[Federal Register Volume 62, Number 122 (Wednesday, June 25, 1997)]
[Rules and Regulations]
[Pages 34166-34168]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-16684]


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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