[Federal Register: October 27, 1994]
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Part III
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
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21 CFR Part 20, et al.
Adverse Experience Reporting Requirements for Human Drug and Licensed
Biological Products; Proposed Rule
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 20, 310, 312, 314, and 600
[Docket No. 93N-0181]
Adverse Experience Reporting Requirements for Human Drug and
Licensed 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 current adverse experience reporting regulations for human drug
products and for licensed biological products to provide consistency
with the elements of FDA Form 3500A and require the use of this new
reporting form; revise certain definitions and reporting periods and
formats as recommended by the International Conference on Harmonization
of Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH) and the World Health Organization's Council for International
Organizations of Medical Sciences (CIOMS); require applicants or
manufacturers, packers, and distributors to develop written procedures
for monitoring and reporting adverse experiences; state that reports of
adverse experiences that are forwarded by FDA to the applicant or
manufacturer, packer, and distributor should not be resubmitted to the
agency; and make other revisions to the regulations to provide
uniformity in adverse experience reporting for human drug products and
licensed biological products. These changes would simplify and
facilitate the reporting of adverse experiences and would enhance
agencywide consistency in the collection of postmarketing adverse
experience data. In addition, FDA is proposing to amend the
requirements for clinical study design and conduct and the sponsor
reporting requirements in the investigational new drug application
(IND) regulations. These amendments are intended to provide more
complete and accurate information that would enable sponsors,
investigators, and FDA to determine serious toxicities of
investigational drugs more expeditiously during clinical studies.
DATES: Submit written comments by January 25, 1995. The agency proposes
that any final rule that may issue based on this proposal become
effective 30 days after its date of publication in the Federal
Register.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT:
Concerning human drug products: Howard P. Muller, Center for Drug
Evaluation and Research (HFD-362), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301-594-1049.
Concerning licensed biological products: Paula S. McKeever, Center
for Biologics Evaluation and Research (HFM-635), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-594-3074.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of June 3, 1993 (58 FR 31596), FDA
announced the availability of a new form for reporting adverse events
and product problems with medications, devices, and other FDA-regulated
medical products. This form is available in two versions. One version
of the form (FDA Form 3500) is to be used by health professionals for
voluntary reporting; the other version of the form (FDA Form 3500A) is
to be used by applicants or manufacturers (including licensed
manufacturers of licensed biological products), and other persons
subject to mandatory reporting requirements under FDA regulations.
Under existing regulations, drug manufacturers, packers, and
distributors and applicants for new drug products and generic drug
products must report adverse events under Sec. Sec. 310.305 and 314.80
(21 CFR 310.305 and 314.80). Elsewhere in this issue of the Federal
Register, FDA is issuing a final rule establishing new Sec. 600.80.
This section makes licensed manufacturers of biological products
subject to certain reporting requirements.
The new form is part of FDA's Medical Products Reporting Program
(MedWatch) and is designed to encourage and facilitate the reporting of
adverse events and product problems for most FDA-regulated human
medical products by the entire health care community, including
manufacturers, distributors, user facilities, and health professionals.
FDA issued the new form to simplify and consolidate the reporting of
suspected adverse events and product problems with human drug products,
biologics, and medical devices, as well as the reporting of adverse
events with other FDA-regulated medical products, such as dietary
supplements. FDA has found that, under the current system, there is
some confusion about what to report to the agency and that the existing
assortment of reporting forms and systems can interfere with the
efficient reporting of suspected problems. FDA has attempted to clarify
and simplify adverse event reporting with the new form by eliminating
redundant or nonessential elements and by clarifying those areas that
have caused confusion.
FDA Form 3500A replaces current Form FDA-1639, as well as most
other adverse event and product problem reporting forms currently
required by the agency. Adverse events associated with vaccines will
continue to be reported through the FDA and Centers for Disease Control
and Prevention Vaccine Adverse Event Reporting System (VAERS). FDA is
proposing to amend the adverse experience reporting requirements for
human drug products and for licensed biological products to be
consistent with the elements of FDA Form 3500A.
In developing FDA Forms 3500 and 3500A, the agency considered
several recommendations from ICH and CIOMS. These organizations were
formed to facilitate international consideration of issues,
particularly safety issues, concerning the use of both foreign and
domestic data in the development and use of drugs and biological
products. 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. ICH
has prepared a draft guideline specific to parts of this issue
entitled: ``Clinical Safety Data Management: Definitions and Standards
for Expedited Reporting.'' In the Federal Register of July 9, 1993 (58
FR 37408), FDA published this draft guideline for public comment.
Several CIOMS working groups have worked to coordinate and standardize
the international reporting of postmarketing adverse drug reactions by
pharmaceutical manufacturers to regulatory authorities. CIOMS Working
Group II has proposed an international system of standardized time
intervals, formats, and inclusion criteria in order to lessen confusion
and reduce preparation time among manufacturers and to enable them to
report postmarketing adverse experiences more rapidly, efficiently, and
effectively (Refs. 1 and 2). FDA believes that many changes recommended
by CIOMS and ICH would result in more effective reporting of serious
adverse experiences to regulatory authorities worldwide. FDA is
proposing to amend the adverse experience reporting requirements for
human drug products and licensed biological products in part to be
consistent with certain standardized definitions, procedures, and
formats proposed by these international organizations.
FDA is also proposing to amend the requirements for clinical study
design and conduct and the sponsor reporting requirements in the IND
regulations. These amendments are intended to provide more complete and
accurate information that would enable sponsors, investigators, and FDA
to determine serious toxicities of investigational drugs more
expeditiously during clinical studies. A clinical study of fialuridine
(FIAU) resulted in several instances of severe liver and pancreatic
injury and five deaths, beginning in June 1993. This incident prompted
FDA to establish a task force to see whether the data available before
the study gave any suggestion of the serious toxicity that emerged, and
whether some differences in process or behavior by investigators and
sponsors might have made it possible or more likely for them to have
anticipated the toxicity in the 1993 study. The proposed IND amendments
contained in this document are largely the result of recommendations by
this task force.
II. Description of the Proposed Rule
A. Replacement of Form FDA-1639 and How to Obtain Copies of FDA Form
3500A
FDA's existing regulations at 21 CFR 20.112, 310.305, and 314.80
refer to Form FDA-1639. The agency is proposing to amend these
regulations to replace references to Form FDA-1639 with new FDA Form
3500A. This change is necessary because new FDA Form 3500A replaces
Form FDA-1639 (58 FR 31596).
The existing regulations at Secs. 310.305(d)(4) and 314.80(f)(4))
also provide an address where a person may obtain copies of Form FDA-
1639. FDA is proposing to amend these regulations to state where a
person can obtain copies of FDA Form 3500A. Ten or fewer copies of FDA
Form 3500A and a copy of the instructions for completing the form can
be obtained from the Division of Epidemiology and Surveillance (HFD-
730), Center for Drug Evaluation and Research, Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857. Large numbers
of copies (greater than 10 copies) may be obtained by writing to the
Consolidated Forms and Publications Distribution Center, Washington
Commerce Center, 3222 Hubbard Rd., Landover, MD 20785.
B. Definitions of ``Data Lock-Point'' and ``International Birth Date''
FDA is proposing to amend Secs. 314.80(a) and 600.80(a) to define
the terms ``data lock-point'' and ``international birth date.'' The
``data lock-point'' is the end of the reporting period (cutoff date)
for data to be incorporated into a specific postmarketing adverse
experience periodic report. On this date, the data available to the
reporter are held for review and evaluation by the applicant or
licensed manufacturer prior to being submitted to FDA. The
international birth date is the date that the first regulatory
authority in the world approved the human drug or biological product
for marketing. As explained further in section II.E. of this document,
each 6-month anniversary of the international birth date is the data
lock-point for data to be incorporated into a specific postmarketing
adverse experience periodic report.
The proposed rule would define these terms because they describe
the standardized international reporting period developed by CIOMS for
submitting postmarketing adverse experience reports. CIOMS developed
this standardized reporting period to lessen confusion and to enable
applicants and licensed manufacturers to prepare and submit similar
reports of adverse experiences to regulatory authorities. It would also
reduce preparation time among applicants and licensed manufacturers
because it eliminates varying due dates presently required for
submitting postmarketing adverse experience reports to regulatory
authorities worldwide. FDA believes the CIOMS reporting schedule, which
decreases reporting rates currently required by FDA for drug and
licensed biological products for the first 3 years of marketing from
every 3 months to every 6 months and increases it thereafter from every
12 months to every 6 months, permits adequate time for reporters to
make periodic submissions to regulatory authorities. In addition, the
agency believes that the proposed reporting frequency is sufficient to
notify FDA of potential postmarketing safety problems that do not
require expedited reporting.
C. Definition of ``Serious''
FDA's existing adverse experience reporting regulations (21 CFR
310.305(b)(4), 312.32(a), 314.80(a), and 600.80(a)) define a serious
adverse experience as one that is ``fatal or life-threatening, is
permanently disabling, requires inpatient hospitalization, or is a
congenital anomaly, cancer, or overdose.'' Consistent with new FDA Form
3500A and with recommendations by the ICH and CIOMS, the proposed rule
would amend this definition to read as follows:
Serious means an adverse drug experience occurring at any dose
that is fatal or life-threatening, results in persistent or
significant disability/incapacity, requires or prolongs inpatient
hospitalization, necessitates medical or surgical intervention to
preclude permanent impairment of a body function or permanent damage
to a body structure, or is a congenital anomaly.
The agency is proposing to remove ``cancer'' from the definition
because cancer would most often be reported under the other broader
elements in the definition. For example, cancer may be reported as
life-threatening or requiring inpatient hospitalization. Other diseases
or conditions that may be life-threatening or require hospitalization,
such as heart disease or myocardial infarction, have not been
identified as separate elements in previous definitions, and the agency
believes it is not necessary to single out cancer.
The proposed amendment would also remove ``overdose'' from the
definition of serious. Reports of overdoses that had serious outcomes
would still be reported under the other broader elements in the
definition. Reports of overdoses that did not lead to outcomes defined
as serious would provide the agency with less critical safety
information.
By adding the phrase ``occurring at any dose'' after ``adverse drug
experience'' in the definition, the agency will ensure that a serious
adverse experience at any dose, whether it is the labeled dose or a
different dose, including an overdose or an underdose, should be
reported.
FDA is also proposing to clarify the phrase ``is permanently
disabling'' by substituting ``results in persistent or significant
disability/incapacity.'' This change is intended to clarify that a
disability need not be permanent to be considered a serious adverse
experience.
The proposed amendments would also modify the phrase ``requires
inpatient hospitalization'' to read ``requires or prolongs inpatient
hospitalization.'' This change is intended to cover those situations
where a serious adverse experience occurs while the patient is already
hospitalized, and the adverse experience prolongs the patient's
hospital stay.
FDA is also proposing to add the phrase ``necessitates medical or
surgical intervention to preclude permanent impairment of a body
function or permanent damage to a body structure.'' The agency believes
such events should be considered serious adverse experiences and should
be reported. This change is also consistent with ICH's proposed
definition of a serious adverse event. FDA notes that a serious adverse
experience would not include the discontinuation of therapy, changes in
dosage, or routine treatment with a prescription medication.
D. Definitions of ``Disability'' and ``Life-Threatening''
The proposed rule would amend Secs. 310.305(b), 314.80(a), and
600.80(a) to define the terms ``disability'' and ``life-threatening.''
These terms further explain what constitutes a serious adverse
experience. ``Disability'' means a substantial disruption of one's
ability to carry out normal life functions. ``Life-threatening'' means
that the patient was, in the view of the initial reporter, at immediate
risk of death from the adverse experience as it occurred. It does not
include an adverse experience that, had it occurred in a more serious
form, might have caused death. For example, product-induced hepatitis
that resolved without evidence of hepatic failure would not be
considered life-threatening even though hepatitis of a more severe
nature can be fatal. Similarly, an allergic reaction resulting in
angioedema of the face would not be life-threatening, even though
angioedema of the larynx, allergic bronchospasm, or anaphylaxis can be
fatal. FDA believes these definitions will help enable reporters to
determine when a serious adverse experience occurs.
E. Periodic Adverse Experience Reports
Current regulations (Secs. 314.80(c)(2)(i) and 600.80(c)(2)(i))
require the submission of periodic postmarketing reports at quarterly
intervals for 3 years from the date of approval of the application, and
then annually. Quarterly 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); each annual report must be submitted
within 60 days of the date of U.S. approval of the application.
FDA is proposing to revise this schedule by requiring the
submission of periodic postmarketing adverse reaction reports every 6
months. The first 6-month anniversary of the international birth date
after the application is approved in the United States is the data
lock-point for the first periodic reporting term. Each subsequent 6-
month anniversary of the international birth date is the data lock-
point for subsequent periodic reporting terms for that particular
product. The proposed rule would require periodic reports to be
submitted to FDA within 45 days after the data lock-point. For example,
a product approved by FDA, or licensed, if a biological product, on
June 15, with an international birth date of April 1, would have its
first data lock-point on October 1, which is less than 6 months after
FDA approval, but which is the 6-month anniversary of the international
birth date. Therefore, the first periodic report would be for the
period of June 15 to October 1 and would be due at FDA by November 14.
The second periodic report would cover October 2 to April 1 and would
be due to the agency no later than May 15.
The proposed rule would create the same reporting schedule based on
the international birth date and data lock-point for licensed
biological product distribution reports under Sec. 600.80(c)(3).
This new reporting schedule is consistent with the standardized
international reporting period proposed by the CIOMS II Working Group.
This working group has recommended that all international regulatory
authorities accept the same reporting schedule in order to lessen
confusion and reduce preparation time by manufacturers, rather than the
current system of varying due dates. FDA believes the CIOMS reporting
schedule, which decreases reporting rates currently required by FDA for
drug and licensed biological products for the first 3 years of
marketing from every 3 months to every 6 months and increases reporting
rates thereafter from every 12 months to every 6 months, permits
adequate time for reporters to make nonexpedited submissions to
regulatory authorities. In addition, FDA believes that the proposed
reporting frequency is sufficient to alert the agency to potential
postmarketing safety problems that are not within the categories
requiring 15-day ``Alert reports.''
Applicants and licensed manufacturers who wish to submit periodic
postmarketing adverse experience reports at different intervals could,
under proposed Secs. 314.80(c)(2)(i) and 600.80(c)(2)(i), submit a
request for a waiver under 21 CFR 314.90 or 600.90 to alter the
reporting intervals for these periodic reports.
Proposed Secs. 314.80(c)(2)(i) and 600.80(c)(2)(i) would also amend
the reporting requirements for periodic postmarketing adverse
experience reports to state that, in cases where the applicant or
licensed manufacturer has received no reports of adverse experiences
during a reporting period, the applicant or licensed manufacturer
should submit a copy of the current approved labeling and a letter to
the agency in place of a periodic postmarketing adverse experience
report. The letter should identify the product, the application number,
and the reporting period, and state that no adverse experience reports
were received during that reporting period.
Sections 314.80(c)(2)(ii) and 600.80(c)(2)(ii) set forth the
contents currently required for a periodic report: (1) 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 interval; (2) a report describing each adverse experience not
previously reported; and (3) a history of actions taken since the last
periodic report. FDA is proposing to amend these regulations to provide
a more extensive list of contents for a periodic postmarketing adverse
experience report, as follows:
1. Title Page, Table of Contents, and Introduction
This section would provide a summary of the periodic report with
page references to detailed data and information.
2. Applicant's Core Safety Data Sheet
The applicant's core safety data sheet would be a document prepared
by the applicant that contains all relevant safety information,
including adverse drug experiences, which the applicant believes should
be listed for the drug in all countries where the drug is marketed. It
may be used by the applicant as the reference document by which an
adverse drug experience is judged to be expected or unexpected for
purposes of this postmarketing periodic report. For all other
determinations of whether an adverse drug experience is expected or
unexpected, the definition in Secs. 314.80(a) or 600.80(a) would apply.
FDA recognizes that the postmarketing periodic report may be
submitted by the applicant to multiple countries and the product may
have different approved labels in the different countries. The use of
the applicant's core safety data sheet as the reference document for
determining whether an adverse drug experience is expected or not may
result in some overreporting of unexpected adverse events that actually
are expected by the U.S. approved product label. This is because the
approved label for the United States may have more safety information
included in it than the manufacturer's core safety data sheet.
An applicant may also use the approved U.S. label as the reference
by which expected and unexpected adverse drug experiences are
determined for the postmarketing periodic report. If an applicant
chooses to use the approved U.S. label for this purpose, it must
clearly be stated in this section of the report. In all instances, if
an adverse event is not listed in the U.S. label, but is in the
manufacturer's core safety data sheet, this shall be clearly noted in
the ``Overall safety evaluation'' (see section II.E.8. of this
document).
This section would also highlight clearly any changes and the
reasons for the changes in the applicant's core safety data sheet since
the previous postmarketing periodic report.
3. The Product's Marketing Status
This section would contain, in tabular form, a chronological
history of the marketing status of the product worldwide (all
regulatory and marketing decisions affecting the product) from the date
it was first approved through its current status. Approvals or
applications voluntarily withdrawn for safety reasons would have to be
included. The product would be listed by chemical (U.S. Adopted Names,
international nonproprietary names, or proper name in accordance with
``Chemical Abstracts Nomenclature Standards'') and brand name(s).
4. Regulatory Actions for Safety Reasons
This section would identify in narrative form the reasons for
significant regulatory authority or manufacturer-initiated actions
taken anywhere in the world, or to be taken imminently, for safety
reasons during the reporting period. This would include, for example,
application withdrawal or license suspension or failure to renew,
distribution restrictions, clinical trial suspension, labeling changes
due to significant safety concerns, dosage modifications, or
pharmaceutical changes.
5. Patient Exposure
This section would include the product's domestic and foreign
marketing distribution data during the reporting period. This
information would be used to calculate the extent of patient exposure.
The method used by the manufacturer to estimate patient exposure would
always be described and would include the total number of dosage units
of each dosage form and strength or potency (e.g., 100,000/5-milligram
tablets, 50,000/10-milliliter vials).
6. Individual Case Histories
These reports would be presented in line listing format with the
following 10 columns: country, source, age, gender, dose, duration of
treatment (prior to event), time to onset, description of reaction (as
reported), outcome (e.g., fatal, resolved), other comments (e.g.,
manufacturer's report number). This format is consistent with that
suggested by CIOMS. In addition, a tabular summary of the number of
adverse events by body system may be included. The individual case
reports would consist of adverse drug experiences that are: (a)
Serious, unexpected reports from published or unpublished clinical
studies where it has been concluded that there is a reasonable
possibility that the drug or licensed biological product caused the
adverse experience; (b) serious, expected or unexpected spontaneous
adverse drug experience reports and nonserious, unexpected spontaneous
adverse experience reports received directly by the applicant or
licensed manufacturer from the initial reporter or received by the
applicant or licensed manufacturer from a drug regulatory authority,
both U.S. or foreign; and (c) serious, expected or unexpected
individual published case histories and nonserious, unexpected
individual published case histories. This section would end with an
analysis by the reporter, in narrative form, of the cases submitted.
The applicant or licensed manufacturer would also attach to the end of
the postmarketing periodic report a completed FDA Form 3500A for all
U.S. spontaneous reports of adverse experiences except those not to be
included in the periodic report as specified in proposed
Secs. 314.80(c)(1)(i) and (c)(1)(ii) and 600.80(c)(1)(i) and
(c)(1)(ii), or those sent by FDA to the applicant or licensed
manufacturer.
7. Safety Studies
This section would analyze and discuss fully and critically all
toxicological, clinical, and epidemiological studies containing
important safety information.
8. Overall Safety Evaluation
This section would provide critical analysis of the safety
information provided in the periodic report as it pertains to serious
unexpected reactions, increased frequencies of known toxicity,
reactions listed in the manufacturer's core safety data sheet but not
included in the U.S. label, drug or licensed biological product
interactions, overdose, drug or licensed biological product abuse,
experiences during pregnancy or lactation, chronic treatment, pediatric
or geriatric treatment, and new safety issues. For each of these areas,
any absence of significant information would be reported. The
evaluation would indicate whether the safety profile of the product
remains consistent with cumulative experience to date and with the
previous manufacturer's core safety data sheet. The evaluation would
specify any action recommended and the reasons for such
recommendations.
9. Other Information
This section would consist of important information received after
the data lock-point. It may include significant new cases or followup
data that affect the interpretation or evaluation of existing reports.
10. FDA Form 3500A
This section would consist of a completed FDA Form 3500A for each
spontaneous U.S. adverse drug experience not reported under paragraphs
(c)(1)(i) and (c)(1)(ii) in Secs. 314.80 and 600.80.
11. Location of Adverse Experience Records
This section would identify the current address(es), including
street, city, State, and zip code, where all adverse experience reports
and records are maintained.
This revised list of contents for periodic postmarketing adverse
experience reports is generally consistent with the international
system of standardized postmarketing periodic reporting procedures and
formats proposed by the CIOMS II Working Group. This standardization
would allow applicants and licensed manufacturers to prepare a single
postmarketing periodic report of adverse experiences for regulatory
authorities worldwide. The agency also believes that the proposed rule
would improve reporting and would enhance FDA's ability to monitor
potential postmarketing safety problems.
As a result of this proposed revised list of contents for periodic
postmarketing adverse experience reports, FDA is proposing to remove
Secs. 314.80(c)(2)(iii) and 600.80(c)(2)(iii). These sections state
that periodic reporting does not apply to information obtained from
postmarketing studies, reports in the scientific literature, and
foreign marketing experience. The proposed revised list of contents
would include such information.
F. IND Amendments
FDA regulations governing the use of investigational drugs in
clinical investigations are contained in part 312 (21 CFR part 312). In
order to conduct a clinical investigation using an investigational
drug, a sponsor must first submit an IND, described in Sec. 312.23,
which contains, among other things, a description of the drug, the
results of preclinical studies intended to show that the drug can be
introduced into humans with reasonable safety, and a proposed protocol
for the investigation. This protocol provides a description of all
aspects of the study, including the identity and qualifications of the
investigators conducting the study, procedures and criteria for
selecting subjects, the amount of the drug to be administered, the
duration of use, the observations to be made to assess the effects of
the drug, and the clinical procedures, laboratory tests, and other
measures carried out to minimize risk to the patient. After the IND
becomes effective and the investigational drug is being administered to
human subjects, the sponsor is required under Sec. 312.32 to make both
telephone and written safety reports on serious and unexpected adverse
experiences associated with the administration of the drug, as well as
written reports only, on other serious adverse events associated with
administration of the drug. Under current Sec. 312.33, the sponsor is
also required to submit an annual report containing significant safety
and other information. If FDA concludes that a study would place
subjects at unreasonable and significant risk, FDA may place a study on
clinical hold. This means that the drug may not be administered to
subjects until the hold is lifted (see Sec. 312.42). FDA may also
terminate the study under Sec. 312.44 based on such safety concerns.
FDA is concerned that these IND reporting requirements may not be
adequate to protect against some unexpected adverse events. For
example, there is a potential for such events to be disguised by
patient conditions that might lead the investigator to conclude that
the experimental drug was not implicated in those events. The agency
believes that certain modifications in the way clinical investigations
are conducted and reported may help to ensure that drug toxicity is
detected as early as possible. A recent internal task force that
examined an incident that involved a fatal drug toxicity that was not
detected in early trials has recommended improvements in IND reporting
that the agency is incorporating into this proposal for public
consideration. These improvements, as explained below, are intended to
provide more frequent and more complete evaluations of potentially
serious adverse effects so that drug-related events can be detected
earlier by sponsors, investigators, and FDA.
A clinical study of a nucleoside analog, FIAU, resulted in several
instances of severe liver injury and five deaths, beginning in June
1993. The study involved 15 subjects with chronic hepatitis B virus
infection. FIAU had been considered a highly promising agent without
recognized serious toxicity. This incident prompted FDA to establish a
task force to see whether the data available prior to the study gave
any suggestion of the serious toxicity that emerged. The task force
examined data from the 1993 FIAU study as well as data from previous
studies on FIAU and a closely related drug conducted by another
sponsor. The data from these previous studies was, or should have been,
available to the sponsor of the 1993 FIAU study. The task force was
also to determine whether some differences in process or behavior by
investigators and sponsors might have made it possible or more likely
to have anticipated the toxicity. The proposed IND amendments contained
in this document are largely the result of recommendations by the task
force (Ref. 3).
Focusing on hepatic and pancreatic adverse events, the task force
reviewed the data and data analyses that were available to
investigators, sponsors, and FDA at the start of the study to determine
whether improvements in the rules governing design, analysis, and
reporting of data from clinical studies were warranted. The task force
found a number of observations and events that suggested an association
between FIAU and hepatic and/or pancreatic abnormalities. However, none
of these events was attributed by the sponsors or investigators to
FIAU. Rather, each event, even when recognized as temporally related to
a study, was attributed by investigators and sponsors to other factors,
such as concomitant drug administration and/or concurrent illness. The
task force found that an overview of the data, in which deaths and
serious adverse experiences were analyzed cumulatively, and, with the
hypothesis that the events were drug related, was not produced and thus
was not available for use by the sponsors, the principal investigators,
or FDA reviewers. Rather, the analyses performed focused on each
individual event and determined a plausible explanation, other than
drug toxicity, for each occurrence. The task force recommended that, to
detect similar patterns of events reflecting toxicity in future
studies, sponsors should conduct cumulative analyses with a systematic
consideration of the possibility that the adverse events are caused by
the investigational drug.
The proposed IND amendments would apply to all investigational
studies conducted under part 312. However, FDA invites comments from
the public and industry on whether any or all of the proposed
requirements should apply only to certain IND's, whose selection could
be determined by application of criteria that could be included in
these regulations, or only to certain phases of drug testing.
1. Clinical Study Design
FDA is proposing to amend the requirements governing IND format and
content in Sec. 312.23. Under current Sec. 312.23(a)(6), an IND must
contain the protocols for each planned study, including information
such as a statement of the study's objectives and purpose, the criteria
for patient selection and exclusion, a description of the study design,
the method for determining the dose(s) to be administered and the
duration of individual patient exposure to the drug, and a description
of clinical procedures, laboratory tests, or other measures to be taken
to monitor the effects of the drug in human subjects and to minimize
risk.
In several instances, FDA's FIAU task force found that deaths and
serious hepatic and pancreatic injuries that appear in retrospect to
have been related to FIAU were attributed by investigators and sponsors
to the subjects' underlying disease or to other drugs the subjects were
taking for their conditions. The task force made several
recommendations intended to improve the likelihood that clinical
studies will identify, early in drug development, drug toxicity that
mimics the underlying disease or the toxicity of concomitant
medications. These recommendations include: (1) Choosing study designs
and safety endpoints that increase a study's ability to distinguish
drug toxicity from underlying disease or other drug toxicity; (2)
prospectively identifying observations that will trigger certain
actions by investigators; and (3) summarizing safety data at regular
intervals with systematic considerations of the possibility that
adverse events are drug related. The proposed rule would create new
Sec. 312.23(a)(6)(iii)(h) to require that the protocols describe any
adverse clinical or laboratory outcomes in the study that are to be
immediately reported to the sponsor. These reportable events might
include death, any life-threatening event, or any other serious event
that might reflect potential drug toxicity, as suggested by preclinical
data, and include abnormal laboratory results falling outside of a
specified range. The identified events and abnormal laboratory values
are to include those that focus attention on toxicity that may target
the same organs and body systems as the underlying disease or
concomitant medications. Under the proposal, these events would be
reported to the sponsor even if they are potentially attributable to
the patient's underlying disease or concomitant medications. Proposed
Sec. 312.23(a)(6)(iii)(h) would also require instructions for
investigators, such as reporting requirements, remeasurement or
challenge procedures, or discontinuation of the drug in response to
identified events.
The task force also recommended that sponsors consider the use of a
control group (for example, placebo, active control, or historical
control) in studies that focus on safety when the underlying disease
process is likely to produce adverse events that might be confused with
drug toxicity. The task force concluded that such controls would help
detect some adverse events. Consequently, proposed
Sec. 312.23(a)(6)(iii)(i) states that sponsors should consider the use
of a formal control group when the underlying disease is likely to
produce adverse events that might be confused with drug toxicity.
The task force also recommended that sponsors attempt to estimate
the expected incidence of death and serious adverse events in the study
population that arise from the underlying disease or concomitant
medications used to treat the disease. This recommendation is reflected
in proposed new Sec. 312.23(a)(6)(iii)(j) that would require sponsors
to provide such estimates. Under the proposal, any deaths or adverse
events that exceed the estimates would create the presumption that the
events are associated with use of the investigational drug, and the
sponsor would be required to submit a written safety report to FDA.
The task force found that the followup periods in some of the FIAU
and related studies were too short to detect some of the adverse events
that occurred because significant adverse events sometimes occurred
weeks to months after dosing with FIAU ended.The task force recommended
that all protocols contained in the IND include an explicit description
of the length and type of followup to be performed so that the agency
may review the followup procedures (task force report at 57).
Accordingly, FDA is proposing to add new Sec. 312.23(a)(6)(iii)(k) to
require that the protocol section of an IND specify and justify the
length and type of followup for subjects after the conclusion of
dosing. The justification may be brief; for example, a reference to a
study of a similar drug with the same followup period. The followup
period would ensure that clinical studies are adequately designed to
detect drug toxicity that occurs after the conclusion of drug dosing.
The sponsor would propose an appropriate followup period based on
preclinical data, experience with other members of the drug class, the
drug's mechanism of action, and prior human experience. The intensity
of the followup may change with time; e.g., a full evaluation might be
scheduled for 2 weeks postdosing, with a telephone followup for
possible serious events at a later time. Ordinarily, in Phase 1 and 2
studies, telephone followup should occur at 3 months after the dosing
is completed, but alternative timeframes and procedures can be proposed
by the sponsor. For some drugs, like FIAU, a review of available data
may suggest that the minimum followup period should be longer than 3
months.
Current regulations in Sec. 312.56 require sponsors to review and
evaluate the evidence relating to a drug's safety and effectiveness as
it is obtained from investigators. The regulations also require
sponsors to report safety information to FDA. The task force observed
that in the FIAU study sponsors may not have had available adequate
resources to evaluate safety data reported by investigators. The
proposed rule would amend Sec. 312.56(c) to require sponsors, in
addition to reviewing and evaluating safety and effectiveness
information, to develop a safety monitoring and evaluation program
before starting clinical trials. This provision is intended to ensure
that sponsors have or will develop adequate resources to evaluate
safety data reported by investigators and is consistent with the task
force's recommendations (see task force report at 57). Consistent with
this proposed requirement, FDA is also proposing in new
Sec. 312.23(a)(3)(v) that an IND contain a description of any safety
monitoring and evaluation program. This description would be in
addition to the introductory statement and general investigational plan
that are required under current regulations.
2. Safety Reports
FDA is proposing several amendments to the requirements for IND
safety reports in Sec. 312.32. FDA is proposing to alter the period for
submitting written safety reports, under Sec. 312.32(c)(1)(i) and
(d)(3), from 10 working days to 15 calendar days, and for submitting
safety reports by telephone, under Sec. 312.32(c)(2), from 3 working
days to 7 calendar days. FDA is also proposing to allow telephone
safety reports to be made by facsimile transmission as well as orally
by telephone. These changes will give sponsors additional time to
gather appropriate data to help interpret the reports before submitting
these reports. FDA believes the extended time period would be
sufficient to alert the agency to potential safety problems, especially
because of the new investigational reporting requirements the agency is
proposing.
Proposed Sec. 312.32(c) would also permit sponsors to submit IND
safety reports to the agency by using FDA Form 3500A. If FDA determined
that insufficient data were submitted on FDA Form 3500A, the agency
could require additional narrative data to be submitted. As explained
elsewhere in this proposal, this amendment is consistent with the
proposal to use this form for postmarketing reporting of human drug and
licensed biological product adverse experiences.
FDA is also proposing to amend the disclaimer contained in
Sec. 312.32(e) to emphasize that safety information submitted to FDA
are not to be considered admissions of causation or liability. The
proposal would substitute the word ``part'' for ``section'' so that the
revised disclaimer would clearly apply to all safety information
submitted under part 312. Summaries of such safety information would
not constitute a statement or admission that there was a causal link
between the administration of the drug and the subsequent adverse
event.
3. Semiannual Reports
FDA is proposing to amend the periodic reporting requirements in
Sec. 312.33 by adding, in addition to the annual report, a semiannual
death and serious adverse experiences report. This change is intended
to ensure that reports of deaths and other serious adverse experiences
in all clinical studies are collected and reviewed in a timely and
comprehensive manner, and that the possibility of drug relatedness is
always considered.
Under current regulations, sponsors must report deaths and serious
and unexpected adverse experiences within 3 or 10 working days only if
the events are associated with the use of the drug. ``Associated with
the use of the drug'' is defined to mean that there is a reasonable
possibility that the experience may have been caused by the drug (see
Sec. 312.32(a)). Deaths and a summary of serious adverse experiences
that occur in a clinical trial that the sponsor concludes are not
associated with use of the drug must be reported only in an IND annual
report. The task force found that many adverse experiences occurring
during the FIAU study that appear, in retrospect, to have been drug
related were not reported in safety reports, although, at times, they
were reported in the annual report as attributable to causes other than
FIAU.
The proposed rule, therefore, would create a new ``semiannual
report'' to require, among other things, the submission of reports of
all deaths, serious adverse experiences, and study discontinuations
resulting from an adverse experience, whether expected or unexpected
and whether or not there was thought to be a possibility that the death
or adverse experience was caused by the drug. In these twice yearly
reports, sponsors would also report all deaths and serious adverse
experiences that occurred during the trial or within the prescribed
followup period. The report would include data not only from studies
conducted under the IND, but also data from all premarketing studies of
the drug conducted worldwide, with an analysis of all unexpected
deaths, serious adverse experiences, and study discontinuations thought
to be related to the study drug from foreign postmarketing clinical
trials and from foreign postmarketing spontaneous or required reporting
systems. Serious adverse events should include laboratory changes that
result in discontinuation or that are identified in the study protocol
as reportable events. Sponsors would present these data both for the 6-
month reporting interval and cumulatively, and submit an analysis of
the data. The agency would expect the analysis to conform generally to
the evaluation of deaths, serious adverse experiences, and
discontinuations in the section entitled ``Integrated Summary of Safety
Information'' in FDA's ``Guideline for the Format and Content of the
Clinical and Statistical Sections of New Drug Applications.'' FDA also
recommends that the sponsor employ, in preparing the analysis, at least
one individual who had no involvement in conducting the clinical study.
The proposal would also require a sponsor to conduct a ``worst-case''
analysis of the safety data, presuming that observed adverse events
were the result of toxicity from the investigational drug, and then
attempt to refute this presumption, with appropriate data and
evaluations (task force report at 59). The analysis should include
estimates of the rate of an analyzed event occurring spontaneously in
the population and specific analyses of cases.
The sponsor would submit the semiannual report for the 6-month
period following the day the IND goes into effect, and for each 6-month
period thereafter, until the end of the followup period specified in
the protocol. The report would be due within 60 days of the end of the
reporting period. The semiannual safety report that is due during the
same period as the annual report would be submitted with the annual
report.
The task force recommended (task force report at 59) that FDA
require the submission of all available autopsy reports and medical
reports concerning all deaths reported in these semiannual reports,
because, in at least one instance during the FIAU study, the cause of
death originally reported was not fully consistent with the autopsy and
terminal medical reports later obtained for that subject. Proposed
Sec. 312.33(b)(2) would require the submission of these reports and
would require the sponsor to clarify any inconsistencies between these
reports and the cause of death reported to FDA by the sponsor. FDA is
proposing this requirement to help ensure that reports covering deaths
submitted to the agency are complete and accurate.
Under proposed Sec. 312.33(b)(3), at the request of the sponsor, or
on its own initiative, FDA may modify certain semiannual reporting
requirements where, for example, the clinical study endpoint is
mortality or where the study is blinded and full compliance with the
reporting requirement would require breaking the blind. FDA is
proposing this provision because studies vary concerning the nature and
seriousness of the disease to be treated, the number of subjects
exposed to the drug, and the general pace at which the drug's
development proceeds.
4. Special Safety Summary
In new Sec. 312.37(a), FDA also proposes an additional mechanism to
allow the agency to obtain safety data on investigational drugs and
summaries of these data not otherwise obtained through other reporting
requirements if, and when, these data are necessary. Most
investigational drugs do not present unusual safety concerns, so that
the safety data contained in the 6-month and annual reports, as well as
the IND safety reports submitted under Sec. 312.32, would provide
adequate information to allow FDA to observe drug safety. Some drugs,
however, may raise significant safety concerns either anticipated or
unanticipated, so that more comprehensive data on events that do not
meet the definition of a serious adverse reaction as well as those that
do are needed. Events that might trigger this heightened scrutiny
include agency experience with similar drugs, animal toxicity study
results, and information derived from IND safety, annual, or semiannual
reports. As recommended by the task force (task force report at 59 and
60), the proposed regulation is drafted in general language to allow
the agency, in consultation with the sponsor, flexibility in
determining when a report should be required and what information it
should contain. This flexibility is considered necessary because the
specifics of the safety summary may vary from study to study. FDA
anticipates that the safety summary will generally not only contain the
results of the cumulative analysis of deaths and serious adverse
experiences contained in the 6-month report, but also an analysis of
related events of lesser seriousness.
Although the task force recommended that FDA require safety
summaries unless an exemption had been granted to the sponsor, FDA is
proposing to require safety summaries only for those studies or
products where the agency has determined that a specific need for them
exists. FDA would generally expect safety summaries to be submitted
within 30 days after they are requested; however, the agency recognizes
that in cases where large amounts of data are required to be summarized
and those data are not readily available or easily summarized, a longer
period of time may be necessary to prepare the summary.
5. Final Clinical Study Report
Information about FIAU risks and benefits that the sponsor might
have derived from the process of collecting and analyzing study results
was delayed or never developed because final reports were not required
for the earlier clinical studies of FIAU and FIAC (a closely related
nucleoside analog). Thus, FDA is proposing in Sec. 312.37(b) to require
sponsors to submit, when required by FDA, a final report or study
summary of a clinical study. FDA anticipates that final reports usually
will not be necessary. Instituting requirements for semiannual
reporting of deaths, serious adverse experiences, and discontinuations,
and for summarization of all safety data will largely fulfill the need
for more careful monitoring and analysis of potential drug toxicity
during drug testing. In some cases, however, it may still be valuable
to have available an analysis of the results of particular trials;
e.g., to provide data on the likely effectiveness of a drug for
purposes of weighing risks against likely benefits to study subjects.
The proposal wouldrequire final clinical study reports to be submitted
within 90 days of a request from FDA, but provides for exceptions under
extraordinary circumstances.
6. Clinical Holds
Section 312.42 currently allows FDA to delay a proposed clinical
investigation or to suspend an ongoing investigation under certain
circumstances. Under the proposal, FDA would amend Sec. 312.42 to allow
the agency to place an investigation on clinical hold if the sponsor
fails to submit a special safety summary or final clinical study
report. If the same or a closely related drug is the subject of a
concurrent investigation, conducted by the same sponsor, proposed
Sec. 312.42(b)(1)(v) would require safety summaries from all
investigations or the agency could place any of the investigations on
clinical hold. FDA believes this is appropriate because data from all
studies involving the drug or closely related drugs may help FDA
evaluate the safety of each study.
7. Termination
FDA is also proposing in Sec. 312.44(b)(1)(viii) to amend the
regulations regarding termination so that failure to submit a
semiannual report would be grounds for terminating an IND. Failure to
submit an annual report is already grounds for terminating an IND, and
FDA is aware of no reason why semiannual and annual reports should be
treated differently in this matter.
FDA considers that failure to implement an adequate safety
monitoring and evaluation program, as described in proposed 21 CFR
312.56(c), would be grounds for either a clinical hold under
Sec. 312.42 or a termination of the IND under Sec. 312.44, since
failure to have a program in place would mean that ``[h]uman subjects
are or would be exposed to an unreasonable and significant risk of
illness or injury,'' which is currently grounds for either a clinical
hold or termination.
8. Review of Ongoing Investigations
FDA is also proposing to amend Sec. 312.64(b) to require
investigators to submit safety data to sponsors necessary to allow
sponsors to comply with the other proposed safety reporting
requirements, such as the proposed semiannual report. The proposed
amendment would require the investigator to comply with safety
reporting requirements established in the protocol for the study.
Current Sec. 312.64(b) requires investigators to report adverse effects
if they may reasonably be regarded as caused by, or probably caused by,
the drug. If the adverse effects are alarming, they are to be reported
to the sponsor immediately. These provisions are being retained as
minimal requirements which must be met, even if the protocol does not
require the events to be reported.
G. Written Procedures for Monitoring Adverse Experiences
FDA is also proposing to amend Secs. 310.305(a) and 314.80(b) for
marketed human drug products and Sec. 600.80(b) for licensed biological
products to require applicants or manufacturers, packers, and
distributors to develop written procedures for the surveillance,
receipt, evaluation, and reporting of adverse experiences to FDA. This
requirement would improve postmarketing surveillance by applicants or
manufacturers and would enhance an applicant's or manufacturer's
ability to evaluate and report adverse experiences to the agency. FDA
believes that this provision would not impose a new burden on
applicants and manufacturers, because it codifies a practice that is
already customary and usual in the pharmaceutical industry for handling
adverse experiences. Based on field inspections, FDA is aware that many
manufacturers already have written procedures for the receipt,
evaluation, and reporting of adverse experiences to FDA. The agency
also notes that the current good manufacturing practice (CGMP)
regulations for finished pharmaceuticals, which apply to manufacturers
of all marketed human drug and biological products, require written
procedures describing the handling of all written and oral complaints
regarding a drug product (21 CFR 211.198).
Furthermore, the agency's ``Guideline For Postmarketing Reporting
of Adverse Drug Experiences'' (Ref. 4), which provides guidance on
adverse drug experiences reported under Secs. 310.305 and 314.80,
states (at page 17) that:
Each applicant should develop standardized, formal procedures
for the surveillance, receipt, evaluation, and reporting of ADE's to
FDA. * * * All applicants should develop procedures that allow
expedited adverse experience report handling, and the applicant
should keep on file documentation of due diligence.
Elsewhere in this issue of the Federal Register FDA is announcing
the availability of a guideline entitled ``Guideline for Adverse
Experience Reporting for Licensed Biological Products.'' This guideline
discusses the reports required by Sec. 600.80 and provides guidance
concerning appropriate means of meeting the reporting requirements.
H. Resubmission of Reports Received From FDA
Under the MedWatch program, FDA will transmit reports of
spontaneously reported serious adverse experiences received by the
agency to the applicant, manufacturer, packer, or distributor (as
appropriate) on an expedited basis. Consequently, FDA is proposing to
revise Secs. 310.305(c), 314.80(b), and 600.80(b) to state that
applicants or manufacturers, packers, and distributors should not
resubmit to the agency reports of adverse experiences that the agency
has forwarded to them. In addition, FDA is proposing to revise
Secs. 314.80(c)(1)(i) and 600.80(c)(1)(i) to remove the phrase
``regardless of source'' from the description of which adverse
experiences are reported to FDA. These revisions are intended to reduce
duplicate reporting of adverse experiences to the agency, consistent
with the reporting instructions in new FDA Form 3500A. FDA notes,
however, that applicants or manufacturers, packers, and distributors
receiving reports forwarded to them by FDA are required to handle these
reports as they would any others and that followup, if obtained, is to
be sent to the agency as specified in the regulation. These followup
reports should be included, where appropriate, in the postmarketing
adverse experience periodic report.
FDA is also proposing that applicants and licensed manufacturers
incorporate into any safety analysis (i.e., periodic reports, increased
frequency reports) the expedited reports received from FDA, whether or
not additional followup information was obtained, and any information
received through Freedom of Information requests.
I. Other Revisions to the Reporting Requirements
FDA is proposing to remove Secs. 314.80(c)(2)(iii) and
600.80(c)(2)(iii). These paragraphs state that periodic reporting for
non-15-day Alert reports does not apply to adverse drug experience
information obtained from postmarketing studies and reports in the
scientific literature and from foreign marketing experience. FDA is
proposing to remove these paragraphs because this information would now
be required under the proposed revisions to the contents of a periodic
report.
Current regulations, at Sec. 314.80(c)(1)(ii), require applicants
and, at Sec. 600,80(c)(1)ii), licensed manufacturers to ``review
periodically (at least as often as the periodic reporting cycle)'' the
frequency of reports of adverse experiences and report any significant
increase in frequency to FDA. Similarly, current Sec. 310.305(c)(4)
requires manufacturers, packers,and distributors to ``review
periodically (at least once each year)'' the frequency of reports of
adverse experiences and report any significant increase in frequency to
FDA. In order to provide consistency with the proposed semiannual
reporting requirements for periodic adverse experience reports under
Secs. 314.80 and 600.80, FDA is proposing to amend Sec. 310.305 to
require manufacturers, packers, and distributors to review
periodically, at least twice each year, the frequency of adverse
experience reports for the purposes of making increased frequency
reports to FDA.
FDA is also proposing to amend Secs. 310.305(c) and 314.80(c) by
reorganizing, renumbering, and retitling the paragraphs in these
sections to distinguish between postmarketing 15-day Alert reports,
followups to postmarketing 15-day Alert reports, and increased
frequency reports. The proposed amendments would also distinguish
between the reporting intervals for postmarketing 15-day Alert reports
and the revised intervals proposed for postmarketing periodic reports.
FDA is also proposing to amend Secs. 310.305(c)(1) through (c)(4)
and 314.80(c)(1)(i), through (c)(1)(iv) to alter the period for
submitting postmarketing ``15-day'' Alert reports from 15 working days
to 15 calendar days. This change should decrease misunderstandings with
the reporting requirements as all timeframes would now be stated in
terms of calendar days. In addition, this change would increase
consistency between the premarketing and postmarketing reporting
requirements.
FDA is also proposing to amend Secs. 310.305(c)(2),
314.80(c)(1)(ii), and 600.80(c)(1)(ii) to require applicants or
manufacturers, packers, and distributors who have been unable to obtain
additional information about adverse experiences that are the subject
of postmarketing 15-day Alert reports to maintain records of their
attempts to seek additional information. These proposed revisions will
help ensure that applicants or manufacturers are making good faith
efforts to investigate adverse experiences that are the subject of
postmarketing 15-day Alert reports.
Finally, FDA is proposing to amend Secs. 310.305(d)(3)(ii) and
314.80(f)(3)(ii) to instruct applicants or manufacturers, packers, and
distributors that, before using an alternative reporting form instead
of FDA Form 3500A, they must obtain approval from MedWatch: The FDA
Medical Products Reporting Program, 5600 Fishers Lane, Rockville, MD
20852-9787. Current regulations require prior approval from the
Division of Epidemiology and Surveillance for human drug products.
J. Distribution Reports
As stated earlier, the proposed rule would change the reporting
interval for licensed biological product distribution reports to be
consistent with the suggested CIOMS standardized reporting period for
postmarketing adverse drug experience periodic reports. Licensed
biological product distribution reports would be based on the
international birth date and data lock-point. The proposal would also
remove Sec. 600.81 and move the regulatory requirements for licensed
biological product distribution reports to Sec. 600.80(c)(3).
K. Multiple Reports
FDA is proposing to amend Sec. 600.80(g) concerning multiple
reports by adding information pertaining to a licensed biological
product for which a licensed manufacturer holds more than one
biological product license. This revision would be consistent with the
requirements in Sec. 314.80(g).
L. Guidelines
FDA is proposing to amend Secs. 314.80(j) and 600.80(j) to indicate
where guidelines for the submission of adverse experience reports may
be obtained. In addition, FDA is adding this information in
Sec. 310.305(g) for the submission of adverse experience reports for
prescription drugs without an approved application. For human drug
products, the guidelines may be obtained from the CDER Executive
Secretariat Staff (HFD-8), Center for Drug Evaluation and Research,
Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855,
and for licensed biological products from the Congressional and
Consumer Affairs Branch (HFM-12), Center for Biologics Evaluation and
Research, Food and Drug Administration, 1401 Rockville Pike, suite
200N, Rockville, MD 20852-1448.
M. Proposed Implementation Scheme
FDA proposes that any final rule that may issue based on this
proposal become effective 30 days after its date of publication in the
Federal Register. All applications for human drug or licensed
biological products approved on or after the effective date of any
final regulation would be subject to the periodic reporting time
periods based on the international birth date. All human drug and
licensed biological product applications approved before the effective
date of any final regulation would use the U.S. approval date as the
international birth date.
III. Request for Comments
Interested persons may, on or before January 25, 1995, submit to
the Dockets Management Branch (address above) written comments
regarding this proposal. Two copies of any comments are to be
submitted, except that individuals may submit one copy. Comments are to
be identified with the docket number found in brackets in the heading
of this document. Received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday.
IV. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) 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
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
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). The agency believes that
this proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the proposed
rule is not a significant regulatory action as defined by the Executive
Order and so is not subject to review under the Executive Order.
The economic costs imposed on the industry as a result of this
proposed rule are the costs associated with reporting deaths, serious
adverse experiences, or clinical study discontinuations. Reporting
burdens on the industry resulting from FDA regulations are analyzed
under the Paperwork Reduction Act of 1980. Based on an estimated total
of 480,602 annual burden hours, FDA has estimated that the total annual
reporting cost to the industry as a result of this proposed rule would
be $ 24,030,100 (the estimated per hour cost to the industry is $ 50).
In addition, the rule may increase certain nonpaperwork activities. For
example, added costs may result if the formal control groups suggested
in Sec. 312.23(a)(6)(iii)(i) prompts additional clinical trial control
arms, or if the implementation of the followup plan required in
Sec. 312.23(a)(6)(iii)(k) provokes more elaborate monitoring
procedures. At this time, FDA cannot predict the extent of these
actions, but welcomes public comment on issues regarding the scope or
cost of these activities.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. The agency certifies that the proposed rule will not
have a significant economic impact on a substantial number of small
entities. Therefore, under the Regulatory Flexibility Act, no further
analysis is required.
VI. Paperwork Reduction Act of 1980
This proposed rule contains information collection requirements
which are subject to review by the Office of Management and Budget
(OMB) under the Paperwork Reduction Act of 1980. The title,
description, and respondents of the information collection requirements
are shown below.
Title: Adverse Experience Reporting Requirements For Human Drug and
Licensed Biological Products.
Description: FDA is proposing to amend its current adverse
experience reporting requirements to replace current Form FDA-1639 with
new FDA Form 3500A; to revise certain definitions and reporting periods
and formats; to require applicants or manufacturers, packers, and
distributors to develop written procedures for monitoring and reporting
adverse experiences; and to make other revisions to provide uniformity
to the reporting regulations. These changes would simplify and
facilitate the reporting of adverse events and product problems under a
single form and help harmonize international adverse event reporting
requirements. In addition, FDA is proposing to amend the sponsor
reporting requirements in part 312.
Description of Respondents: Businesses or other for profit and
small businesses or organizations.
The burden hours for Secs. 310.305 and 314.80 are approved under
OMB information collection number 0910-0230. The burden hours for
Sec. 600.80 have been submitted to OMB for approval and can be found
elsewhere in this issue of the Federal Register. FDA estimates no
change in the burden hours that have already been approved. OMB has
approved use of the new form, under OMB information collection number
0910-0291, through December 1994. The new recordkeeping requirements
under Sec. 310.305(c)(2), 314.80(c)(1)(ii), and 600.80(c)(1)(ii), that
applicants or manufacturers, packers, and distributors maintain records
of unsuccessful attempts to obtain additional followup information on
15-day ``Alert reports,'' would be negligible and would result in no
change in the burden hours that have already been approved.
The new requirements under Secs. 310.305(a), 314.80(b), and
600.80(b), that applicants or manufacturers, packers, and distributors
develop written procedures for the surveillance, receipt, evaluation,
and reporting of adverse experiences, would not impose a new burden
because they codify a practice that is already customary and usual in
the pharmaceutical industry for handling adverse experiences.
The more extensive list of contents for the periodic postmarketing
adverse experience report, in proposed Secs. 314.80(c)(2)(ii) and
600.80(c)(2)(ii), would result in an increased reporting burden on the
industry. As indicated in the accompanying chart, the proposed periodic
reporting requirements would require, on an average, 19 additional
hours for respondents to prepare.
The proposal would also increase the reporting requirements for
sponsors under part 312. As indicated in the accompanying chart, the
proposed amendments to part 312 would result in an increase of 167,900
burden hours on the industry.
Estimated Total Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
Number of Responses per Total annual Hours per
Section respondents respondent responses response Total hours
----------------------------------------------------------------------------------------------------------------
312.23(a)(3) and (a)(6)......... 1,623 1 1,623 4 6,492
312.33(b)....................... 1,517 2.6 3,944 40 157,760
312.37(a)....................... 152 1 152 16 2,432
312.37(b)....................... 152 1 152 8 1,216
314.80(c)(2).................... 528 30.50 16,106 19 306,014
600.80(c)(2).................... 63 5.58 352 19 6,688
---------------
Total..................... 480,602
----------------------------------------------------------------------------------------------------------------
As required by section 3504(h) of the Paperwork Reduction Act of
1980, FDA has submitted a copy of this proposed rule to OMB for its
review of these information collection requirements. Other
organizations and individuals desiring to submit comments regarding the
burden estimate or any aspects of these information collection
requirements, including suggestions for reducing the burden, should
direct them to FDA's Dockets Management Branch (address above) and to
the Office of Information and Regulatory Affairs, OMB, rm. 3208, New
Executive Office Bldg., Washington, DC 20503, Attn: Desk Officer for
FDA.
VII. 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. to 4 p.m., Monday through Friday.
1. ``International Reporting of Adverse Drug Reactions,'' Final
Report of the CIOMS Working Group, 1990.
2. ``International Reporting of Periodic Drug Safety Update
Summaries,'' Final Report of the CIOMS Working Group II, 1992.
3. ``Fialuridine: Hepatic and Pancreatic Toxicity,'' FDA Task
Force Report, November 12, 1993.
4. ``Guideline for Postmarketing Reporting of Adverse Drug
Experiences,'' FDA, Center for Drug Evaluation and Research, March
1992.
List of Subjects
21 CFR Part 20
Confidential business information, Courts, Freedom of information,
Government employees.
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 600
Biologics, 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 20,
310, 312, 314, and 600 be amended as follows:
PART 20--PUBLIC INFORMATION
1. The authority citation for 21 CFR part 20 continues to read as
follows:
Authority: Secs. 201-903 of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 321-393); secs. 301, 302, 303, 307, 310, 311, 351,
352, 354-360F, 361, 362, 1701-1706, 2101 of the Public Health
Service Act (42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263,
263b-263n, 264, 265, 300u-300u-5, 300aa-1); 5 U.S.C. 552; 18 U.S.C.
1905.
Sec. 20.112 [Amended]
2. Section 20.112 Voluntary drug experience reports submitted by
physicians and hospitals is amended in paragraph (a) by removing the
words ``Form FDA-1639'' and adding in their place ``FDA Form 3500''.
PART 310--NEW DRUGS
3. The authority citation for 21 CFR part 310 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301,
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C.
216, 241, 242(a), 262, 263b-263n).
4. Section 310.305 is amended by adding a new sentence at the end
of the concluding text of paragraph (a); by revising paragraphs (b),
(c), (d)(3)(ii), and (d)(4); by removing in paragraph (d)(1) the words
``Form FDA-1639 (Adverse Reaction Report)'' and adding in their place
``FDA Form 3500A''; by removing in paragraph (d)(2), the introductory
text of paragraph (d)(3), and paragraph (d)(3)(i) the words ``Form FDA-
1639'' and adding in their place ``FDA Form 3500A''; by removing in
paragraph (f)(1) the words ``paragraph (c)(5)'' and adding in their
place the words ``paragraph (c)(4)''; and by redesignating paragraph
(g) as paragraph (h) and by adding new paragraph (g) to read as
follows:
Sec. 310.305 Records and reports concerning adverse drug experiences
on marketed prescription drugs for human use without approved new drug
applications.
(a) * * * Manufacturers, packers, and distributors shall also
develop written procedures for the surveillance, receipt, evaluation,
and reporting of adverse drug experiences to FDA.
(b) Definitions. The following definitions of terms apply to this
section:
(1) FDA means the Food and Drug Administration.
(2) Adverse drug experience means any adverse event associated with
the use of a drug in humans, whether or not considered drug related,
including the following: An adverse event occurring in the course of
the use of a drug product in professional practice; an adverse event
occurring from drug overdose; an adverse event occurring from drug
withdrawal; and any failure of expected pharmacological action.
(3) Disability means a substantial disruption of a person's ability
to carry out normal life functions.
(4) Increased frequency means an increase in the rate of occurrence
of a particular adverse drug experience, e.g., an increased number of
reports of particular adverse drug experience after appropriate
adjustment for drug exposure.
(5) Life-threatening means that the patient was, in the view of the
initial reporter, at immediate risk of death from the adverse drug
experience as it occurred. It does not include an adverse drug
experience that, had it occurred in a more serious form, might have
caused death. For example, product-induced hepatitis that resolved
without evidence of hepatic failure would not be considered life-
threatening even though hepatitis of a more severe nature can be fatal.
Similarly, an allergic reaction resulting in angioedema of the face
would not be life-threatening, although angioedema of the larynx,
allergic bronchospasm, or anaphylaxis can be fatal.
(6) Serious means an adverse drug experience occurring at any dose
that is fatal or life-threatening, results in persistent or significant
disability/incapacity, requires or prolongs inpatient hospitalization,
necessitates medical or surgical intervention to preclude permanent
impairment of a body function or permanent damage to a body structure,
or is a congenital anomaly.
(7) Unexpected means an adverse drug experience that is not listed
in the current labeling for the drug product and includes an event that
may be symptomatically and pathophysiologically related to an event
listed in the labeling, but differs from the event because of greater
severity or specificity. For example, under this definition, hepatic
necrosis would be unexpected (by virtue of greater severity) if the
labeling only referred to elevated hepatitic enzymes or hepatitis.
Similarly, cerebral thromboembolism and cerebral vasculitis would be
unexpected (by virtue of greater specificity) if the labeling only
listed cerebral vascular accidents.
(c) Reporting requirements. Each person identified in paragraph
(c)(1) of this section shall report to FDA adverse drug experience
information as described in this section and shall submit one copy of
each report to the Division of Epidemiology and Surveillance (HFD-730),
Center for Drug Evaluation and Research, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857.
(1) Postmarketing 15-Day ``Alert reports''. (i) Any person whose
name appears on the label of a marketed prescription drug product as
its manufacturer, packer, or distributor shall report to FDA each
adverse drug experience received or otherwise obtained that is both
serious and unexpected as soon as possible, but in any case, within 15
calendar days of initial receipt of the information. Each report shall
be accompanied by a copy of the current labeling for the drug product.
(ii) A person identified in paragraph (c)(1)(i) of this section is
not required to submit a 15-day ``Alert report'' for an adverse drug
experience obtained from a postmarketing study (whether or not
conducted under an investigational new drug application) unless the
applicant concludes that there is a reasonable possibility that the
drug caused the adverse experience.
(2) Postmarketing 15-Day ``Alert reports''--followup. Each person
identified in paragraph (c)(1)(i) of this section shall promptly
investigate all serious, unexpected adverse drug experiences that are
the subject of these 15-day postmarketing Alert reports and shall
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.
(3) Increased frequency report. Each person identified in paragraph
(c)(1)(i) of this section shall review periodically (at least twice
each year) the frequency of reports of adverse drug experiences that
are both serious and expected and reports of therapeutic failure (lack
of effect), received or otherwise obtained, and report any significant
increase in frequency as soon as possible, but in any case within 15
calendar days of determining that a significant increase in frequency
exists. Reports of a significant increase in frequency are required to
be submitted in narrative form (including the time period on which the
increased frequency is based, the method of analysis, and the
interpretation of the results) rather than using FDA Form 3500A.
(4) Submission of reports. In order to avoid unnecessary
duplication in the submission of, and followup to, reports required in
this section, including reports required by paragraph (c)(3) of this
section, a packer's or distributor's obligations may be met by
submission of all reports of serious adverse drug experiences to the
manufacturer of the drug product. If a packer or distributor elects to
submit these adverse drug experience reports to the manufacturer rather
than to FDA, it shall submit each report to the manufacturer within 3
calendar days of its receipt by the packer or distributor, and the
manufacturer shall then comply with the requirements of this section
even if its name does not appear on the label of the drug product.
Under this circumstance, the packer or distributor shall maintain a
record of this action which shall include:
(i) A copy of each drug experience report.
(ii) Date the report was received by the packer or distributor.
(iii) Date the report was submitted to the manufacturer.
(iv) Name and address of the manufacturer.
(5) Each report submitted to FDA under this section shall bear
prominent identification as to its contents, i.e., ``15-day Alert
report,'' ``15-day Alert report--followup,'' or ``Increased frequency
report.''
(6) A person identified in paragraph (c)(1)(i) of this section
should not resubmit to FDA reports forwarded to that person by FDA;
however, all followup information must be submitted to FDA.
(d) * * *
(3) * * *
(ii) The format is agreed to in advance by MedWatch: The FDA
Medical Products Reporting Program.
(4) Ten copies or fewer of FDA Form 3500A and/or a copy of the
instructions for completing the form may be obtained from the Division
of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation
and Research, Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857. More than 10 copies of the form may be obtained by
writing to the Consolidated Forms and Publications Distribution Center,
Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 20785.
* * * * *
(g) Guideline. FDA has prepared under Sec. 10.90(b) of this chapter
a guideline for the submission of reports of adverse drug experiences
and suggested followup investigation of reports. Copies of this
guideline may be obtained from the CDER Executive Secretariat Staff
(HFD-8), Center for Drug Evaluation and Research, Food and Drug
Administration, 7500 Standish Pl., Rockville, MD 20855.
* * * * *
PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
5. The authority citation for 21 CFR part 312 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351,
352, 353, 355, 356, 357, 371); sec. 351 of the Public Health Service
Act (42 U.S.C. 262).
6. Section 312.23 is amended by adding new paragraph (a)(3)(v) and
paragraphs (a)(6)(iii)(h) through (a)(6)(iii)(k) to read as follows:
Sec. 312.23 IND content and format.
(a) * * *
(3) * * *
(v) A description of the safety monitoring and evaluation program
developed by the sponsor in order to evaluate safety data reported by
investigators.
* * * * *
(6) * * *
(iii) * * *
(h) A description of any adverse clinical or laboratory outcomes in
the study that are to be reported by the investigators to the sponsor
immediately. This would ordinarily include any death, any life-
threatening event, any serious event that might reflect potential
toxicity, as suggested by preclinical data, laboratory values that
exceed specified limits, or any markedly abnormal laboratory value. The
identified events and abnormal laboratory values are to include those
that focus attention on toxicity that may target the same organs and
body systems as the underlying disease or concomitant medications for
the disease. The events are to be reported to the sponsor even if they
are potentially attributable to the patient's underlying disease or to
other medications the patient may have received. This section of the
protocol shall include instructions for the investigator encountering
such an event, such as reporting requirements, a remeasurement or
challenge procedure, or discontinuation of the study drug.
(i) Sponsors should consider use of a formal control group (for
example, placebo, active, documented historical) in studies that focus
on safety when the underlying disease is likely to produce serious
adverse events that might be confused with drug toxicity.
(j) The sponsor shall estimate the expected incidence of deaths and
serious adverse experiences in the study population that may arise from
the underlying disease or from medications used to treat the underlying
disease. Deaths or serious adverse experiences that exceed these
estimates would create a presumption that the events are associated
with the use of the investigational drug.
(k) The sponsor shall determine and include in each protocol an
appropriate followup period and appropriate followup procedures based
on preclinical data, experience with other members of the drug class,
the drug's mechanism of action, and prior human experience. The sponsor
shall include a brief description of the rationale used in selecting
the followup period and procedures. The intensity of the followup may
change with time; e.g., a full evaluation might be scheduled for 2
weeks after the end of drug dosing, with a telephone followup at a
later time. Ordinarily, in Phase 1 and 2 studies, there should be at
least telephone followup for 3 months after drug dosing is completed,
but alternative timeframes and procedures can be proposed by the
sponsor. In some cases, available information may dictate followup
periods longer than 3 months.
* * * * *
7. Section 312.32 is amended in paragraph (a) by revising the
second sentence in the definition for ``Serious adverse experience,''
paragraph (c)(1)(i), the first sentence in paragraph (c)(2), paragraph
(d)(3), and in paragraph (e) by removing the word ``section'' and
replacing it with the word ``part'' to read as follows:
Sec. 312.32 IND safety reports.
(a) * * *
Serious adverse experience * * * A serious adverse drug experience
means an experience occurring at any dose that is fatal or life-
threatening, results in permanent or significant disability/incapacity,
requires or prolongs inpatient hospitalization, necessitates medical or
surgical intervention to preclude permanent impairment of a body
function or permanent damage to a body structure, or is a congenital
anomaly. * * *
* * * * *
(c) IND safety reports--(1) Written reports. (i) The sponsor shall
notify FDA and all participating investigators in a written IND safety
report of any adverse experience associated with use of the drug that
is both serious and unexpected. This includes notification of any death
or other serious adverse experience that exceeds the estimate of the
expected incidence of deaths and serious adverse experiences required
under Sec. 312.23(a)(6)(iii)(j). Such notification shall be made as
soon as possible and in no event later than 15 calendar days after the
sponsor's initial receipt of the information. Each written notification
may be submitted on FDA Form 3500A or in a narrative form and shall
bear prominent identification of its contents, i.e., ``IND Safety
Report.'' Each written notification to FDA shall be transmitted to the
FDA division of the Center for Drug Evaluation and Research or the
Center for Biologics Evaluation and Research that has responsibility
for review of the IND. If FDA determines that insufficient data were
submitted on FDA Form 3500A, the agency may require further narrative
data to be submitted.
* * * * *
(2) Telephone safety reports. The sponsor shall also notify FDA by
telephone, either orally or by facsimile transmission, of any
unexpected fatal or life-threatening experience associated with the use
of the drug no later than 7 calendar days after the sponsor's initial
receipt of the information. * * *
* * * * *
(d) * * *
(3)If the results of a sponsor's investigation show that an adverse
experience not initially determined to be reportable under paragraph
(c) of this section is so reportable, the sponsor shall report such
experience in a written safety report as soon as possible after the
determination is made, but in no event longer than 15 calendar days.
* * * * *
8. Section 312.33 is revised to read as follows:
Sec. 312.33 Annual and semiannual reports.
(a) Annual reports. A sponsor shall within 60 days of the
anniversary date that the IND went into effect, submit a brief report
of the progress of the investigation that includes:
(1) Individual study information. A brief summary of the status of
each study in progress and each study completed during the previous
year. The summary is required to include the following information for
each study:
(i) The title of the study (with any appropriate study identifiers
such as protocol number), its purpose, a brief statement identifying
the patient population, and a statement as to whether the study is
completed.
(ii) The total number of subjects initially planned for inclusion
in the study, the number entered into the study to date, the number
whose participation in the study was completed as planned, and the
number who dropped out of the study for any reason.
(iii) If the study has been completed, or if interim results are
known, a brief description of any available study results.
(2) Summary information. Information obtained during the previous
year's clinical and nonclinical investigations, including:
(i) A narrative or tabular summary showing the most frequent and
most serious adverse experiences by body system.
(ii) A summary of all IND safety reports submitted during the past
year.
(iii) A list of subjects who died during participation in the
investigation, with the cause of death for each subject.
(iv) A list of subjects who dropped out during the course of the
investigation in association with any adverse experience, whether or
not thought to be drug related.
(v) A brief description of what, if anything, was obtained that is
pertinent to an understanding of the drug's actions, including, for
example, information from controlled trials, and information about
bioavailability.
(vi) A list of the preclinical studies (including animal studies)
completed or in progress during the past year and a summary of the
major preclinical findings.
(vii) A summary of any significant manufacturing or microbiological
changes made during the past year.
(3) A description of the general investigational plan for the
coming year to replace that submitted 1 year earlier. The general
investigational plan shall contain the information required under
Sec. 312.23(a)(3)(iv).
(4) If the investigator brochure has been revised, a description of
the revision and a copy of the new brochure.
(5) A description of any significant Phase 1 protocol modifications
made during the previous year and not previously reported to the IND in
a protocol amendment.
(6) A brief summary of significant foreign marketing developments
with the drug during the past year, such as approval of marketing in
any country or withdrawal or suspension from marketing in any country.
(7) If desired by the sponsor, a log of any outstanding business
with respect to the IND for which the sponsor requests or expects a
reply, comment, or meeting.
(b) Semiannual reports. A sponsor shall submit a report of the
progress of the investigation with respect to safety issues for the 6-
month period following the day the IND goes into effect, and for each
6-month period thereafter, until the end of the followup period
specified in the protocol. The report shall be due within 60 days of
the end of the reporting period. The semiannual safety report that is
due during the same period as the annual report required under
paragraph (a) of this section shall be submitted with the annual
report. These semiannual reports shall include:
(1) A summary and analysis of all deaths, all serious adverse
experiences, and all study discontinuations resulting from an adverse
experience that occurred during the study or within the prescribed
followup period, whether the deaths or adverse experiences were
expected or unexpected and whether or not there is thought to be a
possibility that the death or adverse experience or study
discontinuation was caused by the drug. This summary shall include data
not only from studies conducted under the IND, but also data from all
premarketing studies of the drug conducted worldwide, with an analysis
of all unexpected deaths, serious adverse experiences, and study
discontinuations thought to be related to the study drug from foreign
postmarketing clinical trials and from foreign postmarketing
spontaneous or required reporting systems. For purposes of this
section, serious adverse events shall include laboratory changes
identified in the study protocol as reportable events or that result in
discontinuation. The sponsor shall present in the summary both the data
that accumulated during the reporting period and cumulatively. The
sponsor shall also submit an analysis of the data that assumes that the
investigational drug is responsible for the deaths, serious adverse
experiences, and study discontinuations, and refute, as feasible, this
presumption with appropriate data and evaluations. The expected
incidence of deaths and serious adverse experiences in the study
population that may arise from the underlying disease or from
medications used to treat the underlying disease that was estimated in
the protocol should be considered in this evaluation.
(2) All available autopsy reports and terminal medical reports
concerning all deaths reported in this summary, with a discussion of
any inconsistencies between autopsy and medical reports and the cause
of death reported to FDA by the sponsor.
(3) At the request of the sponsor, or on its own initiative, FDA
may modify the requirements of paragraph (b) of this section. A sponsor
requesting such a modification should submit to the division
responsible for review of the IND a written request for modification
and justification for such modification. FDA shall issue a written
response to the sponsor either granting or denying, in whole or in
part, the request for modification.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
9. Section 312.37 is added to read as follows:
Sec. 312.37 Special safety summary and final clinical study report.
(a) Special safety summary. Upon request of FDA, a sponsor shall
prepare and submit special summaries of safety data regarding the
investigational drug. These summaries may include safety data available
to the sponsor from previous studies of the drug and of closely related
drugs identified in consultation with FDA. Examples of types of events
that may be requested to be summarized include, among others, deaths,
serious adverse experiences, study discontinuations for safety reasons,
patients who reach or exceed safety endpoints as defined in the
protocol, and any unusual or extreme changes in study subjects. The
special safety summary shall be submitted within 30 days after a
request by the agency unless the sponsor demonstrates that
extraordinary circumstances warrant a later date and the agency has
agreed to that later date.
(b) Final clinical study report. Upon request by FDA, a sponsor
shall submit a final report on a clinical study. The final report shall
be submitted within 90 calendar days after a request by the agency
unless the sponsor demonstrates that extraordinary circumstances
warrant a later date and the agency has agreed to that later date.
10. Section 312.42 is amended by adding paragraph (b)(1)(v) to read
as follows:
Sec. 312.42 Clinical holds and requests for modification.
* * * * *
(b) * * *
(1) * * *
(v) The sponsor has failed to submit a special safety summary or
final clinical study report, as required by Sec. 312.37, for the drug
that is the subject of the investigation. This provision applies to
special safety summaries and final clinical study reports from other
investigations on the same drug and special safety summaries and final
clinical study reports requested by FDA for investigations on closely
related drugs conducted by the sponsor.
* * * * *
11. Section 312.44 is amended by revising paragraph (b)(1)(viii) to
read as follows:
Sec. 312.44 Termination.
* * * * *
(b) * * *
(1) * * *
(viii) The sponsor fails to submit an accurate and timely annual or
semiannual safety report of the investigations in accordance with
Sec. 312.33.
* * * * *
12. Section 312.56 is amended by revising paragraph (c) to read as
follows:
Sec. 312.56 Review of ongoing investigations.
* * * * *
(c) Before the initiation of clinical studies, the sponsor shall
develop a safety monitoring and evaluation program to evaluate safety
data reported by the investigator(s). The sponsor shall review and
evaluate the evidence relating to the safety and effectiveness of the
drug as it is obtained from the investigator(s). The sponsor shall make
such reports to FDA regarding information relevant to the safety of the
drug as required under Secs. 312.32 and 312.37. The sponsor shall make
annual and semiannual safety reports in accordance with Sec. 312.33.
* * * * *
13. Section 312.64 is amended by adding two sentences at the end of
paragraph (b) to read as follows:
Sec. 312.64 Investigator reports.
* * * * *
(b) * * * An investigator shall report to the sponsor all adverse
clinical and laboratory outcomes that are required to be reported under
the protocol for the study. These reports shall be made within the time
period specified within the protocol.
* * * * *
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN
ANTIBIOTIC DRUG
14. The authority citation for 21 CFR part 314 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701,
704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321,
331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).
15. Section 314.80 is amended in paragraph (a) by alphabetically
adding definitions for ``Data lock-point,'' ``Disability,''
``International birth date,'' and ``Life-threatening,'' and by revising
the definition of ``Serious;'' by adding two new sentences at the end
of paragraph (b); by revising paragraph (c), the second sentence in
paragraph (d)(1), paragraphs (f)(1), (f)(3)(ii), and (f)(4), and the
last sentence in paragraph (l); by removing in paragraphs (f)(2) and
the introductory text of paragraph (f)(3) the words ``Form FDA-1639''
and adding in their place the words ``FDA Form 3500A''; and by adding a
new sentence at the end of paragraph (j) to read as follows:
Sec. 314.80 Postmarketing reporting of adverse drug experiences.
(a) * * *
* * * * *
Data lock-point means the date designated as the cutoff date for
data to be incorporated into a specific postmarketing adverse drug
experience periodic report. Data available to the applicant after this
date will not be incorporated into the report, unless it represents
important information.
Disability means a substantial disruption of a person's ability to
carry out normal life functions.
* * * * *
International birth date means the date that the first regulatory
authority in the world approved the human drug product for marketing.
Life-threatening means that the patient was, in the view of the
initial reporter, at immediate risk of death from the adverse
experience as it occurred. It does not include an adverse experience
that, had it occurred in a more serious form, might have caused death.
For example, product-induced hepatitis that resolved without evidence
of hepatic failure would not be considered life-threatening even though
hepatitis of a more severe nature can be fatal. Similarly, an allergic
reaction resulting in angioedema of the face would not be life-
threatening, even though angioedema of the larynx, allergic
bronchospasm, or anaphylaxis can be fatal.
Serious means an adverse drug experience occurring at any dose that
is fatal or life-threatening, results in persistent or significant
disability/incapacity, requires or prolongs inpatient hospitalization,
necessitates medical or surgical intervention to preclude permanent
impairment of a body function or permanent damage to a body structure,
or is a congenital anomaly.
* * * * *
(b) * * * Applicants should not resubmit to FDA adverse product
experience reports forwarded to the applicant by FDA; however, they
should submit all followup information to FDA. Applicants shall also
develop written procedures for the surveillance, receipt, evaluation,
and reporting of adverse drug experiences.
(c) Reporting requirements. The applicant shall report to FDA
adverse drug experience information, as described in this section. The
applicant shall submit two copies of each report described in this
section to the Central Document Room, Park Bldg., rm. 2-14, 12420
Parklawn Dr., Rockville, MD 20857. FDA may waive the requirement for
the second copy in appropriate instances.
(1)(i) Postmarketing 15-day ``Alert reports''. The applicant shall
report each adverse drug experience that is both serious and unexpected
as soon as possible but in any case within 15 calendar days of initial
receipt of the information. These reports shall be submitted on FDA
Form 3500A.
(ii) Postmarketing Fifteen-day ``Alert reports''--followup. The
applicant shall promptly investigate all adverse drug experiences that
are the subject of these postmarketing 15-day Alert reports and shall
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. These postmarketing 15-day Alert
reports and followups to them shall be submitted under separate cover
and may not be included, except for summary or tabular purposes, in a
postmarketing adverse drug experience periodic report.
(iii) Increased frequency report. The applicant shall review
periodically (at least as often as the periodic reporting cycle) the
frequency of reports of adverse drug experiences that are both serious
and expected and reports of therapeutic failure (lack of effect),
regardless of source, and report any significant increase in frequency
as soon as possible but in any case within 15 calendar days of
determining that a significant increase in frequency exists. Upon
written notice, FDA may require that applicants review the frequency of
reports of serious, expected adverse drug experiences at intervals
different than the periodic reporting cycle. Reports of a significant
increase in frequency are required to be submitted in narrative form
(including the time period on which the increased frequency is based,
the method of analysis, and the interpretation of the results), rather
than using FDA Form 3500A. 15-day Alert reports based on increased
frequency are required to be submitted under separate cover and may not
be included, except for summary purposes, in a periodic report.
(iv) Submission of reports. The requirements of paragraphs
(c)(1)(i), (c)(1)(ii), and (c)(1)(iii) of this section, concerning the
submission of postmarketing 15-day Alert reports, shall also apply to
any person (other than the applicant) whose name appears on the label
of an approved drug product as a manufacturer, packer, or distributor.
However, in order to avoid unnecessary duplication in the submission to
FDA of reports required by paragraphs (c)(1)(i), (c)(1)(ii), and
(c)(1)(iii) of this section, obligations of a nonapplicant may be met
by submission of all reports of serious adverse drug experiences to the
applicant. If a nonapplicant elects to submit adverse drug experience
reports to the applicant rather than to FDA, it shall submit each
report to the applicant within 3 calendar days of its receipt by the
nonapplicant, and the applicant shall then comply with the requirements
of this section. Under this circumstance, the nonapplicant shall
maintain a record of this action which shall include:
(A) A copy of the drug experience report.
(B) Date the report was received by the nonapplicant.
(C) Date the report was submitted to the applicant.
(D) Name and address of the applicant.
(v) Report identification. Each report submitted under this
paragraph shall bear prominent identification as to its contents, i.e.,
``15-day Alert report,'' ``15-day Alert report--followup,'' or
``Increased frequency report.''
(2) Periodic adverse drug experience reports. (i) The applicant
shall report every 6 months each adverse drug experience not reported
under paragraphs (c)(1)(i) and (c)(1)(ii) of this section. The periodic
reporting term shall be based upon the international birth date of the
human drug product. The first 6-month anniversary of the international
birth date after the application is approved in the United States is
the data lock-point for the first periodic reporting term. Each
subsequent 6-month anniversary of the international birth date is the
data lock-point for subsequent periodic reporting terms for that
particular product. Periodic reports shall be submitted to FDA within
45 days after the data lock-point. Upon written notice, FDA may require
that the applicant submit reports under this section at times other
than those stated. An applicant who wishes to submit periodic reports
at different intervals must submit to FDA a request for a waiver under
Sec. 314.90. Followup information to adverse drug experiences submitted
initially in a periodic report may be submitted in the next periodic
report. If the applicant does not receive any adverse experience
reports during the reporting period, the applicant shall, in place of a
periodic report, send a copy of the current approved U.S. labeling and
a letter identifying the product, the application number, and the
reporting period, stating that no adverse drug experience reports were
received.
(ii) Reports. Each periodic report shall contain:
(A) Title page, table of contents, and introduction. The
introduction shall be a summary of the periodic report with page
references to detailed data and information.
(B) Applicant's core safety data sheet. The applicant's core safety
data sheet shall be a document prepared by the applicant that contains
all relevant safety information, including adverse drug experiences,
which the applicant believes should be listed for the drug in all
countries where the drug is marketed. It may be used by the applicant
as the reference document by which an adverse drug experience is judged
to be expected or unexpected for purposes of this postmarketing
periodic report. For all other determinations of whether an adverse
drug experience is expected or unexpected, the definition in paragraph
(a) of this section shall apply.
(1) FDA recognizes that the postmarketing periodic report may be
submitted by the applicant to multiple countries and the product may
have different approved labels in the different countries. The use of
the applicant's core safety data sheet as the reference document for
determining whether an adverse drug experience is unexpected or not may
result in some overreporting of unexpected adverse events that actually
are expected by the U.S. approved product label. This is because the
approved label for the United States may have more safety information
included in it than the manufacturer's core safety data sheet. If an
adverse event is not listed in the U.S. label, but is in the
manufacturer's core safety data sheet, this shall be clearly noted in
the ``Overall safety evaluation'' (see paragraph (c)(2) (ii)(H) of this
section). This section also shall highlight clearly any changes and the
reasons for the changes in the applicant's core safety data sheet since
the previous postmarketing periodic report.
(2) An applicant may also use the approved U.S. label as the
reference by which expected and unexpected adverse drug experiences are
determined for the postmarketing periodic report. If an applicant
chooses to use the approved U.S. label for this purpose, it shall
clearly be stated in this section of the report.
(C) The product's marketing status. This section shall contain a
table containing a chronological history of the marketing status of the
product worldwide (all regulatory decisions affecting the product and
all market launches) from the date it was first approved through its
current status. Approvals or applications voluntarily withdrawn for
safety reasons shall be included at a minimum. The product shall be
listed by chemical (or proper name) and brand name(s).
(D) Regulatory actions for safety reasons. This section shall
contain a narrative identifying the reasons for significant regulatory
authority or manufacturer-initiated actions taken anywhere in the
world, or to be taken imminently, for safety reasons during the
reporting period. This includes, for example, application withdrawal or
license suspension or failure to renew, distribution restrictions,
clinical trial suspension, labeling changes due to significant safety
concerns, dosage modifications, or pharmaceutical changes.
(E) Patient exposure. This section shall include the product's
domestic and foreign marketing distribution data during the reporting
period. This shall be used to calculate the extent of patient exposure.
The method used by the manufacturer to estimate patient exposure shall
always be described and shall include the total number of dosage units
of each dosage form and strength or potency (e.g., 100,000/5-milligram
tablets, 50,000/10-milliliter vials).
(F) Individual case histories. This section shall consist of
individual case reports of adverse drug experiences thought possibly
associated with the use of the drug that are:
(1) Serious, unexpected reports from published or unpublished
clinical studies where the applicant has concluded that there is a
reasonable possibility that the drug caused the adverse experience;
(2) Serious, expected or unexpected spontaneous adverse drug
experience reports and nonserious, unexpected spontaneous adverse drug
experience reports (causality always assumed in spontaneous reports)
received directly by the applicant from the initial reporter or
received by the applicant from a drug regulatory authority, both U.S.
or foreign; and
(3) Serious, expected or unexpected, individual published case
histories and nonserious, unexpected individual published case
histories.
(4) All of these reports in paragraphs (c)(2)(ii)(F)(1) through
(c)(2)(ii)(F)(3) of this section shall be presented in line listing
format with the following 10 columns: country, source, age, gender,
dose, duration of treatment (prior to event), time to onset,
description of reaction (as reported), outcome (e.g., fatal, resolved),
other comments (e.g., manufacturer's report number). This format is
consistent with that suggested by CIOMS. In addition, a tabular summary
of the number of adverse events by body system may be included. This
section shall end with an analysis by the reporter, in narrative form,
of the cases submitted. The applicant shall also attach to the end of
the postmarketing periodic report a completed FDA Form 3500A for all
U.S. spontaneous reports of adverse drug experiences except those
reported under paragraphs (c)(1)(i) and (c)(1)(ii) of this section, or
those sent by FDA to the applicant.
(G) Safety studies. This section shall contain an analysis and full
critical discussion of all toxicological, clinical, and epidemiological
studies containing important safety information.
(H) Overall safety evaluation. This section shall contain a
critical analysis and full discussion of the safety information
provided in the periodic report as it pertains to serious unexpected
reactions, increased frequencies of known toxicity, reactions listed in
the manufacturer's core safety data sheet but not included in the U.S.
label, drug interactions, overdose, drug abuse, experiences during
pregnancy or lactation, chronic treatment, pediatric or geriatric
treatment, and new safety issues. The applicant shall indicate when any
significant information has not been obtained. The evaluation shall
indicate whether the safety profile of the product remains consistent
with cumulative experience to date and with the previous manufacturer's
core safety data sheet. The evaluation shall specify any action
recommended and the reasons for such recommendations.
(I) Other information. This section shall include important
information received after the data lock-point.
(J) FDA Form 3500A. An FDA Form 3500A shall be used for each
spontaneous U.S. adverse drug experience not reported under paragraphs
(c)(1)(i) and (c)(1)(ii) of this section.
(K) Location of adverse experience records. The current addresses
where all adverse experience reports and records are maintained.
(d) * * *
(1) * * * The 15-day reporting requirements in paragraph
(c)(1)(iii) of this section (i.e., a significant increase in frequency
of a serious, expected adverse drug experience, or of a therapeutic
failure) apply only to the reports found in scientific and medical
journals either as case reports or as the result of a formal clinical
trial. * * *
* * * * *
(f) Reporting FDA Form 3500A. (1) Except as provided in paragraphs
(c)(1)(iii) and (f)(3) of this section, the applicant shall complete
FDA Form 3500A for each report of an adverse drug experience.
* * * * *
(3) * * *
(ii) The format is agreed to in advance by MedWatch: The FDA
Medical Products Reporting Program.
(4) Ten copies or fewer of FDA Form 3500A and/or a copy of the
instructions for completing the form may be obtained from the Division
of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation
and Research, Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857. More than 10 copies of the form may be obtained by
writing to the Consolidated Forms and Publications Distribution Center,
Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 20785.
* * * * *
(j) * * * Copies of this guideline may be obtained from the CDER
Executive Secretariat Staff (HFD-8), Center for Drug Evaluation and
Research, Food and Drug Administration, 7500 Standish Pl., Rockville,
MD 20857.
* * * * *
(l) * * * For purposes of this provision, the term ``applicant''
also includes any person reporting under paragraph (c)(1)(iv) of this
section.
* * * * *
PART 600--BIOLOGICAL PRODUCTS: GENERAL
16. The authority citation for 21 CFR part 600 continues to read as
follows:
Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352,
353, 355, 360, 360i, 371, 374); secs. 215, 351, 352, 353, 361 of the
Public Health Service Act (42 U.S.C. 216, 262, 263, 263a, 264).
17. Section 600.80 as added in a final rule published elsewhere in
this issue of the Federal Register is amended in paragraph (a) by
alphabetically adding definitions for ``Data lock-point,''
``Disability,'' ``International birth date,'' and ``Life-threatening;''
by revising the definition of ``Serious;'' by adding two new sentences
at the end of paragraph (b); by revising paragraph (c), the third
sentence in paragraph (d)(1), paragraph (g), and the last sentence in
paragraph (m); and by adding a new sentence at the end of paragraph (j)
to read as follows:
Sec. 600.80 Postmarketing reporting of adverse experiences.
(a) * * *
* * * * *
Data lock-point means the date designated as the cutoff date for
data to be incorporated into a specific postmarketing adverse
experience periodic report. Data available to the licensed manufacturer
after this date will not be incorporated into the report, unless it
represents important information.
Disability means a substantial disruption of a person's ability to
carry out normal life functions.
* * * * *
International birth date means the date that the first regulatory
authority in the world approved the biological drug product for
marketing.
Life-threatening means that the patient was, in the view of the
initial reporter, at immediate risk of death from the adverse
experience as it occurred. It does not include an adverse experience
that, had it occurred in a more serious form, might have caused death.
For example, product-induced hepatitis that resolved without evidence
of hepatic failure would not be considered life-threatening even though
hepatitis of a more severe nature can be fatal. Similarly, an allergic
reaction resulting in angioedema of the face would not be life-
threatening, even though angioedema of the larynx, allergic
bronchospasm, or anaphylaxis can be fatal.
Serious means an adverse drug experience occurring at any dose that
is fatal or life-threatening, results in persistent or significant
disability/incapacity, requires or prolongs inpatient hospitalization,
necessitates medical or surgical intervention to preclude permanent
impairment of a body function or permanent damage to a body structure,
or is a congenital anomaly.
* * * * *
(b) * * * Licensed manufacturers should not resubmit to FDA adverse
product experience reports forwarded to the licensed manufacturer by
FDA; however, they should submit all followup information to FDA.
Licensed manufacturers shall also develop written procedures for the
surveillance, receipt, evaluation, and reporting of adverse
experiences.
(c) Reporting requirements. The licensed manufacturer shall report
to FDA adverse experience information, as described in this section.
The licensed manufacturer shall submit two copies of each report
described in this section for nonvaccine biological products to the
Center for Biologics Evaluation and Research (HFM-210), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448. Submit all vaccine adverse experience reports to: Vaccine Adverse
Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD 20849-
1100. FDA may waive the requirement for the second copy in appropriate
instances.
(1)(i) Postmarketing 15-day ``Alert reports''. The licensed
manufacturer shall report each adverse experience that is both serious
and unexpected as soon as possible, but in any case within 15 calendar
days of initial receipt of the information. These reports shall be
submitted for nonvaccine biological products on FDA Form 3500A, and,
for vaccines, on a VAERS form.
(ii) Postmarketing 15-day ``Alert reports''--followup. The licensed
manufacturer shall promptly investigate all adverse experiences that
are the subject of these postmarketing 15-day Alert reports and shall
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. These postmarketing 15-day Alert
reports and followups to them shall be submitted under separate cover
and may not be included, except for summary or tabular purposes, in a
postmarketing adverse experience periodic report.
(iii) Increased frequency report. The licensed manufacturer shall
review periodically (at least as often as the periodic reporting cycle)
the frequency of reports of adverse biological product experiences that
are both serious and expected and reports of therapeutic failure (lack
of effect), regardless of source, and report any significant increase
in frequency as soon as possible but in any case within 15 calendar
days of determining that a significant increase in frequency exists.
Upon written notice, FDA may require that licensed manufacturers review
the frequency of reports of serious, expected adverse biological
experiences at intervals different than the periodic reporting cycle.
Reports of a significant increase in frequency are required to be
submitted in narrative form (including the time period on which the
increased frequency is based, the method of analysis, and the
interpretation of the results), rather than using the form designated
by FDA. 15-day Alert reports based on increased frequency are required
to be submitted under separate cover and may not be included, except
for summary purposes, in a periodic report.
(iv) Submission of reports. The requirements of paragraphs
(c)(1)(i), (c)(1)(ii), and (c)(i)(iii) of this section, concerning the
submission of postmarketing 15-day Alert reports, shall also apply to
any person (other than the licensed manufacturer of the final product)
whose name appears on the label of a licensed biological product as a
manufacturer, packer, distributor, shared manufacturer, joint
manufacturer, or any other participant involved in divided
manufacturing. However, in order to avoid unnecessary duplication in
the submission to FDA of reports required by paragraphs (c)(1)(i),
(c)(1)(ii), and (c)(1)(iii) of this section, obligations of a
manufacturer other than the licensed manufacturer, including a licensed
manufacturer of the product other than in its final form, may be met by
submission of all reports of serious adverse experiences to the
licensed manufacturer of the final product. If a manufacturer, other
than the licensed manufacturer, elects to submit reports to the
licensed manufacturer rather than to FDA, it shall submit each report
to the licensed manufacturer within 3 calendar days of its receipt, and
the licensed manufacturer shall then comply with the requirements of
this section. Under this circumstance, the manufacturer shall maintain
a record of this action which shall include:
(A) A copy of all adverse biological product experience reports
submitted to the licensed manufacturer.
(B) Date the report was received by the manufacturer other than the
licensed manufacturer.
(C) Date the report was submitted to the licensed manufacturer.
(D) Name and address of the licensed manufacturer.
(v) Report identification. Each report submitted under this
paragraph shall bear prominent identification as to its contents, i.e.,
``15-day Alert report,'' ``15-day Alert report--followup,'' or
``Increased frequency report.''
(2)(i) Periodic adverse experience reports. The licensed
manufacturer shall report every 6 months each adverse experience not
reported under paragraphs (c)(1)(i) and (c)(1)(ii) of this section. The
periodic reporting term shall be based upon the international birth
date of the biological product. The first 6-month anniversary of the
international birth date after the application is approved in the
United States is the data lock- point for the first periodic reporting
term. Each subsequent 6-month anniversary of the international birth
date is the data lock-point for subsequent periodic reporting terms for
that particular product. Periodic reports shall be submitted to FDA
within 45 days after the data lock-point. Upon written notice, FDA may
require that the licensed manufacturer submit reports under this
section at times other than those stated. A licensed manufacturer who
wishes to submit periodic reports at different intervals must submit to
FDA a request for a waiver under Sec. 600.90. Followup information to
adverse experiences submitted in a periodic report may be submitted in
the next periodic report. If the licensed manufacturer does not receive
any adverse experience reports during the reporting period, the
licensed manufacturer shall, in place of a periodic report, send a copy
of the current approved U.S. labeling and a letter identifying the
product, the application number, and the reporting period, stating that
no adverse experience reports were received.
(ii) Reports. Each periodic report shall contain:
(A) Title page, table of contents, and introduction. The
introduction shall be a summary of the periodic report with page
references to detailed data and information.
(B) Licensed manufacturer's core safety data sheet. The licensed
manufacturer's core safety data sheet shall be a document prepared by
the licensed manufacturer that contains all relevant safety
information, including adverse experiences, which the licensed
manufacturer believes should be listed for the licensed biological
product in all countries where the licensed biological product is
marketed. It may be used by the licensed manufacturer as the reference
document by which an adverse experience is judged to be expected or
unexpected for purposes of this postmarketing periodic report. For all
other determinations of whether an adverse experience is expected or
unexpected, the definition in paragraph (a) of this section shall
apply.
(1) FDA recognizes that the postmarketing periodic report may be
submitted by the licensed manufacturer to multiple countries and the
product may have different approved labels in the different countries.
The use of the licensed manufacturer's core safety data sheet as the
reference document for determining whether an adverse drug experience
is unexpected or not may result in some overreporting of unexpected
adverse events that actually are expected by the U.S. approved product
label. This is because the approved label for the United States may
have more safety information included in it than the licensed
manufacturer's core safety data sheet. If an adverse event is not
listed in the U.S. label, but is in the licensed manufacturer's core
safety data sheet, this shall be clearly noted in the ``Overall safety
evaluation'' (see paragraph (c)(2)(ii)(H) of this section). This
section also shall highlight clearly any changes and the reasons for
the changes in the licensed manufacturer's core safety data sheet since
the previous postmarketing periodic report.
(2) A licensed manufacturer may also use the approved U.S. label as
the reference by which expected and unexpected adverse experiences are
determined for the postmarketing periodic report. If a licensed
manufacturer chooses to use the approved U.S. label for this purpose,
it shall clearly be stated in this section of the report.
(C) The product's marketing status. This section shall contain a
table containing a chronological history of the marketing status of the
product worldwide (all regulatory decisions affecting the product and
all market launches) from the date it was first approved through its
current status. Approvals or applications voluntarily withdrawn for
safety reasons shall be included at a minimum. The product shall be
listed by chemical (or proper name) and brand name(s).
(D) Regulatory actions for safety reasons. This section shall
contain a narrative identifying the reasons for significant regulatory
authority or manufacturer-initiated actions taken anywhere in the
world, or to be taken imminently, for safety reasons during the
reporting period. This includes, for example, licensed application
withdrawal or license suspension or failure to renew, distribution
restrictions, clinical trial suspension, labeling changes due to
significant safety concerns, dosage modifications, or pharmaceutical
changes.
(E) Patient exposure. This section shall include the product's
domestic and foreign marketing distribution data during the reporting
period. This shall be used to calculate the extent of patient exposure.
The method used by the licensed manufacturer to estimate patient
exposure shall always be described and shall include the total number
of dosage units of each dosage form and strength or potency (e.g.,
100,000/5-milligram tablets, 50,000/10-milliliter vials).
(F) Individual case histories. This section shall consist of
individual case reports of adverse experiences thought possibly
associated with the use of the licensed biological product that are:
(1) Serious, unexpected reports from published or unpublished
clinical studies where the licensed manufacturer has concluded that
there is a reasonable possibility that the licensed biological product
caused the adverse experience;
(2) Serious, expected or unexpected spontaneous adverse experience
reports and nonserious, unexpected spontaneous adverse experience
reports (causality always assumed in spontaneous reports) received
directly by the licensed manufacturer from the initial reporter or
received by the licensed manufacturer from a drug regulatory authority,
both U.S. or foreign; and
(3) Serious, expected or unexpected, individual published case
histories and nonserious, unexpected individual published case
histories.
(4) All of these reports under paragraphs (c)(2)(ii)(F)(1) through
(c)(2)(ii)(F)(3) of this section shall be presented in line listing
format with the following 10 columns: country, source, age, gender,
dose, duration of treatment (prior to event), time to onset,
description of reaction (as reported), outcome (e.g., fatal, resolved),
other comments (e.g., manufacturer's report number). This format is
consistent with that suggested by CIOMS. In addition, a tabular summary
of the number of adverse events by body system may be included. This
section shall end with an analysis by the reporter, in narrative form,
of the cases submitted. The licensed manufacturer shall also attach to
the end of the postmarketing periodic report a completed FDA Form 3500A
or VAERS form for all U.S. spontaneous reports of adverse experiences
except those reported under paragraphs (c)(1)(i) and (c)(1)(ii) of this
section, or those sent by FDA to the licensed manufacturer.
(G) Safety studies. This section shall contain an analysis and full
critical discussion of all toxicological, clinical, and epidemiological
studies containing important safety information.
(H) Overall safety evaluation. This section shall contain a
critical analysis and full discussion of the safety information
provided in the periodic report as it pertains to serious unexpected
reactions, increased frequencies of known toxicity, reactions listed in
the manufacturer's core safety data sheet but not included in the U.S.
label, licensed biological product interactions, overdose, licensed
biological product abuse, experiences during pregnancy or lactation,
chronic treatment, pediatric or geriatric treatment, and new safety
issues. The licensed manufacturer shall indicate when any significant
information has not been obtained. The evaluation shall indicate
whether the safety profile of the product remains consistent with
cumulative experience to date and with the previous licensed
manufacturer's core safety data sheet. The evaluation shall specify any
action recommended and the reasons for such recommendations.
(I) Other information. This section shall include important
information received after the data lock-point.
(J) FDA Form 3500A or VAERS Form. An FDA Form 3500A or VAERS form
(for vaccines)shall be used for each spontaneous U.S. adverse
experience not reported under paragraphs (c)(1)(i) and (c)(1)(ii) of
this section.
(K) Location of adverse experience records. The current addresses
where all adverse experience reports and records are maintained.
(3) Distribution reports. The licensed manufacturer shall submit
information about the quantity of the product distributed under the
product license, including the quantity distributed to distributors.
The interval between distribution reports shall be 6 months. The
reporting term shall be based upon the international birth date of the
biological product. The first 6-month anniversary of the international
birth date after the application is approved in the United States is
the data lock-point for the first reporting term. Each subsequent 6-
month anniversary of the international birth date is the data lock-
point for subsequent reporting terms for that particular product.
Distribution reports shall be submitted to FDA within 45 calendar days
after the data lock-point. Upon written notice, FDA may require that
the licensed manufacturer submit distribution reports under this
section at times other than every 6 months. The distribution report
shall consist of the bulk lot number (from which the final container
was filled), the fill lot numbers for the total number of dosage units
of each strength or potency distributed (e.g., 50,000/10-milliliter
vials), the label lot number (if different from fill lot number),
labeled date of expiration, number of doses in fill lot/label lot, date
of release of fill lot/label lot released for distribution at that
time. If any significant amount of a fill lot/label lot is returned,
include this information. Disclosure of financial or pricing data is
not required. As needed, FDA may require submission of more detailed
product distribution information. Upon written notice, FDA may require
that the licensed manufacturer submit reports under this section at
times other than those stated. A licensed manufacturer that wishes to
submit reports at times other than those stated should submit a request
for a waiver under Sec. 600.90.
(d) * * *
(1) * * * The 15-day reporting requirements in paragraph
(c)(1)(iii) of this section (i.e., a significant increase in frequency
of a serious, expected adverse experience or of a therapeutic failure)
apply only to reports found in scientific and medical journals either
as the results of formal clinical trial, or from epidemiologic studies
or analyses of experience in a monitored series of patients. * * *
* * * * *
(g) Multiple reports. A licensed manufacturer should not include in
reports under this section any adverse experience that occurred in
clinical trials if they were previously submitted as part of the
license application. If a report applies to a licensed biological
product for which a licensed manufacturer holds more than one
biological product license, the licensed manufacturer should submit the
report for the license that was first approved. If a report refers to
more than one biological product marketed by a licensed manufacturer,
the licensed manufacturer should submit the report to the license for
the product listed first in the report.
* * * * *
(j) * * * Copies of this guideline may be obtained from the
Congressional and Consumer Affairs Branch (HFM-12), Center for
Biologics Evaluation and Research, Food and Drug Administration, 1401
Rockville Pike, Rockville, MD 20852-1448.
* * * * *
(m) * * * For purposes of this provision, this paragraph also
includes any person reporting under paragraph (c)(1)(iv) of this
section.
Sec. 600.81 [Removed]
18. Section 600.81 Distribution reports (as added in a final rule
published elsewhere in this issue of the Federal Register) is removed.
Dated: October 13, 1994.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 94-26483 Filed 10-26-94; 8:45 am]
BILLING CODE 4160-01-F