[Federal Register Volume 61, Number 209 (Monday, October 28, 1996)]
[Proposed Rules]
[Pages 55602-55607]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-27593]


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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: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to

[[Page 55603]]

amend its postmarketing expedited adverse experience reporting 
regulations to revoke the requirement for increased frequency reports 
for human drug and licensed biological products as expedited reports. 
This action, which is part of the President's regulatory reinvention 
initiative, is based on FDA's determination that increased frequency 
reports, as currently required, have not contributed to timely 
identification of safety problems requiring regulatory action and are 
no longer necessary for FDA surveillance of postmarketing adverse 
experiences. This action would simplify and streamline postmarketing 
expedited reporting of adverse experiences for human drug and licensed 
biological products.

DATES: Written comments by January 13, 1997. 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, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Audrey A. Thomas, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-1049.

SUPPLEMENTARY INFORMATION:

I. Introduction

    On March 4, 1995, President Clinton issued a memorandum titled 
``Regulatory Reinvention Initiative.'' This memorandum, part of the 
reform of the Federal regulatory system, directed heads of departments 
and agencies to undertake a page-by-page review of their existing 
regulations and to eliminate or modify those that are outdated or 
otherwise in need of reform. The President's directive was issued 
because private businesses, especially small ones, often face a 
profusion of overlapping and sometimes conflicting rules from Federal 
regulatory objectives.
    As part of their review, agencies were charged to consider the 
following issues carefully: Is the regulation obsolete; could its 
intended goal be achieved in more efficient, less intrusive ways; are 
there private sector alternatives, such as market mechanisms, that can 
better achieve the public good envisioned by the regulations; could 
private business, setting its own standards and being subject to public 
accountability, do the job as well; and could the States or local 
governments do the job, making the Federal regulation unnecessary.
    In response to the President's regulatory reinvention initiative, 
FDA conducted a comprehensive review of its existing regulations and 
identified regulations to eliminate or modify. Although this proposal 
was not a result of the initial review of regulations, FDA is 
continuing its efforts to carry out the President's program. The 
current proposal to revoke parts of its regulations in Secs. 310.305, 
314.80, and 600.80 (21 CFR 310.305, 314.80, and 600.80) that require 
postmarketing expedited increased frequency reports of adverse 
experiences for human drug and licensed biological products is part of 
the continuing effort.

II. Background

    In the Federal Register of February 22, 1985 (50 FR 7452), FDA 
published revised regulations governing the approval for marketing of 
new drugs for human use, which included revisions to its adverse 
experience reporting requirements. Under Sec. 314.80(c)(1)(ii), any 
applicant with an approved new drug application (NDA) is required to 
submit expedited increased frequency reports for any significant 
increase in frequency of an adverse experience that is both serious and 
expected. In the Federal Register of July 3, 1986 (51 FR 24476), FDA 
published regulations for adverse experience reporting for marketed 
prescription drugs without approved NDA's or abbreviated new drug 
applications (ANDA's). Under Sec. 310.305(c)(4), any manufacturer, 
packer, or distributor of a marketed prescription drug without an 
approved NDA or ANDA is required to submit expedited increased 
frequency reports for any significant increase in frequency of an 
adverse experience that is both serious and expected. In the Federal 
Register of April 28, 1992 (57 FR 17950), FDA published regulations for 
ANDA's, including requirements for adverse experience reporting for 
drugs with approved ANDA's and abbreviated antibiotic drug applications 
(AADA's). Under Sec. 314.98 (21 CFR 314.98), any applicant with an 
approved ANDA or AADA is required to comply with the requirements of 
Sec. 314.80 regarding the reporting and recordkeeping of adverse 
experiences. In the Federal Register of October 27, 1994 (59 FR 54034), 
FDA finalized regulations for adverse experience reporting for licensed 
biological products. Under Sec. 600.80(c)(1)(ii), manufacturers of 
licensed biological products are required to submit expedited increased 
frequency reports for any significant increase in frequency of an 
adverse experience that is both serious and expected.
    Under Secs. 310.305(c)(4), 314.80(c)(1)(ii) and (c)(1)(iii), and 
600.80(c)(1)(ii) and (c)(1)(iii), applicants and manufacturers, 
packers, and distributors, including licensed manufacturers, are 
required to review periodically (at least as often as the periodic 
reporting cycle) 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. For 
drugs with an approved NDA or ANDA, or licensed biological products, 
the reporting interval is quarterly in the first 3 years of marketing 
and annually thereafter (Secs. 314.80(c)(2) and 600.80(c)(2)), while 
for marketed prescription drugs without an approved NDA or ANDA, the 
reporting interval is annually (Sec. 310.305(c)(4)). Operationally, 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). Reporting is 
adjusted by the ratio of estimated drug use for the reporting interval 
to that of the comparison interval. If the number of reports received 
during the reporting interval is less than four, an increased frequency 
report is not required (see CDER's ``Guideline for Postmarketing 
Reporting of Adverse Drug Experiences,'' March 1992 and/or CBER's 
``Guideline for Adverse Experience Reporting for Licensed Biological 
Products,'' October 1993).
    These regulations are intended to ensure that applicants and 
manufacturers, packers, and distributors, including licensed 
manufacturers, identify increases in the incidence of serious, labeled 
adverse experiences 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. FDA intended for these reports to detect 
increasing incidences of serious, labeled adverse experiences that were 
not anticipated from premarketing clinical trials and that would 
necessitate labeling changes or other regulatory actions.
    FDA is proposing to amend its postmarketing expedited adverse 
experience reporting regulations by revoking the requirement for 
expedited increased frequency reports in Secs. 310.305(c)(4), 
314.80(c)(1)(ii), and 600.80(c)(1)(ii). This action would not

[[Page 55604]]

affect the requirement for expedited reporting of all serious, 
unexpected adverse experiences. Applicants and manufacturers, packers, 
and distributors, including licensed manufacturers, 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). FDA is also proposing to revoke the definition 
of ``increased frequency'' in Secs. 310.305(b)(5), 314.80(a), and 
600.80(a). This term is defined as an increase in the rate of 
occurrence of a particular adverse drug (or biological product) 
experience, e.g., an increased number of reports of a particular 
adverse drug (or biological product) experience after appropriate 
adjustment for drug (or biological product) exposure.
    In the Federal Register of October 27, 1994 (59 FR 54046), FDA 
proposed to amend, among other things, its regulations for periodic 
postmarketing reporting of adverse experiences for human drug and 
licensed biological products in Secs. 314.80(c)(2) and 600.80(c)(2). 
FDA proposed to amend the requirements for the content of periodic 
adverse experience reports by adding a section for overall safety 
evaluation. This section 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. FDA based this proposed revision on recommendations 
developed by the World Health Organization's Council for International 
Organizations of Medical Sciences (CIOMS) Working Group II. 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 draft guideline for periodic 
reporting entitled ``Clinical Safety Data Management: Periodic Safety 
Update Reports for Marketed Drugs'' (the ICH E2C guideline). The ICH 
E2C draft guideline, published in the Federal Register of April 5, 1996 
(61 FR 15352), 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. Thus, under this 
guideline, regulatory authorities would 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 after consensus is reached by ICH on a final guideline on 
postmarketing periodic safety update reports.

III. FDA's Experience With Increased Frequency Reports

    FDA has found that increased frequency reports have rarely prompted 
regulatory action during the time that the agency has been receiving 
such reports. These reports have been of little value in identifying 
increased incidences of serious, labeled experiences.
    From January 1, 1987, to May 31, 1995, FDA received approximately 
1,800 increased frequency reports. Over this period, FDA identified 
only a small number of drug/biological product safety problems where 
increased frequency reports played a role in risk assessment that 
resulted in regulatory action, three examples of which are given below. 
For each of the examples, the safety problems may have been detected in 
other safety reports required by FDA such as periodic adverse 
experience reports, field alert reports, or annual reports.
    One safety problem involved buprenorphine, a narcotic agonist-
antagonist analgesic approved in 1985 and labeled at that time as 
causing less respiratory depression than morphine. In 1986, FDA 
received an increased frequency report for respiratory depression with 
buprenorphine, prompting careful monitoring. This resulted in labeling 
changes and warnings that buprenorphine may depress respiration in a 
manner equivalent to an equianalgesic dose of morphine.
    A second safety problem involved an increased frequency report of 
neurotoxicity caused by a medication administration error when 
vincristine, an antineoplastic, was mistaken for methotrexate, another 
antineoplastic, and administered intrathecally. This resulted in the 
repackaging of vincristine to avoid confusion with methotrexate.
    A third safety problem involved Orthoclone OKT3, a monoclonal 
antibody used as an immunosuppressant for treatment of acute allograft 
rejection in renal, cardiac, and hepatic transplant patients. In 1990, 
FDA received an increased frequency report for anaphylaxis and serum 
sickness associated with Orthoclone OKT3. Two of three anaphylaxis 
patients were undergoing second courses of therapy. This report 
resulted in labeling amendments including the addition of a boxed 
warning on the risk of anaphylaxis after any dose and a boldface 
paragraph providing further details.
    FDA has also received increased frequency reports for adverse 
experiences that were previously identified as potential problems in 
premarketing clinical trials. For example, based on FDA's review of NDA 
data on ketorolac, an analgesic, the agency was aware of its potential 
for causing upper gastrointestinal bleeding (UGIB) and renal failure 
when given at higher doses. Following approval in 1989, the sponsor was 
asked to conduct a postmarketing safety study. Meanwhile, in 1992, FDA 
received increased frequency reports for UGIB and renal failure. 
However, a causal relationship between these adverse experiences and 
ketorolac could not be established from the increased frequency reports 
because of uncertainties caused by the underlying illness, concomitant 
drug administration, and the indication (postsurgical analgesia) for 
which ketorolac was being used. Following a review of the postmarketing 
safety study, FDA required labeling changes to address the safety 
problems associated with ketorolac. Thus, the increased frequency 
reports did not contribute to the risk assessment that resulted in this 
regulatory action.
    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. For such unexpected 
reactions, warnings can be added to the labeling without quantifying 
the incidence of the reaction. Warnings for expected adverse reactions 
(such as those obtained in increased frequency reports) are already in 
the labeling. In addition, risk information regarding incidence cannot 
generally be ascertained from an increased frequency report but 
requires controlled studies.

IV. Limitations of Increased Frequency Reports

    Increased frequency information is derived from incidence rates. An 
incidence rate is estimated by dividing the number of adverse 
experiences (numerator) by the number of persons exposed to a drug or 
biological product (denominator). For increased frequency reports, 
applicants and manufacturers, including licensed manufacturers,

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compare incidence rates estimated for the reporting interval with rates 
estimated for the previous reporting interval.
    FDA is aware of several factors that affect the accuracy of 
incidence rates. First, health care providers do not report all adverse 
experiences. The percentage of adverse experiences reported is unknown 
and varies unpredictably over time. Hence, the numerator cannot be 
reliably estimated. Second, the number of persons exposed to a drug or 
biological product during a reporting period is not precisely known; it 
is estimated from sales or production data. The lag time between 
production or sales by the manufacturer and consumption by patients can 
vary, thus adding further distortion to comparisons between reporting 
periods. Hence, the denominator is not always reliably estimated. 
Third, adverse experience reports may be used for calculating increased 
frequencies even though the suspect drug or biological product did not 
necessarily cause the adverse experience. Assessment of causality is 
frequently limited by incomplete data and uncertainty caused by the 
underlying illness, indication, or other drug exposures. Fourth, 
increased frequency calculations are based on the dates when adverse 
experience reports are received by the sponsor. If health care 
providers hold adverse experience reports and submit them all at one 
time, there can be a cluster of adverse experiences that fall into one 
reporting period creating a false-positive signal.
    Thus, the reliability of increased frequency reports is limited 
because of the difficulty in accurately estimating incidence rates. FDA 
has concluded that these concerns make it difficult to rely on 
increased frequency reports as a tool for identifying important safety 
problems requiring labeling changes or other regulatory action.

V. Public Comments on Increased Frequency Report Requirements

    In the October 27, 1994, proposed rule, FDA proposed to amend its 
regulations for expedited and periodic premarketing and postmarketing 
safety reporting of adverse experiences for human drug and biological 
products. The proposal included revisions to the postmarketing 
increased frequency report requirements under Secs. 310.305, 314.80, 
and 600.80. FDA proposed to amend these requirements by altering the 
time period for submitting increased frequency reports from 15 working 
days to 15 calendar days, and by revising the reporting interval. Under 
proposed Sec. 310.305, this interval would be increased from at least 
once a year to at least twice a year, and, under proposed Secs. 314.80 
and 600.80, this interval would be revised from at least quarterly for 
the first 3 years of marketing and annually thereafter to at least 
twice a year. FDA did not receive any comments on these proposed 
increased frequency reporting revisions.
    However, FDA received comments from 12 pharmaceutical companies and 
1 individual regarding other aspects of the current increased frequency 
reporting requirements that were not within the scope of the October 
27, 1994, proposal. FDA considered these comments in developing the 
current proposal.
    Nine comments opposed the requirement for increased frequency 
reports. One comment stated that there is ``common agreement'' that 
increased frequency assessments have not provided information on 
significant safety risks to patients. Another comment stated that it 
was not aware of any important safety signal that had been identified 
by an increased frequency report. One comment stated that there is no 
benefit to be gained from increased frequency assessments, especially 
for drugs that are not the subject of an approved application. Another 
comment noted that applicants have available other mechanisms to 
identify and characterize changes in the nature and frequency of 
adverse experiences reported to them. Another comment noted that no 
provision exists for increased frequency calculations in the 
recommendations of either ICH or CIOMS. Three comments recommended that 
FDA revoke the requirement unless the agency can show that these 
reports have produced safety information not otherwise obtainable (for 
example, important labeling revisions or the initiation of other 
communication to enhance the safe and effective use of drugs).
    One comment opposed increased frequency reports of therapeutic 
failure for over-the-counter (OTC) drugs subject to an approved 
application. The comment contended that such reports are generally not 
unexpected from consumers of OTC drugs and are unlikely to involve 
serious outcomes. The comment requested that FDA limit these reports to 
prescription drugs and to cases involving serious consequences. Another 
comment requested that FDA limit increased frequency reports of 
therapeutic failure to U.S. reports.
    One comment requested clarification of the methodology for 
estimating increased frequency rates because the FDA guideline 
describing these methods is vague. The comment noted that the 
``Guideline for Postmarketing Reporting of Adverse Drug Experiences'' 
refers to the use of either an arithmetical or statistical method of 
analysis without specifying either method. The comment said that use of 
the arithmetic method can produce an increased frequency calculation 
that would not be replicated by the statistical method (and conversely 
for the statistical method), thus leading to conflicting 
interpretations of increased frequency. Another comment requested 
clarification of the sources of data to be used for increased frequency 
analyses because of confusion caused by Secs. 314.80(d)(1) and 
600.80(d)(1), which state that increased frequency reports required 
under Secs. 314.80(c)(1)(ii) and 600.80(c)(1)(ii) apply only to reports 
found in scientific and medical journals, either as the result of a 
formal clinical trial or from epidemiological studies or analyses of 
experience in a monitored series of patients.

VI. Request for Comments

    Interested persons may, on or before January 13, 1997, 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.

VII. 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.

VIII. Paperwork Reduction Act of 1995

    This proposed 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).

IX. 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,

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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 Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because this proposed rule would simplify and 
streamline current requirements, 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.

X. Effective Date

    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.

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, it is proposed that 21 CFR parts 310, 
314, and 600 be 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), 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) In order 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, in order to avoid unnecessary duplication in the submission to 
FDA, 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

[[Page 55607]]

product whose name appears on the label of a licensed biological 
product as a manufacturer, packer, distributer, 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: October 17, 1996.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 96-27593 10-25-96; 8:45 am]
BILLING CODE 4160-01-F