[Federal Register: June 25, 1997 (Volume 62, Number 122)]
[Rules and Regulations]
[Page 34166-34168]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr25jn97-5]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 310, 314, and 600
[Docket No. 96N-0108]
Postmarketing Expedited Adverse Experience Reporting for Human
Drug and Licensed Biological Products; Increased Frequency Reports
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending its
regulations on expedited reporting of postmarketing adverse experiences
to revoke the requirement for increased frequency reports as expedited
reports for human drug and licensed biological products. This action,
which is part of the President's regulatory reinvention initiative, is
based on FDA's determination that expedited increased frequency reports
have not contributed to the timely identification of safety problems
requiring regulatory action and are no longer necessary for FDA
surveillance of postmarketing adverse experiences. This action is
intended to streamline postmarketing expedited reporting of adverse
experiences for human drug and licensed biological products. This
action will not affect the requirement for expedited reporting of all
serious, unexpected adverse experiences.
EFFECTIVE DATE: July 25, 1997.
FOR FURTHER INFORMATION CONTACT:
For information concerning human drug products: Audrey A. Thomas,
Center for Drug Evaluation and Research (HFD-7), Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-5625.
For information concerning human licensed biological products:
Marcel E. Salive, Center for Biologics Evaluation and Research (HFM-
220), Food and Drug Administration, 1401 Rockville Pike, suite 200S,
Rockville, MD 20852-1448, 301-827-3974.
SUPPLEMENTARY INFORMATION:
I. Background
Under current Secs. 310.305(c)(4), 314.80(c)(1)(ii) and
(c)(1)(iii), and 600.80(c)(1)(ii) and (c)(1)(iii) (21 CFR
310.305(c)(4), 314.80(c)(1)(ii) and (c)(1)(iii), and 600.80(c)(1)(ii)
and (c)(1)(iii)), applicants, manufacturers, packers, and distributors,
including licensed manufacturers and other manufacturers of biological
products, are required to review periodically the frequency of reports
of adverse 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 working days of determining that a significant
increase in frequency exists. An increased frequency exists if the
adjusted reporting for the reporting interval is at least two times
greater than the adjusted reporting for the comparison interval
(previous reporting interval). These regulations were issued by FDA to
ensure that applicants, manufacturers, packers, and distributors,
including licensed manufacturers and other manufacturers of biological
products, identify increases in the incidence of serious, labeled
adverse experiences that are not anticipated from premarketing clinical
trials and that occur with changes in medical practice, such as using a
drug or biological product in higher risk populations, at higher
dosages, or concomitantly with other drugs or biological products
causing interactions.
In the Federal Register of October 28, 1996 (61 FR 55602), FDA
proposed to amend its postmarketing expedited adverse experience
reporting regulations to revoke the requirement for expedited increased
frequency reports in Secs. 310.305(c)(4), 314.80(c)(1)(ii) and
(c)(1)(iii), and 600.80(c)(1)(ii) and (c)(1)(iii), and to revoke the
definition of ``increased frequency'' in Secs. 310.305(b)(5),
314.80(a), and 600.80(a). As explained in the proposal, FDA determined
that increased frequency reports rarely prompted regulatory action
during the time that the agency received such reports, and the reports
proved to be of little value in identifying increased incidences of
serious, labeled experiences. This action does not affect the
requirement for expedited reporting of all serious, unexpected adverse
experiences. Applicants, manufacturers, packers, and distributors,
including licensed manufacturers and other manufacturers of biological
products, must continue to submit 15-day Alert reports and followup
reports for serious, unexpected events, as required under
Secs. 310.305(c), 314.80(c), 314.98, and 600.80(c).
II. Rationale
Several factors have contributed to FDA's decision to revoke the
requirement for expedited increased frequency reports. Key factors
include: (1) Safety problems that have been the subject of these
reports could have been detected in other safety reports, (2) the
reliability of increased frequency reports is limited, and (3) this
action is consistent with recent international efforts to harmonize
reporting requirements. These factors are discussed in more detail in
the following paragraphs.
Only a small number of drug/biological product safety problems
where expedited increased frequency reports played a role in risk
assessment have resulted in regulatory action. In each case, the safety
problems could have been detected in other safety reports required by
FDA such as periodic adverse experience reports, field alert reports,
or annual reports. FDA has found that expedited postmarketing adverse
experience reporting systems are best used to identify rare, unexpected
adverse drug reactions such as aplastic anemia, hepatic necrosis, renal
failure, or anaphylaxis that were not detected in preclinical studies
or clinical trials during drug development.
The reliability of increased frequency reports is limited because
of the difficulty in accurately estimating incidence rates. Increased
frequency information is derived from incidence rates, which are
estimated by dividing
[[Page 34167]]
the number of adverse experiences by the number of persons exposed to a
drug or biological product. Reporters compare incidence rates estimated
for the reporting interval with rates estimated for the previous
reporting interval. However, a number of uncertainties contribute to
the unreliability of incidence rates. For example, health care
providers do not report all adverse experiences or may report them to
the sponsor many months after they became aware of them. The number of
persons exposed to a drug or biological product during a reporting
period is not precisely known; it is only estimated based on sales or
production data. The lag time between production or sales by the
manufacturer and consumption by patients can vary, adding further
distortion to comparisons between reporting periods. Finally, because
of incomplete data and the uncertainty caused by the underlying
illness, indication, or other drug exposures, adverse experience
reports may be attributed to a drug or biological product even though
it may not necessarily have caused the adverse experience.
FDA's decision to revoke the requirement for expedited increased
frequency reports is also consistent with recent international
harmonization initiatives. In the Federal Register of October 27, 1994
(59 FR 54046), FDA proposed amending, among other things, its
regulations for periodic postmarketing reporting of adverse experiences
for human drug and licensed biological products based on
recommendations developed by the World Health Organization's Council
for International Organizations of Medical Sciences (CIOMS) Working
Group II. The revised regulations would include a section for overall
safety evaluation that would contain a critical analysis and full
discussion of the safety information provided in the periodic report as
it pertains to a number of matters, including increased frequencies of
known toxicity. Recently, the International Conference on Harmonisation
of Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH) developed, based on the CIOMS II proposals, a final guideline
for periodic reporting entitled ``Clinical Safety Data Management:
Periodic Safety Update Reports for Marketed Drugs.'' The guideline,
published in the Federal Register of May 19, 1997 (62 FR 27470),
recommends that the overall safety evaluation section of periodic
safety update reports highlight any new information on increased
frequencies of known adverse drug reactions, including comments on
whether it is believed that these data reflect a meaningful change in
adverse drug reaction occurrences. Under this guideline, regulatory
authorities will be able to obtain reports of increased frequencies
from periodic reports. FDA plans to finalize its proposed amendments to
the periodic postmarketing safety reporting regulations in a future
issue of the Federal Register. These amendments will be based on the
CIOMS and ICH recommendations.
III. Comments on the Proposed Rule
The agency received five comments from industry and the public. All
of the comments supported FDA's decision to revoke the requirement for
expedited increased frequency reports, stating that these reports have
not contributed to timely identification of safety problems requiring
regulatory action, nor to information for physicians or patient care.
All of the comments expressed the belief that because serious and
unexpected reports of adverse experiences are investigated and reported
under the 15-day Alert report requirement and because overall safety
and adverse experience data are summarized in periodic reports, FDA's
action to revoke the requirement of increased frequency reports will
result in the elimination of resource intensive procedures and provide
industry with more time to focus on evaluation of serious and
unexpected adverse drug experiences and other important medical product
events.
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. Paperwork Reduction Act of 1995
This final rule does not require information collections and, thus,
is not subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (Pub. L. 104-13).
VI. Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).
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 final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the final
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 Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because this final rule will simplify and streamline
current requirements, the Commissioner of Food and Drugs certifies that
the final 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.
List of Subjects
21 CFR Part 310
Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.
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, 21 CFR parts 310, 314, and 600 are
amended as follows:
PART 310--NEW DRUGS
1. 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).
2. Section 310.305 is amended by revising paragraph (a), by
removing paragraph (b)(5), by removing paragraph (c)(4), by
redesignating paragraphs (c)(5) and (c)(6) as paragraphs (c)(4) and
(c)(5),
[[Page 34168]]
respectively, by revising the first sentence of newly redesignated
paragraph (c)(4), and by revising paragraph (f)(1) 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) Scope. FDA is requiring manufacturers, packers, and
distributors of marketed prescription drug products that are not the
subject of an approved new drug or abbreviated new drug application to
establish and maintain records and make reports to FDA of all serious,
unexpected adverse drug experiences associated with the use of their
drug products.
* * * * *
(c) * * *
(4) To avoid unnecessary duplication in the submission of, and
followup to, reports required in 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. * * *
* * * * *
(f) Recordkeeping. (1) Each manufacturer, packer, and distributor
shall maintain for a period of 10 years records of all adverse drug
experiences required under this section to be reported, including raw
data and any correspondence relating to the adverse drug experiences,
and the records required to be maintained under paragraph (c)(4) of
this section.
* * * * *
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN
ANTIBIOTIC DRUG
3. 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).
4. Section 314.80 is amended by removing the definition for
Increased frequency in paragraph (a), by removing paragraph (c)(1)(ii),
by redesignating paragraphs (c)(1)(iii) and (c)(1)(iv) as paragraphs
(c)(1)(ii) and (c)(1)(iii), respectively, by revising the first two
sentences in the introductory text of newly redesignated paragraph
(c)(1)(ii), by removing the last sentence in paragraph (d)(1), by
revising paragraph (f)(1), and by revising the last sentence in
paragraph (l) to read as follows:
Sec. 314.80 Postmarketing reporting of adverse drug experiences.
* * * * *
(c) * * *
(1) * * *
(ii) The requirements of paragraph (c)(1)(i) of this section,
concerning the submission of 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, to avoid unnecessary duplication in the submission to FDA of,
and followup to, reports required by paragraph (c)(1)(i) of this
section, obligations of a nonapplicant may be met by submission of all
reports of serious adverse drug experiences to the applicant. * * *
* * * * *
(f) Reporting Form FDA-1639. (1) Except as provided in paragraph
(f)(3) of this section, the applicant shall complete a Form FDA-1639
(Adverse Reaction Report) for each report of an adverse drug
experience.
* * * * *
(l) * * * For purposes of this provision, the term ``applicant''
also includes any person reporting under paragraph (c)(1)(ii) of this
section.
* * * * *
PART 600--BIOLOGICAL PRODUCTS: GENERAL
5. 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, 2125
of the Public Health Service Act (42 U.S.C. 216, 262, 263, 263a,
264, 300aa-25).
6. Section 600.80 is amended by removing the definition for
Increased frequency in paragraph (a), by removing paragraph (c)(1)(ii),
by redesignating paragraphs (c)(1)(iii) and (c)(1)(iv) as paragraphs
(c)(1)(ii) and (c)(1)(iii), respectively, by revising the first
sentence in the introductory text of newly redesignated paragraph
(c)(1)(ii), by removing the last sentence in paragraph (d)(1), by
revising paragraph (f)(1), and by revising the last sentence in
paragraph (m) to read as follows:
Sec. 600.80 Postmarketing reporting of adverse experiences.
* * * * *
(c) * * *
(1) * * *
(ii) The requirements of paragraph (c)(1)(i) of this section,
concerning the submission of 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. * * *
* * * * *
(f) Reporting forms. (1) Except as provided in paragraph (f)(3) of
this section, the licensed manufacturer shall complete the reporting
form designated by FDA (FDA-3500A, or, for vaccines, a VAERS form) for
each report of an adverse experience.
* * * * *
(m) * * * For purposes of this provision, this paragraph also
includes any person reporting under paragraph (c)(1)(ii) of this
section.
Dated: June 19, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-16684 Filed 6-20-97; 3:54 pm]
BILLING CODE 4160-01-F