Guidance
for Industry: Postmarketing Adverse Experience Reporting for Human Drug and Licensed
Biological Products -- Clarification of What to Report
I. INTRODUCTION
The FDA has undertaken
a major effort to clarify and revise its regulations regarding
pre- and postmarketing safety reporting requirements for
human drug and biological products. With regard to the
postmarketing safety reporting regulations for human drug
and licensed biological products, the Agency published
a proposed rule in the Federal Register of October
27, 1994 (59 FR 54046), to amend these requirements,
as well as others, to implement international standards,
and to facilitate the reporting of adverse experiences.
The FDA is still considering comments submitted in response
to this proposed rule and will be finalizing the proposed
amendments based on those comments as well as on recommendations
developed by the International Conference on Harmonisation
of Technical Requirements for Registration of Pharmaceuticals
for Human Use (ICH) and by the World Health Organization's
Council for International Organizations of Medical Sciences
(CIOMS).
In response to the President's
regulatory reinvention initiative, which directed departments
and agencies to eliminate or modify regulations that are
outdated or otherwise in need of reform, the FDA recently
published a final rule in the Federal Register (62 FR 34166;
June 25, 1997). This final rule revokes the postmarketing
safety reporting requirement to submit expedited increased
frequency reports for human drug and licensed biological
products.
At this time, the Agency
is considering recommendations recently developed by ICH
and plans to propose additional amendments to its postmarketing
safety reporting regulations. Throughout this effort, the
Agency intends to develop guidances for industry to provide
recommendations on how industry can best fulfill the postmarketing
safety reporting requirements. The FDA plans to prepare
a single consolidated guidance document on this topic once
the process is concluded.
Over the years, changes
in marketing practices in the United States have led to
expanded contacts between drug and biologics manufacturers
and consumers. This has resulted in the acquisition of
new types of safety information not previously obtained
by industry. In addition, the FDA has noted an increase
in the number of individual case reports of adverse experiences
that are submitted to the Agency with insufficient data
to begin the evaluation of a report. Overall, the largest
increase has been in the number of reports submitted on
adverse experiences classified as nonserious and labeled (i.e.,
listed in the approved labeling for marketed products).
This guidance for industry
has been developed to clarify what information should be
obtained before an individual case of an adverse experience
should be considered for submission to the FDA and how
safety information from solicited contacts with patients
should be handled. The guidance also informs applicants
and licensed manufacturers that the FDA is willing to entertain
waiver requests for periodic submission of individual case
reports for adverse experiences that are determined to
be nonserious and labeled. The Agency believes that the
recommendations in this guidance document will improve
the quality of postmarketing safety reports and decrease
the industry's current safety reporting burden without
jeopardizing public health.
This guidance document
should be used in conjunction with CDER's Guideline
for Postmarketing Reporting of Adverse Drug Experiences (March
1992) and CBER's Guideline for Adverse Experience Reporting
for Licensed Biological Products (October 1993). Hard
copies of the guidances of March 1992 and October 1993
are available from CDER's Drug Information Branch and CBER's
Office of Communication, Training and Manufacturers Assistance,
respectively (addresses above). Electronic versions of
these guidances are also available on the Internet at http://www.fda.gov/medwatch/report/mfg.htm.
II. DATA ELEMENTS
FOR A SAFETY REPORT
Applicants of approved
new drug applications (NDA), abbreviated new drug applications
(ANDA), and antibiotic applications, manufacturers of marketed
prescription drugs for human use without approved NDAs
or ANDAs, and licensed manufacturers of approved biologic
product license applications are required to report adverse
experiences to the FDA under 21 CFR 310.305, 314.80, 314.98,
and 600.80. Before considering any clinical incident
for submission to the FDA in an expedited or periodic safety
report, applicants, manufacturers, and licensed manufacturers
should have knowledge of the following four data elements:
a. an identifiable patient;
b. an identifiable reporter;
c. a suspect drug or
biological product; and
d. an adverse event or fatal outcome.
In other words, if any
of these basic elements remain unknown after being actively
sought by the applicant, manufacturer, or licensed manufacturer,
a report on the incident should not be submitted to the
FDA because reports without such information make interpretation
of their significance difficult, at best, and impossible,
in most instances. The applicant, manufacturer, and licensed
manufacturer should maintain records of their efforts to
obtain the basic elements for an individual case in their
corporate drug or biological product safety files. If reports
lacking any of the four basic elements are submitted to
the FDA, they will be returned to the reporter marked "insufficient
data for a report." If the reporter is an applicant,
manufacturer, or licensed manufacturer, they also will
be reminded to actively seek the basic elements for the
report and to maintain a record of such efforts.
With regard to an
identifiable patient, reports of the type "some
patients got anaphylaxis" should be excluded until
further information about the patients is obtained; a
report stating that "an elderly woman had anaphylaxis" or "a
young man experienced anaphylaxis" should be included
because there is enough information to suspect that specific
patients were involved. Patients should not be identified
by name or address; instead, the applicant, manufacturer,
and licensed manufacturer should assign a code (e.g.,
patient initials) to each report. An adverse event should
at a minimum consist of signs (including abnormal laboratory
findings), symptoms, or disease diagnosis for purposes
of reporting. Thus, a report stating that a patient "experienced
unspecified injury," or a patient "suffered
irreparable damages" should not be included until
more specific information about the adverse event can
be determined. With regard to fatal outcome, the
FDA expects applicants, manufacturers, and licensed manufacturers
to submit reports of patient deaths even if the adverse
event is unknown.
The four basic elements
are consistent with international harmonization initiatives.
For more information on these initiatives, refer to section
III.B.3 of the International Conference on Harmonization; Guideline
on Clinical Safety Data Management: Definitions and Standards
for Expedited Reporting (ICH E2A document; 60 FR 11284;
March 1, 1995) and the definition of Minimum Standard
of Information in the final report of CIOMS Working
Group I (International Reporting of Adverse Drug Reactions,
1990) or the definition of CIOMS Reportable Case Histories
(CIOMS Report) in the final report of CIOMS Working
Group II (International Reporting of Periodic Drug-Safety
Update Summaries, 1992).
III. INDIVIDUAL CASE
REPORTS BASED ON SOLICITED INFORMATION
The FDA has determined,
for purposes of postmarketing safety reporting under 21
CFR 310.305, 314.80, 314.98, and 600.80, that information
concerning potential adverse experiences derived during
planned contacts and active solicitation of information
from patients (e.g., company-sponsored patient support
programs, disease management programs) should be handled
as safety information obtained from a postmarketing study.
Applicants, manufacturers, and licensed manufacturers should
not report safety information obtained through these types
of patient contacts unless the adverse event meets the
regulatory definitions of serious and unexpected and
there is a reasonable possibility that the drug or biological
product caused the adverse experience (see 21 CFR 310.305(c)(1)(ii),
314.80(c)(2)(iii), 314.80(e), 600.80(c)(2)(iii), and 600.80(e)).
IV. INDIVIDUAL CASE
REPORTS OF NONSERIOUS, LABELED ADVERSE EXPERIENCES
The FDA encourages applicants
and licensed manufacturers to submit requests to the Agency
(address below), under 21 CFR 314.90(a) and 600.90(a),
to waive the requirement to submit Form FDA-1639 or FDA
Form 3500A to the FDA for each adverse experience that
is determined to be both nonserious and labeled (21 CFR
314.80(c)(2) and 600.80(c)(2)). As part of this waiver
request, applicants and licensed manufacturers should indicate
that individual case reports of adverse experiences with
the four basic elements (see section II) that are determined
to be both nonserious and labeled would be held in their
corporate drug or biologic product safety files. Applicants
and licensed manufacturers should also indicate that upon
request by the FDA, they would submit one or more of these
reports to the Agency within five calendar days after receipt
of the request.
As described in the guidances
of March 1992 and October 1993, the FDA expects applicants
and licensed manufacturers to continue to include in their
periodic reports a listing by body system of all adverse
experience terms and counts of occurrences for nonserious,
labeled adverse experiences.
At this time, the FDA
does not intend to grant licensed manufacturers waiver
requests for new biological molecular entities within one
year of licensure or for blood products, plasma derivatives,
or vaccines. The Agency believes that it is important to
continue periodic review of all reports of adverse experiences
for these products to identify safety problems due to lot-to-lot
variations and to monitor the safety of new biological
products.
Applicants of marketed
human drug products should submit written waiver requests,
under 21 CFR 314.90(a), to:
Dr. Murray Lumpkin
Deputy Center Director for Review
Management
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane, HFD-2
Rockville, MD 20857
Licensed manufacturers
of human licensed biological products should submit written
waiver requests, under 21 CFR 600.90(a), to:
Dr. Marcel Salive
Division of Biostatistics & Epidemiology
Center for Biologics Evaluation and
Research
Food and Drug Administration
1401 Rockville Pike, HFM-220
Rockville, MD 20852-1448