[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]
=======================================================================
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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regulations and to eliminate or modify those that are outdated or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,
[[Page 55605]]
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,
[[Page 55606]]
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
