iv) Clinical trial suspension;
(v) Dosage modification;
(vi) Changes in target population or indications; and
(vii) Formulation changes.
(2) This section of the IPSR also contains a narrative identifying
the safety-related reasons that led to these actions with relevant
documentation appended when appropriate.
(3) Any communication with health care professionals (e.g., Dear
Healthcare Professional letters) resulting from such actions must also
be described with copies appended.
(D) Changes to CCSI. This section of the IPSR describes changes to
the CCSI (e.g., new contraindications, precautions, warnings, SADRs, or
interactions) made during the period covered by the IPSR. A copy of any
modified section of the CCSI must be included. The applicant must use
the CCSI in effect at the beginning of the reporting period for the
IPSR. The revised CCSI is to be used as the reference document for the
next reporting period.
(E) Worldwide patient exposure. (1) This section of the IPSR
includes, for the reporting period, an estimate of the worldwide
patient exposure to the drug product(s) covered by the IPSR (i.e.,
number of patients, average or median dose received, and average or
median length of treatment). The method used to estimate patient
exposure must always be described. If the patient exposure is
impossible to estimate or is meaningless, an explanation of and
justification for such conclusions must be provided. If patient
exposure is impossible to estimate, other measures of exposure, such as
patient-days, number of prescriptions, or number of dosage units, may
be used. If these or other more precise measures are not available and
an adequate explanation for the lack of such information is provided,
bulk sales may be used.
(2) When possible, data broken down by gender and age (especially
pediatric versus adult) must be provided. For the pediatric population,
data must be reported, if possible, by age group (e.g., neonates,
infants, children, adolescents). If these data are not available, an
explanation must be included.
(3) When a pattern of reports indicates a potential problem,
details by country (with locally recommended dosage regimens) or other
segmentation (e.g., indication, dosage form) must be presented.
(F) Safety studies. This section of the IPSR contains a discussion
of nonclinical, clinical, and epidemiological studies that contain
important safety information, as follows:
(1) All applicant-sponsored studies newly analyzed during the
reporting period (copies of full reports should be appended only if new
safety issues are raised or confirmed; FDA may request copies of other
studies, if necessary);
(2) New studies specifically planned, initiated, or continuing
during the reporting period that examine a safety issue, whether actual
or hypothetical; and
(3) Published safety studies in the scientific and medical
literature, including relevant published abstracts from meetings
(provide literature citation).
(G) Other information. This section of the IPSR includes a
discussion of medically relevant lack of efficacy reports (e.g., might
represent a significant hazard to the treated population) for a
product(s) used to treat serious or life-threatening diseases.
(H) Overall safety evaluation. This section of the IPSR contains a
concise, yet comprehensive, analysis of all of the safety information
provided in the IPSR. In addition, this section of the IPSR must
include an assessment by the applicant of the significance of the data
collected during the reporting period, as well as from the perspective
of cumulative experience.
(1) The applicant must highlight any new information on:
(i) Serious, unlisted SADRs;
(ii) Increased reporting frequencies of listed SADRs, including
comments on whether it is believed that the data reflect a meaningful
change in SADR occurrence;
(iii) A change in characteristics of listed SADRs (e.g., severity,
outcome, target population); and
(iv) Nonserious, unlisted SADRs.
(2) As part of the overall safety evaluation, the applicant must
also explicitly address any new safety issue including but not limited
to the following (lack of significant new information for each of the
following must be mentioned):
(i) Drug interactions;
(ii) Experience with overdose, whether deliberate or accidental,
and its treatment;
(iii) Drug abuse or intentional misuse;
(iv) Positive or negative experiences during pregnancy or
lactation;
(v) Effects with long-term treatment; and
(vi) Experience in special patient groups (e.g., pediatric,
geriatric, organ impaired). For the pediatric population, data must be
evaluated, if possible, by age group (e.g., neonates, infants,
children, adolescents).
(I) Conclusion. This section of the IPSR:
(1) Indicates new safety information that is not in accord with
previous cumulative experience and with the CCSI in use at the
beginning of the reporting period (e.g., new evidence that strengthens
a possible causal relationship between the drug product and an SADR
such as positive rechallenge, an epidemiological association or new
laboratory studies); and
(2) Specifies and justifies any action recommended or initiated,
including changes in the CCSI.
(J) Appendices. This section of the IPSR includes:
(1) Company core data sheet. Provide a copy of the company core
data sheet covered by this IPSR (i.e., in effect at the beginning of
the period covered by the IPSR), as well as the company core data sheet
for the next reporting period. Company core data sheets must be
numbered and dated and include the date of last revision.
(2) U.S. labeling. Provide a copy of the current approved U.S.
labeling. Specify any safety information that is included in the CCSI
but not in the U.S. labeling and provide an explanation for the
discrepancy. Describe any safety-related changes or proposed changes to
the U.S. labeling made during the reporting period (include the
supplement number(s) and date(s) of submission for the supplement(s))
and any suggested change(s) that should be considered based on the
safety analysis in this IPSR.
(3) Spontaneous reports submitted to the applicant by an individual
other than a health care professional. Provide a brief discussion of
the impact on the overall safety evaluation of any spontaneously
reported serious SADRs, whether domestic or foreign, and any
spontaneously reported nonserious SADRs occurring in the United States,
obtained or otherwise received during the reporting period by the
applicant from an individual other than a health care professional
(e.g., reports from consumers).
[[Page 12485]]
(4) SADRs with unknown outcome. Provide a brief discussion of the
impact on the overall safety evaluation of any spontaneously reported
unlisted and listed SADRs with unknown outcome obtained or otherwise
received during the reporting period by the applicant from health care
professionals and other individuals.
(5) Class action lawsuits. Provide a brief discussion of the impact
on the overall safety evaluation of any safety information obtained or
otherwise received during the reporting period by the applicant from
class action lawsuits.
(6) Lack of efficacy reports. Provide an assessment of whether it
is believed that the frequency of any lack of efficacy reports,
obtained or otherwise received during the reporting period, is greater
than would be predicted by the premarketing clinical trials for the
drug product.
(7) Information on resistance to antimicrobial drug products.
Provide information, received or otherwise obtained by the applicant,
on resistance to antimicrobial drug products intended to treat
infectious diseases. Include information on changes in U.S. microbial
in vitro susceptibility, the relationship of changes in U.S. microbial
in vitro susceptibility and clinical outcomes, therapeutic failure that
may possibly be due to resistance to the antimicrobial drug product,
and whether the U.S. labeling should be revised because of the
information on antimicrobial resistance learned during the period
covered by this IPSR.
(8) Medication errors. Provide a brief discussion of the impact on
the overall safety evaluation of all domestic reports of medication
errors submitted during the reporting period under paragraph (c)(2)(v)
of this section.
(9) U.S. patient exposure. Provide, for the reporting period, an
estimate of the U.S. patient exposure to the drug product(s) covered by
the IPSR (i.e., number of patients, average or median dose received,
and average or median length of treatment). The method used to estimate
patient exposure must always be described. If the patient exposure is
impossible to estimate or is meaningless, an explanation of and
justification for such conclusions must be provided. If patient
exposure is impossible to estimate, other measures of exposure, such as
patient-days, number of prescriptions, or number of dosage units, may
be used. If these or other more precise measures are not available and
an adequate explanation for the lack of such information is provided,
bulk sales may be used.
(10) Location of safety records. Provide a list of the current
address(es) where all safety reports and other safety-related records
for the drug product are maintained.
(11) Contact person. Provide the name and telephone number for the
licensed physician(s) responsible for the content and medical
interpretation of the information contained within the IPSR. Include,
if available, the fax number and e-mail address for the licensed
physician(s).
(iv) Pediatric use supplements. After approval of a pediatric use
supplement to an approved application (i.e., a supplement for use of
the human drug product in the pediatric population), the applicant must
submit PSURs to FDA as prescribed under paragraph (c)(3)(ii) of this
section according to the following schedule: Semiannually for 2 years
after U.S. approval of the supplement, annually for the next 3 years,
and then every 5 years thereafter. These applicants must also submit
IPSRs to FDA as prescribed under paragraph (c)(3)(iii) of this section
at 7.5 years and 12.5 years after U.S. approval of the supplement. The
data lock point for the PSUR and IPSR is the month and day of the
international birth date of the drug substance or any other month and
day agreed on by the applicant and FDA.
(v) Semiannual submission of individual case safety reports. (A) An
applicant holding an application for a human drug product approved
under section 505(c) of the act must submit to FDA semiannually (i.e.,
every 6 months) after U.S. approval of the application a separate
report that consists of individual case safety reports for certain
spontaneously reported SADRs for the human drug product. The individual
case safety reports must be submitted to FDA on the form designated by
the agency under paragraph (c)(4) of this section. The data lock point
for the report is the month and day of the international birth date of
the drug product or any other month and day agreed on by the applicant
and FDA. This report must be identified as ``individual case safety
reports--semiannual submission.''
(B) Applicants that submit TPSRs to FDA for the drug product must
submit an individual case safety report for each serious, expected
SADR, whether domestic or foreign, and each nonserious, unexpected SADR
occurring in the United States that is submitted to the applicant
during the reporting period from all spontaneous sources (i.e., health
care professionals and other individuals). Applicants that submit PSURs
to FDA for the drug product must submit an individual case safety
report for each serious, listed SADR, whether domestic or foreign, and
each nonserious, unlisted SADR occurring in the United States that is
submitted to the applicant during the reporting period from all
spontaneous sources. If a full data set is not available for a serious
SADR, the applicant must submit the information required under
paragraph (c)(1)(iv) of this section.
(C) Followup information on SADRs submitted in an individual case
safety report--semiannual submission may be submitted in the next
individual case safety report--semiannual submission unless such
information changes the classification of the SADR to a serious,
unexpected SADR. In these cases, the followup information must be
submitted to FDA as a 15-day followup report (see paragraph (c)(2)(vii)
of this section).
(4) Reporting format. (i)(A) Except as provided in paragraphs
(c)(4)(i)(B), (c)(4)(i)(D), and (c)(4)(v) of this section, the
applicant must complete an FDA Form 3500A for each individual case
safety report of an SADR. Reports based on information about individual
cases or case series in the scientific literature must be submitted on
an FDA Form 3500A(s).
(B) Foreign SADRs may be submitted either on an FDA Form 3500A or,
if preferred, on a CIOMS I form.
(C) Each domestic report of an actual or potential medication error
must be submitted on an FDA Form 3500A.
(D) Reports of overall findings or data in the aggregate from
published and unpublished in vitro, animal, epidemiological, or
clinical studies must be submitted in a narrative format.
(ii) Each SADR in an individual case safety report must be coded on
the FDA Form 3500A or CIOMS I form using the appropriate ``preferred
term'' in the latest version of MedDRA (the medical dictionary for
regulatory activities) in use at the time the applicant becomes aware
of the individual case safety report. For individual case safety
reports of medication errors, the report must be coded both as a
medication error and, if applicable, with the preferred term for any
SADRs associated with the medication error.
(iii) Each completed FDA Form 3500A or CIOMS I form should refer
only to an individual case.
(iv) Each completed FDA Form 3500A or CIOMS I form must include the
name and telephone number (and fax number and e-mail address, if
available) for the licensed physician responsible for the content and
medical interpretation of the data contained within the form (i.e.,
contact person for the company).
(v) Instead of using FDA Form 3500A, the applicant may use a
computer-generated facsimile of FDA Form 3500A provided that it is
readable, includes
[[Page 12486]]
appropriate identifying information, and contains all the elements
(i.e., format, sections, blocks, titles, descriptors within blocks,
text for disclaimer) of FDA Form 3500A in the identical enumerated
sequence of the form. For individual case safety reports in which no
suspect medical device is involved, a one-page FDA Form 3500A is
acceptable.
(d) Multiple reports. An applicant should not include in reports
under this section any SADRs that occurred in clinical trials if they
were previously submitted as part of the approved application. If a
report applies to a drug for which an applicant holds more than one
approved application, the applicant should submit the report to the
application that was first approved. If a report refers to more than
one drug marketed by an applicant, the applicant should submit the
report to the application for the drug listed first in the report.
(e) Patient privacy. The names and addresses of individual patients
should not be included in reports under this section; instead, the
applicant and its contractors should assign a unique code to each
report, preferably not more than eight characters (i.e., numbers and/or
letters) in length. The name of the reporter from whom the information
was received should be included. Names of patients, individual
reporters, health care professionals, hospitals, and geographic
identifiers in safety reports are not releasable to the public under
FDA's public information regulations in part 20 of this chapter.
(f) Recordkeeping. Each applicant must maintain for a period of 10
years records of all safety information pertaining to its drug product,
received or otherwise obtained, including raw data, any correspondence
relating to the safety information, and any reports of SADRs or
medication errors not submitted to FDA or only provided to FDA in a
summary tabulation. Each applicant must also retain for a period of 10
years any records required to be maintained under this section. When
appropriate, FDA may require an applicant to submit any or all of these
records to the agency within 5 calendar days after receipt of the
request.
(g) Written procedures. Each applicant must develop and maintain
written procedures for the surveillance, receipt, evaluation, and
reporting of postmarketing safety information to FDA.
(h) Withdrawal of approval. If an applicant fails to establish and
maintain records and make reports required under this section, FDA may
withdraw approval of the application and, thus, prohibit continued
marketing of the drug product that is the subject of the application.
(i) Disclaimer. A report or information submitted by an applicant
under this section (and any release by FDA of that report or
information) does not necessarily reflect a conclusion by the applicant
or FDA that the report or information constitutes an admission that the
drug caused or contributed to an SADR. An applicant need not admit, and
may deny, that the report or information submitted under this section
constitutes an admission that the drug caused or contributed to an
SADR.
8. Section 314.81 is amended by removing paragraph (b)(2)(v), by
redesignating paragraphs (b)(2)(vi) through (b)(2)(ix) as paragraphs
(b)(2)(v) through (b)(2)(viii), respectively, and by revising paragraph
(b)(2)(i) and newly redesignated paragraph (b)(2)(v) to read as
follows:
Sec. 314.81 Other postmarketing reports.
* * * * *
(b) * * *
(2) * * *
(i) Summary. A brief summary of significant new information from
the previous year that might affect the effectiveness of the drug
product or the sections of the drug product labeling that are not
related to safety. The report must also contain a brief description of
actions the applicant has taken or intends to take as a result of this
new information, for example, submit an efficacy labeling supplement or
initiate a new study. The summary must briefly state whether
supplements for pediatric use have been submitted and whether new
studies in the pediatric population to support appropriate labeling for
the pediatric population have been initiated.
* * * * *
(v) Clinical data. (A) Published clinical trials of the drug (or
abstracts of them), including clinical trials on effectiveness;
clinical trials on new uses; and biopharmaceutic, pharmacokinetic, and
clinical pharmacology studies conducted by or otherwise obtained by the
applicant. Review articles, papers describing safety related
information or the use of the drug product in medical practice, papers
and abstracts in which the drug is used as a research tool, promotional
articles, press clippings, and papers that do not contain tabulations
or summaries of original data should not be reported.
(B) Summaries of completed unpublished clinical trials, or
prepublication manuscripts if available, conducted by, or otherwise
obtained by, the applicant. Supporting information should not be
reported. (A study is considered completed 1 year after it is
concluded.)
(C) Analysis of available efficacy data in the pediatric population
and changes proposed in the labeling based on this information. An
assessment of data needed to ensure appropriate labeling for the
pediatric population must be included.
* * * * *
9. Section 314.98 is amended in paragraph (a) by adding the
abbreviation ``(ANDA)'' after the phrase ``abbreviated new drug
application'', by removing the citation ``Sec. 314.94'' and by adding
in its place the phrase ``section 505(j) of the Act'', by removing the
phrase ``adverse drug experiences'' and by adding in its place the
phrase ``suspected adverse drug reactions'', and by adding two
sentences to the end of the paragraph; and in paragraph (b) by removing
the phrase ``Division of Epidemiology and Surveillance (HFD-730),
Center for Drug Evaluation and Research, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857'' and by adding in its place the
word ``FDA'' to read as follows:
Sec. 314.98 Postmarketing reports.
(a) * * * For purposes of postmarketing periodic safety reporting,
applicants must determine the data lock point (i.e., month and day of
the international birth date or any other month and day agreed by the
applicant and FDA) for their periodic safety reports based on the data
lock point of postmarketing periodic safety reports for other drug
products containing the same drug substance (i.e., innovator new drug
application (NDA) product that is the same drug product as the ANDA
product, or other ANDA products with the same drug substance if the
innovator NDA product is no longer on the market). Applicants must
determine the type of postmarketing periodic safety report required to
be submitted to FDA (i.e., traditional periodic safety report (TPSR),
periodic safety update report (PSUR) or interim periodic safety report
(IPSR)) and the frequency of submission for these reports based on the
U.S. approval date of the application for the innovator NDA product.
* * * * *
PART 320--BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS
10. The authority citation for 21 CFR part 320 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 355, 371.
[[Page 12487]]
11. Section 320.31 is amended by revising paragraph (d) to read as
follows:
Sec. 320.31 Applicability of requirements regarding an
``Investigational New Drug Application.''
* * * * *
(d) A bioavailability or bioequivalence study in humans other than
one described in paragraphs (a) through (c) of this section is exempt
from the requirements of part 312 of this chapter, except for the
safety reporting requirements under Sec. 312.32 of this chapter, if
the following conditions are satisfied:
(1) If the study is one described under Sec. 320.38(b) or Sec.
320.63, the person conducting the study, including any contract
research organization, must retain reserve samples of any test article
and reference standard used in the study and release the reserve
samples to FDA upon request in accordance with and for the period
specified in Sec. 320.38;
(2) An in vivo bioavailability or bioequivalence study in humans
must be conducted in compliance with the requirements for institutional
review set forth in part 56 of this chapter and informed consent set
forth in part 50 of this chapter; and
(3) Safety reports as prescribed under Sec. 312.32 of this chapter
must be transmitted to all participating investigators and the
appropriate FDA division in the Center for Drug Evaluation and Research
(i.e., safety reports for the reference listed drug must be sent to the
new drug review division that has responsibility for that drug, safety
reports for the investigational drug product must be sent to the
Director, Division of Bioequivalence, Office of Generic Drugs). Each
written notification under this paragraph must bear prominent
identification of its contents, i.e., ``bioavailability/bioequivalence
safety report.'' For reporting purposes under this paragraph, an
unexpected suspected adverse drug reaction (SADR) is any SADR, the
specificity or severity of which is not consistent with the U.S.
labeling for the reference listed drug.
PART 600--BIOLOGICAL PRODUCTS: GENERAL
12. The authority citation for 21 CFR part 600 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371,
374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.
13. Section 600.80 is revised to read as follows:
Sec. 600.80 Postmarketing reporting of suspected adverse reactions.
(a) Definitions. The following definitions of terms apply to this
section:
Active query means direct verbal contact (i.e., in person or by
telephone or other interactive means such as a video conference) with
the initial reporter of a suspected adverse reaction (SAR) or
medication error by a health care professional (e.g., physician,
physician assistant, pharmacist, dentist, nurse, any individual with
some form of health care training) representing the applicant. For
SARs, active query entails, at a minimum, a focused line of questioning
designed to capture clinically relevant information associated with the
licensed biological product and the SAR, including, but not limited to,
information such as baseline data, patient history, physical exam,
diagnostic results, and supportive lab results.
Actual medication error means a medication error that involves an
identifiable patient whether the error was prevented prior to
administration of the product or, if the product was administered,
whether the error results in a serious SAR, nonserious SAR, or no SAR.
Blood component means as defined in Sec. 606.3(c) of this chapter.
Company core data sheet means a document prepared by the applicant
containing, in addition to safety information, material relating to
indications, dosing, pharmacology, and other information concerning the
biological product. The only purpose of this document is to provide the
company core safety information (CCSI) for periodic safety update
reports (PSURs), interim periodic safety reports (IPSRs), and certain
individual case safety reports--semiannual submissions (i.e., if PSURs
are submitted for the product).
Company core safety information (CCSI) means all relevant safety
information contained in the company core data sheet that the applicant
proposes to include in the approved product labeling in all countries
where the applicant markets the biological product. It is the reference
information by which an SAR is determined to be ``listed'' or
``unlisted'' for PSURs, IPSRs, and certain individual case safety
reports--semiannual submissions (i.e., if PSURs are submitted for the
product).
Contractor means any person (e.g., manufacturer, joint
manufacturer, packer, or distributor whether or not its name appears on
the label of the product; licensee; contract research organization)
that has entered into a contract with the applicant (includes
participants involved in divided manufacturing) to manufacture, pack,
sell, distribute, or develop the licensed biological product or to
maintain, create, or submit records regarding SARs or medication
errors.
Data lock point means the date designated as the cut-off date for
data to be included in a postmarketing periodic safety report.
Disability means a substantial disruption of a person's ability to
conduct normal life functions.
Full data set means completion of all the applicable elements on
FDA Form 3500A or the vaccine adverse event reporting system (VAERS)
form (or on a Council for International Organizations of Medical
Sciences (CIOMS) I form for reports of foreign SARs), including a
concise medical narrative of the case (i.e., an accurate summary of the
relevant data and information pertaining to an SAR or medication
error).
International birth date means the date the first regulatory
authority in the world approved the first marketing application for a
human biological product.
Life-threatening SAR means any SAR that, in the view of the initial
reporter, places the patient at immediate risk of death from the SAR as
it occurred. It does not include an SAR that, had it occurred in a more
severe form, might have caused death.
Listed SAR means an SAR whose nature, specificity, severity, and
outcome are consistent with the information in the CCSI.
Medication error means any preventable event that may cause or lead
to inappropriate medication use or patient harm while the medication is
in the control of the health care professional, patient, or consumer.
Such events may be related to professional practice, health care
products, procedures, and systems including: Prescribing; order
communication; product labeling, packaging, and nomenclature;
compounding; dispensing; distribution; administration; education;
monitoring; and use.
Minimum data set means the report includes an identifiable patient,
an identifiable reporter, a suspect biological product, and an SAR.
Nonserious SAR means any SAR that is determined not to be a serious
SAR.
Potential medication error means an individual case safety report
of information or complaint about product name, labeling, or packaging
similarities that does not involve a patient.
SAR with unknown outcome means an SAR that cannot be classified,
after
[[Page 12488]]
active query, as either serious or nonserious.
Serious SAR means any SAR that results in any of the following
outcomes: Death, a life-threatening SAR, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant
disability/incapacity, or a congenital anomaly/birth defect. Important
medical events that may not result in death, be life-threatening, or
require hospitalization may be considered a serious SAR when, based
upon appropriate medical judgment, they may jeopardize the patient or
subject and may require medical or surgical intervention to prevent one
of the outcomes listed in this definition. Examples of such medical
events include allergic bronchospasm requiring intensive treatment in
an emergency room or at home, blood dyscrasias or convulsions that do
not result in inpatient hospitalization, or the development of drug
dependency or drug abuse.
Spontaneous report means a communication from an individual (e.g.,
health care professional, consumer) to a company or regulatory
authority that describes an SAR or medication error. It does not
include cases identified from information solicited by the applicant,
shared manufacturer, or contractor, such as individual case safety
reports or findings derived from a study, company-sponsored patient
support program, disease management program, patient registry,
including pregnancy registries, or any organized data collection
scheme. It also does not include information compiled in support of
class action lawsuits.
Suspected adverse reaction (SAR) means a noxious and unintended
response to any dose of a biological product for which there is a
reasonable possibility that the product caused the response. In this
definition, the phrase ``a reasonable possibility'' means that the
relationship cannot be ruled out.
Unexpected SAR means any SAR that is not included in the current
U.S. labeling for the licensed biological product. Reactions that may
be symptomatically and pathophysiologically related to a reaction
included in the U.S. labeling, but differ from the labeled reaction
because of greater severity or specificity, would be unexpected. For
example, under this definition, hepatic necrosis would be unexpected
(by virtue of greater severity) if the U.S. labeling only referred to
elevated hepatic enzymes or hepatitis. Similarly, cerebral
thromboembolism and cerebral vasculitis would be unexpected (by virtue
of greater specificity) if the U.S. labeling only included cerebral
vascular accidents. ``Unexpected,'' as used in this definition, refers
to an SAR that has not been previously observed (i.e., included in the
U.S. labeling); it does not refer to an SAR that might be anticipated
from the pharmacological properties of the licensed biological product.
SARs that are mentioned in the U.S. labeling as occurring with a class
of products but not specifically mentioned as occurring with the
particular product are considered unexpected.
Unlisted SAR means an SAR whose nature, specificity, severity, or
outcome is not consistent with the information included in the CCSI.
(b) Review of safety information. (1) Any person having a biologics
license under Sec. 601.20 of this chapter must promptly review all
safety information pertaining to its product obtained or otherwise
received by the applicant from any source, foreign or domestic,
including information derived from commercial marketing experience,
postmarketing clinical investigations, postmarketing epidemiology/
surveillance studies, animal or in vitro studies, electronic
communications with applicants via the Internet (e.g., e-mail), reports
in the scientific literature, and unpublished scientific papers, as
well as reports from foreign regulatory authorities that have not been
previously reported to the Food and Drug Administration (FDA) by the
applicant.
(2) Individual case safety reports that are forwarded to the
applicant by FDA must not be resubmitted to the agency by the
applicant; however, applicants must include information from these
individual case safety reports in any comprehensive safety analysis
subsequently submitted to FDA. In addition, applicants must submit to
FDA all followup information for these individual case safety reports.
(c) Reporting requirements. For nonvaccine biological products, the
applicant must submit to FDA two copies of each postmarketing expedited
report (described under paragraphs (c)(2)(i) through (c)(2)(vii) of
this section) and each postmarketing periodic safety report of an
individual case safety reports--semiannual submission (described under
paragraph (c)(3)(v) of this section) pertaining to its product. For
nonvaccine biological products, the applicant must also submit to FDA
one copy of a PSUR, IPSR, or traditional periodic safety report (TPSR)
along with one copy for each approved application for a human licensed
biological product covered by the report. For vaccines, the applicant
must submit to VAERS two copies of each safety report pertaining to its
product and required under this section. FDA may waive the requirement
for multiple copies in appropriate instances. Upon written notice, FDA
may require, when appropriate, that the applicant submit reports under
this section to the agency at times other than those stated. An
applicant that wishes to submit reports under this section at different
intervals must submit to FDA a request for a waiver under Sec. 600.90.
(1) Determination of outcome, minimum data set, and full data set--
(i)(A) Initial determinations. Upon initial receipt of an SAR report,
the applicant must immediately determine the outcome for the SAR
(whether the SAR is serious or nonserious) and at least the minimum
data set for the individual case safety report. For reports of actual
medication errors that do not result in an SAR and potential medication
errors, the applicant must immediately determine the minimum
information for the individual case safety report (minimum information
described under paragraphs (c)(1)(iii)(B) and (c)(1)(iii)(C) of this
section). If the applicant is not able to immediately determine the
information in this paragraph, active query must be used to obtain it
as soon as possible.
(B) Spontaneous reports. For spontaneous reports, the applicant
must always assume, for safety reporting purposes under this section,
that there is at least a reasonable possibility, in the opinion of the
initial reporter, that the biological product caused the spontaneously
reported event.
(C) Clinical trials. For a clinical trial, the possibility that the
biological product caused the SAR or that a medication error has
occurred must be assumed if either the investigator or the applicant
believes that such a reasonable possibility exists.
(ii) SARs with unknown outcome. For an SAR with unknown outcome
that cannot be immediately determined, the applicant must continue to
use active query to attempt to determine the outcome of the SAR within
30 calendar days after initial receipt of the SAR report by the
applicant. The applicant must maintain a record of its efforts to
determine the outcome for an SAR with unknown outcome.
(iii) (A) Minimum data set for SAR reports. The applicant must not
submit an individual case safety report for an SAR to FDA if the report
does not contain a minimum data set; instead, the applicant must
maintain records of any information received or otherwise obtained for
the SAR along with a record of its efforts to obtain a minimum data
set.
[[Page 12489]]
(B) Minimum information for reports of actual medication errors
that do not result in an SAR. For reports of actual medication errors
that do not result in an SAR, an individual case safety report must be
submitted to FDA even though the report does not contain a minimum data
set (i.e., does not have an SAR). These reports must contain at least
an identifiable patient, an identifiable reporter, and a suspect
biological product.
(C) Minimum information for potential medication error reports. For
reports of potential medication errors, an individual case safety
report must be submitted to FDA even though the report does not contain
a minimum data set (i.e., does not have an identifiable patient or an
SAR). These reports must contain at least an identifiable reporter and
a suspect biological product.
(iv) Full data set. For reports of serious SARs, always expedited
reports (see paragraph (c)(2)(iv) of this section), and medication
error reports (see paragraph (c)(2)(v) of this section), the applicant
must submit a full data set. If a full data set is not available for
the report, the applicant must use active query to obtain this
information. If a full data set is not obtainable after active query,
the applicant must:
(A) Submit all safety information, received or otherwise obtained,
for the report;
(B) Indicate the reason(s) for its inability to acquire a full data
set; and
(C) Document its efforts to obtain a full data set (i.e.,
description of unsuccessful steps taken to obtain this information).
(v) Serious SARs not initially reported by a health care
professional. For a serious SAR that was not initially reported to the
applicant by a health care professional (e.g., report from a consumer),
the applicant must contact the health care professional associated with
the care of the patient using active query to gather further medical
perspective on the case and to acquire a full data set for the report.
If the applicant is unable to contact the health care professional, it
must include in the report for the serious SADR:
(A) The reason(s) for its inability to contact the health care
professional; and
(B) A description of its efforts to contact the health care
professional.
(vi) Nonserious SARs. For reports of nonserious SARs with a minimum
data set, except for those resulting from a medication error, all
safety information received or otherwise obtained by the applicant must
be submitted to FDA even though information in addition to the minimum
data set is not required to be acquired. Reports of nonserious SARs
resulting from a medication error require a full data set under
paragraph (c)(1)(iv) of this section.
(2) Postmarketing ``expedited reports''--(i) Serious and unexpected
SAR. The applicant must report to FDA each SAR, received or otherwise
obtained, that is both serious and unexpected, whether foreign or
domestic, as soon as possible, but in no case later than 15 calendar
days after receipt by the applicant of the minimum data set for the
serious, unexpected SAR. If a full data set is not available for the
serious and unexpected SAR report at the time of initial submission of
the report to FDA, the applicant must submit the information required
under paragraph (c)(1)(iv) of this section and also submit a 30-day
followup report as required by paragraph (c)(2)(vi) of this section.
(ii) Information sufficient to consider product administration
changes. The applicant must also report to FDA information, received or
otherwise obtained, whether foreign or domestic, that would be
sufficient, based upon appropriate medical judgment, to consider
changes in product administration. The applicant must submit this
information to FDA as soon as possible, but in no case later than 15
calendar days after determination by the applicant that the information
qualifies for expedited reporting. Examples of such information include
any significant unanticipated safety finding or data in the aggregate
from an in vitro, animal, epidemiological, or clinical study, whether
or not conducted under an investigational new drug application (IND),
that suggests a significant human risk, such as reports of
mutagenicity, teratogenicity, or carcinogenicity, or reports of a lack
of efficacy with a biological product used in treating a life-
threatening or serious disease. The applicant must maintain a record of
its efforts to determine whether the information required to be
reported under this paragraph qualifies for expedited reporting.
(iii) Unexpected SAR with unknown outcome. The applicant must also
report to FDA each SAR that is unexpected and for which the
determination of an outcome is unattainable (i.e., SAR with unknown
outcome) within 45 calendar days after initial receipt by the applicant
of the minimum data set for the unexpected SAR. The applicant must
document in the expedited report the reason(s) for the inability to
determine the outcome.
(iv) Always expedited report. (A) The applicant must also report to
FDA each SAR, received or otherwise obtained, whether foreign or
domestic, that is the subject of an always expedited report. These
reports must be submitted to FDA as soon as possible, but in no case
later than 15 calendar days after receipt by the applicant of the
minimum data set for the report. The following medically significant
SARs, which may jeopardize the patient or subject and/or require
medical or surgical intervention to treat the patient or subject, are
subject to an always expedited report:
(1) Congenital anomalies,
(2) Acute respiratory failure,
(3) Ventricular fibrillation,
(4) Torsades de pointe,
(5) Malignant hypertension,
(6) Seizure,
(7) Agranulocytosis,
(8) Aplastic anemia,
(9) Toxic epidermal necrolysis,
(10) Liver necrosis,
(11) Acute liver failure,
(12) Anaphylaxis,
(13) Acute renal failure,
(14) Sclerosing syndromes,
(15) Pulmonary hypertension,
(16) Pulmonary fibrosis,
(17) Confirmed or suspected transmission of an infectious agent by
a marketed drug or biological product,
(18) Confirmed or suspected endotoxin shock, and
(19) Any other medically significant SAR that FDA determines to be
the subject of an always expedited report (i.e., may jeopardize the
patient or subject and/or require medical or surgical intervention to
treat the patient or subject).
(B) SARs that are the subject of an always expedited report must be
submitted to FDA whether unexpected or expected and whether or not the
SAR leads to a serious outcome. If a full data set is not available for
an always expedited report at the time of initial submission of the
report to FDA, the applicant must submit the information required under
paragraph (c)(1)(iv) of this section and also submit a 30-day followup
report as required by paragraph (c)(2)(vi) of this section.
(v) Medication error--(A) Actual medication error. The applicant
must also submit to FDA each domestic report of an actual medication
error, received or otherwise obtained, as soon as possible, but in no
case later than 15 calendar days after receipt by the applicant of the
minimum data set for a report of an SAR or, if an SAR does not occur,
the minimum information described under paragraph (c)(1)(iii)(B) of
this section (i.e., identifiable patient, identifiable reporter, and
suspect biological product).
(B) Potential medication error. The applicant must also submit to
FDA each domestic report of a potential
[[Page 12490]]
medication error, received or otherwise obtained, as soon as possible,
but in no case later than 15 calendar days after receipt by the
applicant of the minimum information described under paragraph
(c)(1)(iii)(C) of this section (i.e., identifiable reporter and suspect
biological product).
(C) Full data set. If a full data set is not available for an
actual or potential medication error report at the time of initial
submission of the report to FDA, the applicant must submit the
information required under paragraph (c)(1)(iv) of this section and
also submit a 30-day followup report as required by paragraph
(c)(2)(vi) of this section.
(vi) The 30-day followup report. The applicant must use active
query to obtain additional information for any expedited report under
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that
does not contain a full data set and must submit a followup report to
FDA within 30 calendar days after initial submission of the expedited
report to FDA by the applicant. If a full data set is still not
obtainable, the 30-day followup report must contain the information
required under paragraph (c)(1)(iv) of this section. Any new safety
information in the 30-day followup report must be highlighted. Any new
information received or otherwise obtained after submission of a 30-day
followup report must be submitted to FDA as a 15-day followup report
under paragraph (c)(2)(vii) of this section.
(vii) The 15-day followup report. The applicant must report to FDA
any new information, received or otherwise obtained, for any expedited
or followup report (except for initial expedited reports under
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that do
not contain a full data set) within 15 calendar days of initial receipt
of the new information by the applicant. Expedited reports under
paragraphs (c)(2)(i), (c)(2)(iv), and (c)(2)(v) of this section that do
not contain a full data set at the time of initial submission of the
report to FDA are subject to the 30-day followup reporting requirements
under paragraph (c)(2)(vi) of this section rather than the 15-day
followup reporting requirements under this paragraph.
(viii) Supporting documentation. (A) If the patient dies, the
applicant must submit a copy of the autopsy report to FDA, if it is
available. If an autopsy report is not available, the applicant must
submit a death certificate to FDA. If an autopsy report becomes
available after the applicant has submitted a death certificate to the
agency, the autopsy report must be submitted to FDA. If the patient was
hospitalized, the applicant must submit a copy of the hospital
discharge summary to FDA, if it is available. If any of these documents
is not in English, the document must be accompanied by an English
translation. Applicants must use active query to obtain these
documents. These documents must be submitted to FDA as 15-day followup
reports (see paragraph (c)(2)(vii) of this section) within 15 calendar
days of initial receipt of the document by the applicant. If these
documents are not submitted to FDA in a 15-day followup report within 3
months after submission of the initial expedited report for the death
or hospitalization, the agency will assume that active query by the
applicant has not resulted in access to these documents. In this case,
a record of the reason(s) for the lack of such documentation and the
effort that was made to obtain the documentation must be maintained by
the applicant.
(B) Each expedited report must contain in the narrative a list of
other relevant documents (e.g., medical records, laboratory results,
data from studies) for the report that are maintained by the applicant.
When appropriate, FDA may require an applicant to submit copies of one
or more of these documents to the agency within 5 calendar days after
receipt of the request.
(ix) Scientific literature. An expedited report based on
information from the scientific literature applies only to reports
found in scientific and medical journals. These expedited reports must
be accompanied by a copy of the published article.
(x) Submission of safety reports by contractors and shared
manufacturers. (A) Contractors and shared manufacturers must submit to
the applicant (includes participants involved in divided manufacturing)
safety reports of any SARs or medication errors for the applicant's
biological product, obtained or otherwise received, within 5 calendar
days of initial receipt of the report by the contractor or shared
manufacturer. The contractor and shared manufacturer must submit a
safety report for an SAR to the applicant even if the report does not
contain a minimum data set. Upon receipt of the safety report from a
contractor or shared manufacturer, the applicant must comply with the
postmarketing safety reporting requirements of this section.
(B) A contract between the applicant and a contractor must specify
the postmarketing safety reporting responsibilities of the contractor.
The applicant is responsible for ensuring that the contractors and
shared manufacturers of its licensed biological products comply with
these postmarketing safety reporting responsibilities.
(C) The contractor and shared manufacturer must maintain a record
of each submission to the applicant under paragraph (c)(2)(x)(A) of
this section that includes:
(1) A copy of each safety report;
(2) The date the report was initially received by the contractor or
shared manufacturer;
(3) The date the report was submitted to the applicant; and
(4) The name and address of the applicant.
(D) The recordkeeping, written procedures, and disclaimer
provisions under paragraphs (f), (g), and (j) of this section apply to
contractors and shared manufacturers.
(xi) Report identification. Each expedited report submitted to FDA
under paragraphs (c)(2)(i) through (c)(2)(vii) of this section must
bear prominent identification as to its contents, e.g., ``expedited
report--serious and unexpected SAR,'' ``expedited report--30-day
followup report.'' Each type of report (e.g., serious and unexpected
SAR reports, 30-day followup reports) must be submitted to FDA under
separate cover. Reports of medication errors must indicate whether the
error is actual or potential and if actual, whether a serious SAR,
nonserious SAR, or no SAR occurred, e.g., ``expedited report--actual
medication error--nonserious SAR,'' ``expedited report--potential
medication error.''
(3) Postmarketing periodic safety reports. The applicant must
submit postmarketing periodic safety reports under this section (i.e.,
TPSRs, PSURs, IPSRs, individual case safety reports--semiannual
submission) to FDA within 60 calendar days after the data lock point
for the report. The applicant must include a cover letter containing a
list of the biologics license application number(s) (i.e., BLA
number(s)) for the human biological product(s) covered by the
postmarketing periodic safety report. The international birth date for
combination products is the international birth date of the human
licensed biological product most recently approved for marketing.
(i) Traditional periodic safety reports (TPSRs). Each applicant
holding a biologics license under Sec. 601.20 of this chapter for a
human biological product approved before January 1, 1998, must submit
either a PSUR as prescribed under paragraph (c)(3)(ii) of this section
or a TPSR as described under this paragraph every 5 years after U.S.
[[Page 12491]]
approval of the application. In addition, these applicants must submit
either an IPSR as described under paragraph (c)(3)(iii) of this section
or a TPSR as described under this paragraph 7.5 years and 12.5 years
after U.S. approval of the application. The data lock point for the
TPSR, PSUR, or IPSR is the month and day of the international birth
date of the licensed biological product or any other month and day
agreed on by the applicant and FDA. Each TPSR must contain:
(A) Summary. This section of the TPSR includes:
(1) A narrative summary and analysis of serious, expected SARs and
nonserious, unexpected SARs occurring in the United States that were
submitted to the applicant during the reporting period from all
spontaneous sources (i.e., health care professionals and other
individuals) (with an index consisting of a line listing of the
applicant's manufacturer report number and SAR term(s));
(2) An analysis of the expedited reports submitted during the
reporting period under paragraphs (c)(2)(i) through (c)(2)(vii) of this
section (all expedited reports must be appropriately referenced by the
applicant's manufacturer report number, SAR term(s), if appropriate,
and date of submission to FDA);
(3) A discussion of any increased reporting frequency of serious,
expected SARs, including comments on whether it is believed that the
data reflect a meaningful change in SAR occurrence, and an assessment
of whether it is believed that the frequency of lack of efficacy
reports is greater than would be predicted by the premarketing clinical
trials for the biological product; and
(4) The applicant's conclusion as to what, if any, safety-related
actions should be taken based on the analysis of the safety data in the
TPSR (e.g., labeling changes, studies initiated).
(B) Summary tabulations. This section of the TPSR includes summary
tabulations (i.e., lists of all SAR terms and counts of occurrences)
presented by body system or by standard organ system classification
scheme for:
(1) All serious expected SARs, nonserious unexpected SARs,
nonserious expected SARs, and expected SARs with unknown outcome
occurring in the United States that are submitted to the applicant
during the reporting period from all spontaneous sources (i.e., health
care professionals and other individuals);
(2) All serious unexpected SARs, unexpected SARs with unknown
outcome, and always expedited reports that were previously submitted to
FDA in an expedited report under paragraphs (c)(2)(i), (c)(2)(iii), and
(c)(2)(iv) of this section (include cumulative data for serious
unexpected SARs, i.e., all cases reported to date);
(3) All reports of SARs not previously submitted to FDA by the
applicant (e.g., reports submitted to applicants by FDA, reports
obtained from FDA from freedom of information requests at the
discretion of the applicant, reports from class action lawsuits); and
(4) All domestic reports of medication errors previously submitted
to FDA under paragraph (c)(2)(v) of this section. For actual medication
errors, provide summary tabulations of serious SARs, nonserious SARs,
and no SARs. For potential medication errors, provide the number of
reports for specific errors;
(C) History of safety-related actions taken. This section of the
TPSR includes a history of safety-related actions taken since the last
periodic safety report (e.g., labeling changes, studies initiated);
(D) Location of safety records. This section of the TPSR includes a
list of the current address(es) where all safety reports and other
safety-related records for the licensed biological product(s) are
maintained; and
(E) Contact person. This section of the TPSR includes the name and
telephone number for the licensed physician(s) responsible for the
content and medical interpretation of the information contained within
the TPSR. Include, if available, the fax number and e-mail address for
the licensed physician(s).
(ii) Periodic safety update report (PSUR). An applicant holding a
biologics license under Sec. 601.20 of this chapter for a human
biological product approved on or after January 1, 1998, must submit a
PSUR to FDA according to the following schedule: Semiannually (i.e.,
every 6 months) for 2 years after U.S. approval of the application,
annually for the next 3 years, and then every 5 years thereafter. The
data lock point for the PSUR is the month and day of the international
birth date of the licensed biological product or any other month and
day agreed on by the applicant and FDA. Each PSUR must contain:
(A) Title page, table of contents, and introduction. (1) The title
page includes, at a minimum, the following information:
(i) Name and international birth date of the licensed biological
product(s) that is the subject of the PSUR,
(ii) Various dosage forms and formulations of the biological
product(s) covered by the PSUR,
(iii) Name and address of the applicant,
(iv) Reporting period covered by the PSUR, and
(v) Date of the PSUR.
(2) The introduction:
(i) Provides a brief description of how the PSUR relates to
previous reports and circumstances;
(ii) References relevant biological products reported in other
periodic safety reports (e.g., a combination product reported in a
separate PSUR); and
(iii) Indicates any data duplication with other PSURs.
(B) Worldwide marketing status. This section of the PSUR contains a
table of the chronological history of the worldwide marketing status of
the biological product(s) covered by the PSUR from the date the
product(s) was first approved (i.e., the international birth date)
through its current status (i.e., cumulative information). This table
consists of:
(1) Dates of biological product approval and renewal;
(2) Safety-related restrictions on product use;
(3) Indications for use and special populations covered by the
biological product approval;
(4) Lack of approval of the biological product in any dosage form
or for any indication for use by any regulatory authority(ies);
(5) Withdrawal of a pending marketing application for the
biological product by the applicant for safety- or efficacy-related
reasons;
(6) Dates of market launches; and
(7) Trade name(s).
(C) Actions taken for safety reasons. (1) This section of the PSUR
includes details on the following types of regulatory authority-
initiated (e.g., by FDA) and/or applicant-initiated actions related to
safety that were taken during the period covered by the PSUR and
between the data lock point and PSUR submission (i.e., ``late-
breaking'' safety concerns):
(i) Withdrawal or suspension of biological product approval or
indication for use approval;
(ii) Failure to obtain a marketing authorization renewal or to
obtain an approval for a new indication for use;
(iii) Restrictions on distribution (products recalled for safety
reasons);
(iv) Clinical trial suspension;
(v) Dosage modification;
(vi) Changes in target population or indications; and
(vii) Formulation changes.
(2) This section of the PSUR also contains a narrative identifying
the safety-related reasons that led to these actions with relevant
documentation appended when appropriate.
[[Page 12492]]
(3) Any communication with health care professionals (e.g., Dear
Healthcare Professional letters) resulting from such actions must also
be described with copies appended.
(D) Changes to CCSI. This section of the PSUR describes changes to
the CCSI (e.g., new contraindications, precautions, warnings, SARs, or
interactions) made during the period covered by the PSUR. A copy of any
modified section of the CCSI must be included. The applicant must use
the CCSI in effect at the beginning of the reporting period for the
PSUR. The revised CCSI is to be used as the reference document for the
next reporting period.
(E) Worldwide patient exposure. (1) This section of the PSUR
includes, for the reporting period, an estimate of the worldwide
patient exposure to the biological product(s) covered by the PSUR
(i.e., number of patients, average or median dose received, and average
or median length of treatment). The method used to estimate patient
exposure must always be described. If the patient exposure is
impossible to estimate or is meaningless, an explanation of and
justification for such conclusions must be provided. If patient
exposure is impossible to estimate, other measures of exposure, such as
patient-days, number of prescriptions, or number of dosage units, may
be used. If these or other more precise measures are not available and
an adequate explanation for the lack of such information is provided,
bulk sales may be used.
(2) When possible, data broken down by gender and age (especially
pediatric versus adult) must be provided. For the pediatric population,
data must be reported, if possible, by age group (e.g., neonates,
infants, children, adolescents). If these data are not available, an
explanation must be included.
(3) When a pattern of reports indicates a potential problem,
details by country (with locally recommended dosage regimens) or other
segmentation (e.g., indication, dosage form) must be presented.
(F) Individual case safety reports. (1) This section of the PSUR
includes summary tabulations of individual case safety reports (e.g.,
serious unlisted SARs, serious listed SARs, nonserious unlisted SARs,
nonserious listed SARs) for the following SARs obtained or otherwise
received during the reporting period:
(i) All serious and nonserious SARs from spontaneous sources that
were submitted to applicants by a health care professional,
(ii) All serious SARs from studies, individual patient INDs, or, in
foreign countries, from named-patient ``compassionate'' use,
(iii) All serious SARs and nonserious unlisted SARs from the
scientific literature,
(iv) All serious SARs from regulatory authorities, and
(v) Serious SARs from other sources such as reports created by
poison control centers and epidemiological data bases.
(2) The summary tabulations must be made up of lists by body system
or by standard organ system classification scheme of all SAR terms and
counts of occurrences. For SARs that are determined to be both serious
and unlisted, include cumulative data (i.e., all cases reported to
date).
(3) The applicant must conclude this section with a brief
discussion of the data concerning the individual case safety reports in
the PSUR (e.g., discussion of medical significance or mechanism).
(G) Safety studies. This section of the PSUR contains a discussion
of nonclinical, clinical, and epidemiological studies that contain
important safety information, as follows:
(1) All applicant-sponsored studies newly analyzed during the
reporting period (copies of full reports should be appended only if new
safety issues are raised or confirmed; FDA may request copies of other
studies, if necessary);
(2) New studies specifically planned, initiated, or continuing
during the reporting period that examine a safety issue, whether actual
or hypothetical; and
(3) Published safety studies in the scientific and medical
literature, including relevant published abstracts from meetings
(provide literature citation).
(H) Other information. This section of the PSUR includes:
(1) A discussion of medically relevant lack of efficacy reports
(e.g., might represent a significant hazard to the treated population)
for a product(s) used to treat serious or life-threatening diseases;
and
(2) Any important new information received after the data lock
point (e.g., significant new cases).
(I) Overall safety evaluation. This section of the PSUR contains a
concise, yet comprehensive, analysis of all of the safety information
provided in the PSUR, including new information provided under
paragraph (c)(3)(ii)(H)(2) of this section. In addition, this section
of the PSUR includes an assessment by the applicant of the significance
of the data collected during the reporting period, as well as from the
perspective of cumulative experience.
(1) The applicant must highlight any new information on:
(i) Serious, unlisted SARs;
(ii) Increased reporting frequencies of listed SARs, including
comments on whether it is believed that the data reflect a meaningful
change in SAR occurrence;
(iii) A change in characteristics of listed SARs (e.g., severity,
outcome, target population); and
(iv) Nonserious, unlisted SARs.
(2) As part of the overall safety evaluation, the applicant must
also explicitly address any new safety issue including but not limited
to the following (lack of significant new information for each of the
following must be mentioned):
(i) Drug interactions;
(ii) Experience with overdose, whether deliberate or accidental,
and its treatment;
(iii) Drug abuse or intentional misuse;
(iv) Positive or negative experiences during pregnancy or
lactation;
(v) Effects with long-term treatment; and
(vi) Experience in special patient groups (e.g., pediatric,
geriatric, organ impaired). For the pediatric population, data must be
evaluated, if possible, by age group (e.g., neonates, infants,
children, adolescents).
(J) Conclusion. This section of the PSUR:
(1) Indicates new safety information that is not in accord with
previous cumulative experience and with the CCSI in use at the
beginning of the reporting period (e.g., new evidence that strengthens
a possible causal relationship between the biological product and an
SAR, such as positive rechallenge, an epidemiological association, or
new laboratory studies); and
(2) Specifies and justifies any action recommended or initiated,
including changes in the CCSI.
(K) Appendices. This section of the PSUR includes:
(1) Company core data sheet. Provide a copy of the company core
data sheet covered by this PSUR (i.e., in effect at the beginning of
the period covered by the PSUR), as well as the company core data sheet
for the next reporting period. Company core data sheets must be
numbered and dated and include the date of last revision.
(2) U.S. labeling. Provide a copy of the current approved U.S.
labeling. Specify any safety information that is included in the CCSI
but not in the U.S. labeling, and provide an explanation for the
[[Page 12493]]
discrepancy. Describe any safety-related changes or proposed changes to
the U.S. labeling made during the reporting period (include the
supplement number(s) and date(s) of submission for the supplement(s))
and any suggested change(s) that should be considered based on the
safety analysis in this PSUR.
(3) Spontaneous reports submitted to the applicant by an individual
other than a health care professional. Provide summary tabulations
(e.g., serious unlisted SARs, serious listed SARs, nonserious unlisted
SARs, nonserious listed SARs) for all spontaneously reported serious
SARs, whether domestic or foreign, and all spontaneously reported
nonserious SARs occurring in the United States, obtained or otherwise
received during the reporting period by the applicant from an
individual other than a health care professional (e.g., reports from
consumers). These summary tabulations must consist of lists by body
system or by standard organ system classification scheme of all SAR
terms and counts of occurrences. For those SARs that are determined to
be both serious and unlisted, include cumulative data (i.e., all cases
reported to date by individuals other than a health care professional).
Include a brief discussion of the impact of the spontaneous reports
described in this appendix on the overall safety evaluation.
(4) SARs with unknown outcome. Provide summary tabulations for
unlisted and listed SARs with unknown outcome from all spontaneous
sources (i.e., health care professionals and other individuals),
obtained or otherwise received by the applicant during the reporting
period. These summary tabulations must consist of lists by body system
or by standard organ system classification scheme of all SAR terms and
counts of occurrences. Include a brief discussion of the impact of the
spontaneous reports described in this appendix on the overall safety
evaluation.
(5) Class action lawsuits. Provide summary tabulations (e.g.,
serious unlisted SARs, serious listed SARs, nonserious unlisted SARs,
nonserious listed SARs) for all SARs obtained or otherwise received
during the reporting period by the applicant from class action
lawsuits. These summary tabulations must consist of lists by body
system or by standard organ system classification scheme of all SAR
terms and counts of occurrences. For those SARs that are determined to
be both serious and unlisted, include cumulative data. Include a brief
discussion of the impact of the reports described in this appendix on
the overall safety evaluation.
(6) Lack of efficacy reports. Provide an assessment of whether it
is believed that the frequency of lack of efficacy reports, obtained or
otherwise received during the reporting period, is greater than would
be predicted by the premarketing clinical trials for the biological
product.
(7) Medication errors. Provide summary tabulations of all domestic
reports of medication errors submitted during the reporting period
under paragraph (c)(2)(v) of this section. For actual medication
errors, provide summary tabulations of serious SARs, nonserious SARs,
and no SARs (for serious SARs, include cumulative data, i.e., all cases
reported to date). For potential medication errors, provide the number
of reports for specific errors. If an SAR occurs, the summary
tabulations must consist of lists by body system or by standard organ
system classification scheme of all SAR terms and counts of
occurrences. Include a brief discussion of the impact on the overall
safety evaluation of these reports.
(8) U.S. patient exposure. Provide, for the reporting period, an
estimate of the U.S. patient exposure to the biological product(s)
covered by the PSUR (i.e., number of patients, average or median dose
received, and average or median length of treatment). The method used
to estimate patient exposure must always be described. If the patient
exposure is impossible to estimate or is meaningless, an explanation of
and justification for such conclusions must be provided. If patient
exposure is impossible to estimate, other measures of exposure, such as
patient-days, number of prescriptions, or number of dosage units, may
be used. If these or other more precise measures are not available and
an adequate explanation for the lack of such information is provided,
bulk sales may be used.
(9) Location of safety records. Provide a list of the current
address(es) where all safety reports and other safety-related records
for the licensed biological product(s) are maintained.
(10) Contact person. Provide the name and telephone number for the
licensed physician(s) responsible for the content and medical
interpretation of the data and information contained within the PSUR.
Include, if available, the fax number and e-mail address for the
licensed physician(s).
(iii) Interim periodic safety report (IPSR). An applicant holding a
biologics license under Sec. 601.20 of this chapter for a human
biological product approved on or after January 1, 1998, must submit an
IPSR to FDA 7.5 years and 12.5 years after U.S. approval of the
application. The data lock point for the IPSR is the month and day of
the international birth date of the licensed biological product or any
other month and day agreed on by the applicant and FDA. The reporting
period for the IPSR covers the period between the last PSUR or TPSR and
the data lock point for the IPSR (e.g., between years 5 and 7.5 for an
IPSR with a data lock point 7.5 years after U.S. approval of the
application). Each IPSR must contain:
(A) Title page, table of contents, and introduction. (1) The title
page includes, at a minimum, the following information:
(i) Name and international birth date of the licensed biological
product(s) that is the subject of the IPSR,
(ii) Various dosage forms and formulations of the biological
product(s) covered by the IPSR,
(iii) Name and address of the applicant,
(iv) Reporting period covered by the IPSR, and
(v) Date of the IPSR.
(2) The introduction: (i) Provides a brief description of how the
IPSR relates to previous reports and circumstances,
(ii) References relevant biological products reported in other
periodic safety reports (e.g., a combination product reported in a
separate IPSR), and
(iii) Indicates any data duplication with other IPSRs.
(B) Worldwide marketing status. This section of the IPSR contains a
table of the chronological history of the worldwide marketing status of
the biological product(s) covered by the IPSR from the date the
product(s) was first approved (i.e., the international birth date)
through its current status (i.e., cumulative information). This table
consists of:
(1) Dates of biological product approval and renewal;
(2) Safety-related restrictions on product use;
(3) Indications for use and special populations covered by the
biological approval;
(4) Lack of approval of the biological product in any dosage form
or for any indication for use by any regulatory authority(ies);
(5) Withdrawal of a pending marketing application for the
biological product by the applicant for safety- or efficacy-related
reasons;
(6) Dates of market launches; and
(7) Trade name(s).
(C) Actions taken for safety reasons. (1) This section of the IPSR
includes details on the following types of regulatory authority-
initiated (e.g., by FDA) and/or applicant-initiated actions
[[Page 12494]]
related to safety that were taken during the period covered by the IPSR
and between the data lock point and IPSR submission (i.e., ``late-
breaking'' safety concerns):
(i) Withdrawal or suspension of biological product approval or
indication for use approval;
(ii) Failure to obtain a marketing authorization renewal or to
obtain an approval for a new indication for use;
(iii) Restrictions on distribution (products recalled for safety
reasons);
(iv) Clinical trial suspension;
(v) Dosage modification;
(vi) Changes in target population or indications; and
(vii) Formulation changes.
(2) This section of the IPSR also contains a narrative identifying
the safety-related reasons that led to these actions with relevant
documentation appended when appropriate.
(3) Any communication with health care professionals (e.g., Dear
Healthcare Professional letters) resulting from such actions must also
be described with copies appended.
(D) Changes to CCSI. This section of the IPSR describes changes to
the CCSI (e.g., new contraindications, precautions, warnings, SARs, or
interactions) made during the period covered by the IPSR. A copy of any
modified section of the CCSI must be included. The applicant must use
the CCSI in effect at the beginning of the reporting period for the
IPSR. The revised CCSI is to be used as the reference document for the
next reporting period.
(E) Worldwide patient exposure. (1) This section of the IPSR
includes, for the reporting period, an estimate of the worldwide
patient exposure to the biological product(s) covered by the IPSR
(i.e., number of patients, average or median dose received, and average
or median length of treatment). The method used to estimate patient
exposure must always be described. If the patient exposure is
impossible to estimate or is meaningless, an explanation of and
justification for such conclusions must be provided. If patient
exposure is impossible to estimate, other measures of exposure, such as
patient-days, number of prescriptions, or number of dosage units, may
be used. If these or other more precise measures are not available and
an adequate explanation for the lack of such information is provided,
bulk sales may be used.
(2) When possible, data broken down by gender and age (especially
pediatric versus adult) must be provided. For the pediatric population,
data must be reported, if possible, by age group (e.g., neonates,
infants, children, adolescents). If these data are not available, an
explanation must be included.
(3) When a pattern of reports indicates a potential problem,
details by country (with locally recommended dosage regimens) or other
segmentation (e.g., indication, dosage form) must be presented.
(F) Safety studies. This section of the IPSR contains a discussion
of nonclinical, clinical, and epidemiological studies that contain
important safety information, as follows:
(1) All applicant-sponsored studies newly analyzed during the
reporting period (copies of full reports should be appended only if new
safety issues are raised or confirmed; FDA may request copies of other
studies, if necessary);
(2) New studies specifically planned, initiated, or continuing
during the reporting period that examine a safety issue, whether actual
or hypothetical; and
(3) Published safety studies in the scientific and medical
literature, including relevant published abstracts from meetings
(provide literature citation).
(G) Other information. This section of the IPSR includes a
discussion of medically relevant lack of efficacy reports (e.g., might
represent a significant hazard to the treated population) for a
product(s) used to treat serious or life-threatening diseases.
(H) Overall safety evaluation. This section of the IPSR contains a
concise, yet comprehensive, analysis of all of the safety information
provided in the IPSR. In addition, this section of the IPSR includes an
assessment by the applicant of the significance of the data collected
during the reporting period, as well as from the perspective of
cumulative experience.
(1) The applicant must highlight any new information on:
(i) Serious, unlisted SARs;
(ii) Increased reporting frequencies of listed SARs, including
comments on whether it is believed that the data reflect a meaningful
change in SAR occurrence;
(iii) A change in characteristics of listed SARs (e.g., severity,
outcome, target population); and
(iv) Nonserious, unlisted SARs.
(2) As part of the overall safety evaluation, the applicant must
also explicitly address any new safety issue including but not limited
to the following (lack of significant new information for each of the
following must be mentioned):
(i) Drug interactions;
(ii) Experience with overdose, whether deliberate or accidental,
and its treatment;
(iii) Drug abuse or intentional misuse;
(iv) Positive or negative experiences during pregnancy or
lactation;
(v) Effects with long-term treatment; and
(vi) Experience in special patient groups (e.g., pediatric,
geriatric, organ impaired). For the pediatric population, data must be
evaluated, if possible, by age group (e.g., neonates, infants,
children, adolescents).
(I) Conclusion. This section of the IPSR:
(1) Indicates new safety information that is not in accord with
previous cumulative experience and with the CCSI in use at the
beginning of the reporting period (e.g., new evidence that strengthens
a possible causal relationship between the biological product and an
SAR, such as positive rechallenge, an epidemiological association or
new laboratory studies); and
(2) Specifies and justifies any action recommended or initiated,
including changes in the CCSI.
(J) Appendices. This section of the IPSR includes:
(1) Company core data sheet. Provide a copy of the company core
data sheet covered by this IPSR (i.e., in effect at the beginning of
the period covered by the IPSR), as well as the company core data sheet
for the next reporting period. Company core data sheets must be
numbered and dated and include the date of last revision.
(2) U.S. labeling. Provide a copy of the current approved U.S.
labeling. Specify any safety information that is included in the CCSI
but not in the U.S. labeling and provide an explanation for the
discrepancy. Describe any safety-related changes or proposed changes to
the U.S. labeling made during the reporting period (include the
supplement number(s) and date(s) of submission for the supplement(s))
and any suggested change(s) that should be considered based on the
safety analysis in this IPSR.
(3) Spontaneous reports submitted to the applicant by an individual
other than a health care professional. Provide a brief discussion of
the impact on the overall safety evaluation of any spontaneously
reported serious SARs, whether domestic or foreign, and any
spontaneously reported nonserious SARs occurring in the United States,
obtained or otherwise received during the reporting period by the
applicant from an individual other than a health care professional
(e.g., reports from consumers).
[[Page 12495]]
(4) SARs with unknown outcome. Provide a brief discussion of the
impact on the overall safety evaluation of any spontaneously reported
unlisted and listed SARs with unknown outcome obtained or otherwise
received during the reporting period by the applicant from health care
professionals and other individuals.
(5) Class action lawsuits. Provide a brief discussion of the impact
on the overall safety evaluation of any safety information obtained or
otherwise received during the reporting period by the applicant from
class action lawsuits.
(6) Lack of efficacy reports. Provide an assessment of whether it
is believed that the frequency of any lack of efficacy reports,
obtained or otherwise received during the reporting period, is greater
than would be predicted by the premarketing clinical trials for the
biological product.
(7) Medication errors. Provide a brief discussion of the impact on
the overall safety evaluation of all domestic reports of medication
errors submitted during the reporting period under paragraph (c)(2)(v)
of this section.
(8) U.S. patient exposure. Provide, for the reporting period, an
estimate of the U.S. patient exposure to the biological product(s)
covered by the IPSR (i.e., number of patients, average or median dose
received, and average or median length of treatment). The method used
to estimate patient exposure must always be described. If the patient
exposure is impossible to estimate or is meaningless, an explanation of
and justification for such conclusions must be provided. If patient
exposure is impossible to estimate, other measures of exposure, such as
patient-days, number of prescriptions, or number of dosage units, may
be used. If these or other more precise measures are not available and
an adequate explanation for the lack of such information is provided,
bulk sales may be used.
(9) Location of safety records. Provide a list of the current
address(es) where all safety reports and other safety-related records
for the licensed biological product(s) are maintained.
(10) Contact person. Provide the name and telephone number for the
licensed physician(s) responsible for the content and medical
interpretation of the information contained within the IPSR. Include,
if available, the fax number and e-mail address for the licensed
physician(s).
(iv) Pediatric use supplements. After approval of a pediatric use
supplement to an approved application (i.e., a supplement for use of
the human biological product in the pediatric population), the
applicant must submit PSURs to FDA as prescribed under paragraph
(c)(3)(ii) of this section according to the following schedule:
Semiannually for 2 years after U.S. approval of the supplement,
annually for the next 3 years, and then every 5 years thereafter. These
applicants must also submit IPSRs to FDA as prescribed under paragraph
(c)(3)(iii) of this section at 7.5 years and 12.5 years after U.S.
approval of the supplement. The data lock point for the PSUR and IPSR
is the month and day of the international birth date of the licensed
biological product or any other month and day agreed on by the
applicant and FDA.
(v) Semiannual submission of individual case safety reports. (A) An
applicant holding a biologics license under Sec. 601.20 of this
chapter for a human biological product must submit to FDA semiannually
(i.e., every 6 months) after U.S. approval of the application a
separate report that consists of individual case safety reports for
certain spontaneously reported SARs for the biological product. The
individual case safety reports must be submitted on the form designated
by the agency under paragraph (c)(4) of this section. The data lock
point for the report is the month and day of the international birth
date of the licensed biological product or any other month and day
agreed on by the applicant and FDA. This report must be identified as
``individual case safety reports--semiannual submission.''
(B) Applicants that submit TPSRs to FDA for the licensed biological
product must submit an individual case safety report for each serious,
expected SAR, whether domestic or foreign, and each nonserious,
unexpected SAR occurring in the United States that is submitted to the
applicant during the reporting period from all spontaneous sources
(i.e., health care professionals and other individuals). Reports for
vaccines must include an individual case safety report for each
nonserious, expected SAR and each expected SAR with unknown outcome
occurring in the United States that is submitted to the applicant
during the reporting period from all spontaneous sources. Applicants
that submit PSURs to FDA for the licensed biological product must
submit an individual case safety report for each serious, listed SAR,
whether domestic or foreign, and each nonserious, unlisted SAR
occurring in the United States that is submitted to the applicant
during the reporting period from all spontaneous sources. Reports for
vaccines must include an individual case safety report for each
nonserious, listed SAR and each listed SAR with unknown outcome
occurring in the United States that is submitted to the applicant
during the reporting period from all spontaneous sources. If a full
data set is not available for a report of a serious SAR, the applicant
must submit the information required under paragraph (c)(1)(iv) of this
section.
(C) Followup information to SARs submitted in an individual case
safety report--semiannual submission may be submitted in the next
individual case safety report--semiannual submission unless such
information changes the classification of the SAR to a serious,
unexpected SAR. In these cases, the followup information must be
submitted to FDA as a 15-day followup report (see paragraph (c)(2)(vii)
of this section).
(4) Reporting format. (i)(A) Except as provided in paragraphs
(c)(4)(i)(B), (c)(4)(i)(D), and (c)(4)(v) of this section, the
applicant must complete the reporting form designated by FDA for each
individual case safety report of an SAR (FDA Form 3500A or, for
vaccines, a VAERS form). Reports based on information about individual
cases or case series in the scientific literature must be submitted on
an FDA Form 3500A(s) or, for vaccines, on a VAERS form(s).
(B) Foreign SARs may be submitted either on an FDA Form 3500A or,
if preferred, on a CIOMS I form; foreign SARs for vaccines may be
submitted either on a VAERS form or, if preferred, on a CIOMS I form.
(C) Each domestic report of an actual or potential medication error
must be submitted on an FDA Form 3500A, or, for vaccines, on a VAERS
form.
(D) Reports of overall findings or data in the aggregate from
published and unpublished in vitro, animal, epidemiological, or
clinical studies must be submitted in a narrative format.
(ii) Each SAR in an individual case safety report must be coded on
the FDA Form 3500A, VAERS form, or CIOMS I form using the appropriate
``preferred term'' in the latest version of MedDRA (the medical
dictionary for regulatory activities) in use at the time the applicant
becomes aware of the individual case safety report. For individual case
safety reports of medication errors, the report must be coded both as a
medication error and, if applicable, with the preferred term for any
SARs associated with the medication error.
(iii) Each completed FDA Form 3500A, VAERS form, or CIOMS I form
should refer only to an individual case.
(iv) Each completed FDA Form 3500A, VAERS form or CIOMS I form must
include the name and telephone number (and fax number and e-mail
address, if available) for the licensed
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physician responsible for the content and medical interpretation of the
data contained within the form (i.e., contact person for the company).
(v) Instead of using FDA Form 3500A (or a VAERS form for vaccines),
the applicant may use a computer-generated facsimile of FDA Form 3500A
(or the VAERS form for vaccines) provided that it is readable, includes
appropriate identifying information, and contains all the elements
(i.e., format, sections, blocks, titles, descriptors within blocks,
text for disclaimer) of FDA Form 3500A (or the VAERS form for vaccines)
in the identical enumerated sequence of the form. For individual case
safety reports in which no suspect medical device is involved, a one-
page FDA Form 3500A is acceptable.
(d) Multiple reports. An applicant should not include in reports
under this section any SARs that occurred in clinical trials if they
were previously submitted as part of the license application. If a
report refers to more than one biological product marketed by an
applicant, the applicant should submit the report to the license for
the product listed first in the report.
(e) Patient privacy. For nonvaccine biological products, the names
and addresses of individual patients should not be included in reports
under this section; instead, the applicant, shared manufacturer and
contractors should assign a unique code to each report, preferably not
more than eight characters (i.e., numbers and/or letters) in length.
The name of the reporter from whom the information was received should
be included. Names of patients, individual reporters, health care
professionals, hospitals, and geographic identifiers in safety reports
are not releasable to the public under FDA's public information
regulations in part 20 of this chapter. For vaccine SAR reports, these
data will become part of the CDC Privacy Act System 09-20-0136,
``Epidemiologic Studies and Surveillance of Disease Problems.''
Information identifying the person who received the vaccine or that
person's legal representative will not be made available to the public,
but may be available to the vaccinee or legal representative.
(f) Recordkeeping. Each applicant must maintain for a period of 10
years records of all safety information pertaining to its product,
received or otherwise obtained, including raw data, any correspondence
relating to the safety information, and any reports of SARs or
medication errors not submitted to FDA or only provided to FDA in a
summary tabulation. Each applicant must also retain for a period of 10
years any records required to be maintained under this section. When
appropriate, FDA may require an applicant to submit any or all of these
records to the agency within 5 calendar days after receipt of the
request.
(g) Written procedures. Each applicant must develop and maintain
written procedures for the surveillance, receipt, evaluation, and
reporting of safety information to FDA.
(h) Revocation of license. If an applicant fails to establish and
maintain records and make reports required under this section with
respect to a licensed biological product, FDA may revoke the license
for such a product in accordance with the procedures of Sec. 601.5 of
this chapter.
(i) Exemptions. Manufacturers of the following listed products are
not required to submit safety reports under this section:
(1) Whole blood or components of whole blood. These products are
subject to the reporting requirements for blood and blood components in
Sec. 606.170 of this chapter.
(2) In vitro diagnostic products, including assay systems for the
detection of antibodies or antigens to retroviruses. These products are
subject to the reporting requirements for devices.
(j) Disclaimer. A report or information submitted by an applicant
under this section (and any release by FDA of that report or
information) does not necessarily reflect a conclusion by the applicant
or FDA that the report or information constitutes an admission that the
biological product caused or contributed to an SAR. An applicant need
not admit, and may deny, that the report or information submitted under
this section constitutes an admission that the biological product
caused or contributed to an SAR.
PART 601--LICENSING
14. The authority citation for 21 CFR part 601 continues to read as
follows:
Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353,
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C.
216, 241, 262, 263, 264; sec. 122, Pub. L. 105-115, 111 Stat. 2322
(21 U.S.C. 355 note).
Sec. 601.28 [AMENDED]
15. Section 601.28 Annual reports of postmarketing pediatric
studies is amended by removing the second sentence in paragraph (a) and
the phrase ``safety and'' in the first sentence in paragraph (b).
PART 606--CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD
COMPONENTS
16. The authority citation for 21 CFR part 606 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371,
374; 42 U.S.C. 216, 262, 263a, 264.
17. Section 606.170 is revised to read as follows:
Sec. 606.170 Suspected adverse reaction investigation and reporting.
(a) Any reports of complaints of suspected adverse reactions
(SARs), as defined in Sec. 600.80(a) of this chapter, regarding each
unit of blood or blood product arising as a result of blood collection
or transfusion must be investigated promptly and thoroughly. Records of
the complaint and investigation must be maintained. The collection or
transfusing facility must prepare and maintain a written report of the
investigation of SARs, including followup and conclusions, as part of
the record for that lot or unit of final product. If it is determined
that there was an SAR related to transfusion or possibly related to the
collection procedure, then copies of all such reports must be forwarded
to and maintained by the manufacturer or collection facility.
(b) For any serious SAR, as defined in Sec. 600.80(a) of this
chapter, except for a fatality, the facility performing the
compatibility testing (if the SAR is related to transfusion) or the
collecting facility (if the SAR is related to the blood collection
procedure), must submit a written report to the Center for Biologics
Evaluation and Research (CBER), at FDA within 45 calendar days after
determination of the serious SAR. The written report must be submitted
using the reporting format provided in Sec. 600.80(c)(4) of this
chapter.
(c) For an SAR that results in a fatality, the Director, Office of
Compliance and Biologics Quality, at CBER must be notified by
telephone, facsimile, express mail, or electronically transmitted mail
as soon as possible. Within 7 calendar days after the fatality, the
collection facility (if the fatality is related to blood collection) or
the facility performing the compatibility tests (if the fatality is
related to transfusion) must submit a written report to CBER, FDA,
using the reporting format provided in Sec. 600.80(c)(4) of this
chapter.
(Information collection requirements approved by the Office of
Management and Budget under control number 0910-0116)
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Dated: December 13, 2002.
Mark B. McClellan,
Commissioner of Food and Drugs.
Dated: January 29, 2003.
Tommy G. Thompson,
Secretary of Health and Human Services.
[FR Doc. 03-5204 Filed 3-13-03; 8:45 am]
BILLING CODE 4160-01-P