[Federal Register Volume 59, Number 207 (Thursday, October 27, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-26483]


[[Page Unknown]]

[Federal Register: October 27, 1994]


_______________________________________________________________________

Part III





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Part 20, et al.




Adverse Experience Reporting Requirements for Human Drug and Licensed 
Biological Products; Proposed Rule
DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 20, 310, 312, 314, and 600

[Docket No. 93N-0181]

 
Adverse Experience Reporting Requirements for Human Drug and 
Licensed Biological Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
its current adverse experience reporting regulations for human drug 
products and for licensed biological products to provide consistency 
with the elements of FDA Form 3500A and require the use of this new 
reporting form; revise certain definitions and reporting periods and 
formats as recommended by the International Conference on Harmonization 
of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) and the World Health Organization's Council for International 
Organizations of Medical Sciences (CIOMS); require applicants or 
manufacturers, packers, and distributors to develop written procedures 
for monitoring and reporting adverse experiences; state that reports of 
adverse experiences that are forwarded by FDA to the applicant or 
manufacturer, packer, and distributor should not be resubmitted to the 
agency; and make other revisions to the regulations to provide 
uniformity in adverse experience reporting for human drug products and 
licensed biological products. These changes would simplify and 
facilitate the reporting of adverse experiences and would enhance 
agencywide consistency in the collection of postmarketing adverse 
experience data. In addition, FDA is proposing to amend the 
requirements for clinical study design and conduct and the sponsor 
reporting requirements in the investigational new drug application 
(IND) regulations. These amendments are intended to provide more 
complete and accurate information that would enable sponsors, 
investigators, and FDA to determine serious toxicities of 
investigational drugs more expeditiously during clinical studies.

DATES: Submit written comments by January 25, 1995. 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, rm. 1-23, 12420 Parklawn Dr., 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:

    Concerning human drug products: Howard P. Muller, Center for Drug 
Evaluation and Research (HFD-362), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-1049.
    Concerning licensed biological products: Paula S. McKeever, Center 
for Biologics Evaluation and Research (HFM-635), Food and Drug 
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-594-3074.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of June 3, 1993 (58 FR 31596), FDA 
announced the availability of a new form for reporting adverse events 
and product problems with medications, devices, and other FDA-regulated 
medical products. This form is available in two versions. One version 
of the form (FDA Form 3500) is to be used by health professionals for 
voluntary reporting; the other version of the form (FDA Form 3500A) is 
to be used by applicants or manufacturers (including licensed 
manufacturers of licensed biological products), and other persons 
subject to mandatory reporting requirements under FDA regulations. 
Under existing regulations, drug manufacturers, packers, and 
distributors and applicants for new drug products and generic drug 
products must report adverse events under Sec. Sec. 310.305 and 314.80 
(21 CFR 310.305 and 314.80). Elsewhere in this issue of the Federal 
Register, FDA is issuing a final rule establishing new Sec. 600.80. 
This section makes licensed manufacturers of biological products 
subject to certain reporting requirements.
    The new form is part of FDA's Medical Products Reporting Program 
(MedWatch) and is designed to encourage and facilitate the reporting of 
adverse events and product problems for most FDA-regulated human 
medical products by the entire health care community, including 
manufacturers, distributors, user facilities, and health professionals. 
FDA issued the new form to simplify and consolidate the reporting of 
suspected adverse events and product problems with human drug products, 
biologics, and medical devices, as well as the reporting of adverse 
events with other FDA-regulated medical products, such as dietary 
supplements. FDA has found that, under the current system, there is 
some confusion about what to report to the agency and that the existing 
assortment of reporting forms and systems can interfere with the 
efficient reporting of suspected problems. FDA has attempted to clarify 
and simplify adverse event reporting with the new form by eliminating 
redundant or nonessential elements and by clarifying those areas that 
have caused confusion.
    FDA Form 3500A replaces current Form FDA-1639, as well as most 
other adverse event and product problem reporting forms currently 
required by the agency. Adverse events associated with vaccines will 
continue to be reported through the FDA and Centers for Disease Control 
and Prevention Vaccine Adverse Event Reporting System (VAERS). FDA is 
proposing to amend the adverse experience reporting requirements for 
human drug products and for licensed biological products to be 
consistent with the elements of FDA Form 3500A.
    In developing FDA Forms 3500 and 3500A, the agency considered 
several recommendations from ICH and CIOMS. These organizations were 
formed to facilitate international consideration of issues, 
particularly safety issues, concerning the use of both foreign and 
domestic data in the development and use of drugs and biological 
products. ICH has worked to promote the harmonization of technical 
requirements for the registration of pharmaceutical products among 
three regions: The European Union, Japan, and the United States. ICH 
has prepared a draft guideline specific to parts of this issue 
entitled: ``Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting.'' In the Federal Register of July 9, 1993 (58 
FR 37408), FDA published this draft guideline for public comment. 
Several CIOMS working groups have worked to coordinate and standardize 
the international reporting of postmarketing adverse drug reactions by 
pharmaceutical manufacturers to regulatory authorities. CIOMS Working 
Group II has proposed an international system of standardized time 
intervals, formats, and inclusion criteria in order to lessen confusion 
and reduce preparation time among manufacturers and to enable them to 
report postmarketing adverse experiences more rapidly, efficiently, and 
effectively (Refs. 1 and 2). FDA believes that many changes recommended 
by CIOMS and ICH would result in more effective reporting of serious 
adverse experiences to regulatory authorities worldwide. FDA is 
proposing to amend the adverse experience reporting requirements for 
human drug products and licensed biological products in part to be 
consistent with certain standardized definitions, procedures, and 
formats proposed by these international organizations.
    FDA is also proposing to amend the requirements for clinical study 
design and conduct and the sponsor reporting requirements in the IND 
regulations. These amendments are intended to provide more complete and 
accurate information that would enable sponsors, investigators, and FDA 
to determine serious toxicities of investigational drugs more 
expeditiously during clinical studies. A clinical study of fialuridine 
(FIAU) resulted in several instances of severe liver and pancreatic 
injury and five deaths, beginning in June 1993. This incident prompted 
FDA to establish a task force to see whether the data available before 
the study gave any suggestion of the serious toxicity that emerged, and 
whether some differences in process or behavior by investigators and 
sponsors might have made it possible or more likely for them to have 
anticipated the toxicity in the 1993 study. The proposed IND amendments 
contained in this document are largely the result of recommendations by 
this task force.

II. Description of the Proposed Rule

A. Replacement of Form FDA-1639 and How to Obtain Copies of FDA Form 
3500A

    FDA's existing regulations at 21 CFR 20.112, 310.305, and 314.80 
refer to Form FDA-1639. The agency is proposing to amend these 
regulations to replace references to Form FDA-1639 with new FDA Form 
3500A. This change is necessary because new FDA Form 3500A replaces 
Form FDA-1639 (58 FR 31596).
    The existing regulations at Secs. 310.305(d)(4) and 314.80(f)(4)) 
also provide an address where a person may obtain copies of Form FDA-
1639. FDA is proposing to amend these regulations to state where a 
person can obtain copies of FDA Form 3500A. Ten or fewer copies of FDA 
Form 3500A and a copy of the instructions for completing the form can 
be obtained from the Division of Epidemiology and Surveillance (HFD-
730), Center for Drug Evaluation and Research, Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857. Large numbers 
of copies (greater than 10 copies) may be obtained by writing to the 
Consolidated Forms and Publications Distribution Center, Washington 
Commerce Center, 3222 Hubbard Rd., Landover, MD 20785.

B. Definitions of ``Data Lock-Point'' and ``International Birth Date''

    FDA is proposing to amend Secs. 314.80(a) and 600.80(a) to define 
the terms ``data lock-point'' and ``international birth date.'' The 
``data lock-point'' is the end of the reporting period (cutoff date) 
for data to be incorporated into a specific postmarketing adverse 
experience periodic report. On this date, the data available to the 
reporter are held for review and evaluation by the applicant or 
licensed manufacturer prior to being submitted to FDA. The 
international birth date is the date that the first regulatory 
authority in the world approved the human drug or biological product 
for marketing. As explained further in section II.E. of this document, 
each 6-month anniversary of the international birth date is the data 
lock-point for data to be incorporated into a specific postmarketing 
adverse experience periodic report.
    The proposed rule would define these terms because they describe 
the standardized international reporting period developed by CIOMS for 
submitting postmarketing adverse experience reports. CIOMS developed 
this standardized reporting period to lessen confusion and to enable 
applicants and licensed manufacturers to prepare and submit similar 
reports of adverse experiences to regulatory authorities. It would also 
reduce preparation time among applicants and licensed manufacturers 
because it eliminates varying due dates presently required for 
submitting postmarketing adverse experience reports to regulatory 
authorities worldwide. FDA believes the CIOMS reporting schedule, which 
decreases reporting rates currently required by FDA for drug and 
licensed biological products for the first 3 years of marketing from 
every 3 months to every 6 months and increases it thereafter from every 
12 months to every 6 months, permits adequate time for reporters to 
make periodic submissions to regulatory authorities. In addition, the 
agency believes that the proposed reporting frequency is sufficient to 
notify FDA of potential postmarketing safety problems that do not 
require expedited reporting.

C. Definition of ``Serious''

    FDA's existing adverse experience reporting regulations (21 CFR 
310.305(b)(4), 312.32(a), 314.80(a), and 600.80(a)) define a serious 
adverse experience as one that is ``fatal or life-threatening, is 
permanently disabling, requires inpatient hospitalization, or is a 
congenital anomaly, cancer, or overdose.'' Consistent with new FDA Form 
3500A and with recommendations by the ICH and CIOMS, the proposed rule 
would amend this definition to read as follows:
    Serious means an adverse drug experience occurring at any dose 
that is fatal or life-threatening, results in persistent or 
significant disability/incapacity, requires or prolongs inpatient 
hospitalization, necessitates medical or surgical intervention to 
preclude permanent impairment of a body function or permanent damage 
to a body structure, or is a congenital anomaly.
    The agency is proposing to remove ``cancer'' from the definition 
because cancer would most often be reported under the other broader 
elements in the definition. For example, cancer may be reported as 
life-threatening or requiring inpatient hospitalization. Other diseases 
or conditions that may be life-threatening or require hospitalization, 
such as heart disease or myocardial infarction, have not been 
identified as separate elements in previous definitions, and the agency 
believes it is not necessary to single out cancer.
    The proposed amendment would also remove ``overdose'' from the 
definition of serious. Reports of overdoses that had serious outcomes 
would still be reported under the other broader elements in the 
definition. Reports of overdoses that did not lead to outcomes defined 
as serious would provide the agency with less critical safety 
information.
    By adding the phrase ``occurring at any dose'' after ``adverse drug 
experience'' in the definition, the agency will ensure that a serious 
adverse experience at any dose, whether it is the labeled dose or a 
different dose, including an overdose or an underdose, should be 
reported.
    FDA is also proposing to clarify the phrase ``is permanently 
disabling'' by substituting ``results in persistent or significant 
disability/incapacity.'' This change is intended to clarify that a 
disability need not be permanent to be considered a serious adverse 
experience.
    The proposed amendments would also modify the phrase ``requires 
inpatient hospitalization'' to read ``requires or prolongs inpatient 
hospitalization.'' This change is intended to cover those situations 
where a serious adverse experience occurs while the patient is already 
hospitalized, and the adverse experience prolongs the patient's 
hospital stay.
    FDA is also proposing to add the phrase ``necessitates medical or 
surgical intervention to preclude permanent impairment of a body 
function or permanent damage to a body structure.'' The agency believes 
such events should be considered serious adverse experiences and should 
be reported. This change is also consistent with ICH's proposed 
definition of a serious adverse event. FDA notes that a serious adverse 
experience would not include the discontinuation of therapy, changes in 
dosage, or routine treatment with a prescription medication.

D. Definitions of ``Disability'' and ``Life-Threatening''

    The proposed rule would amend Secs. 310.305(b), 314.80(a), and 
600.80(a) to define the terms ``disability'' and ``life-threatening.'' 
These terms further explain what constitutes a serious adverse 
experience. ``Disability'' means a substantial disruption of one's 
ability to carry out normal life functions. ``Life-threatening'' means 
that the patient was, in the view of the initial reporter, at immediate 
risk of death from the adverse experience as it occurred. It does not 
include an adverse experience that, had it occurred in a more serious 
form, might have caused death. For example, product-induced hepatitis 
that resolved without evidence of hepatic failure would not be 
considered life-threatening even though hepatitis of a more severe 
nature can be fatal. Similarly, an allergic reaction resulting in 
angioedema of the face would not be life-threatening, even though 
angioedema of the larynx, allergic bronchospasm, or anaphylaxis can be 
fatal. FDA believes these definitions will help enable reporters to 
determine when a serious adverse experience occurs.

E. Periodic Adverse Experience Reports

    Current regulations (Secs. 314.80(c)(2)(i) and 600.80(c)(2)(i)) 
require the submission of periodic postmarketing reports at quarterly 
intervals for 3 years from the date of approval of the application, and 
then annually. Quarterly reports must be submitted within 30 days of 
the close of the quarter (the first quarter beginning on the date of 
U.S. approval of the application); each annual report must be submitted 
within 60 days of the date of U.S. approval of the application.
    FDA is proposing to revise this schedule by requiring the 
submission of periodic postmarketing adverse reaction reports every 6 
months. The first 6-month anniversary of the international birth date 
after the application is approved in the United States is the data 
lock-point for the first periodic reporting term. Each subsequent 6-
month anniversary of the international birth date is the data lock-
point for subsequent periodic reporting terms for that particular 
product. The proposed rule would require periodic reports to be 
submitted to FDA within 45 days after the data lock-point. For example, 
a product approved by FDA, or licensed, if a biological product, on 
June 15, with an international birth date of April 1, would have its 
first data lock-point on October 1, which is less than 6 months after 
FDA approval, but which is the 6-month anniversary of the international 
birth date. Therefore, the first periodic report would be for the 
period of June 15 to October 1 and would be due at FDA by November 14. 
The second periodic report would cover October 2 to April 1 and would 
be due to the agency no later than May 15.
    The proposed rule would create the same reporting schedule based on 
the international birth date and data lock-point for licensed 
biological product distribution reports under Sec. 600.80(c)(3).
    This new reporting schedule is consistent with the standardized 
international reporting period proposed by the CIOMS II Working Group. 
This working group has recommended that all international regulatory 
authorities accept the same reporting schedule in order to lessen 
confusion and reduce preparation time by manufacturers, rather than the 
current system of varying due dates. FDA believes the CIOMS reporting 
schedule, which decreases reporting rates currently required by FDA for 
drug and licensed biological products for the first 3 years of 
marketing from every 3 months to every 6 months and increases reporting 
rates thereafter from every 12 months to every 6 months, permits 
adequate time for reporters to make nonexpedited submissions to 
regulatory authorities. In addition, FDA believes that the proposed 
reporting frequency is sufficient to alert the agency to potential 
postmarketing safety problems that are not within the categories 
requiring 15-day ``Alert reports.''
    Applicants and licensed manufacturers who wish to submit periodic 
postmarketing adverse experience reports at different intervals could, 
under proposed Secs. 314.80(c)(2)(i) and 600.80(c)(2)(i), submit a 
request for a waiver under 21 CFR 314.90 or 600.90 to alter the 
reporting intervals for these periodic reports.
    Proposed Secs. 314.80(c)(2)(i) and 600.80(c)(2)(i) would also amend 
the reporting requirements for periodic postmarketing adverse 
experience reports to state that, in cases where the applicant or 
licensed manufacturer has received no reports of adverse experiences 
during a reporting period, the applicant or licensed manufacturer 
should submit a copy of the current approved labeling and a letter to 
the agency in place of a periodic postmarketing adverse experience 
report. The letter should identify the product, the application number, 
and the reporting period, and state that no adverse experience reports 
were received during that reporting period.
    Sections 314.80(c)(2)(ii) and 600.80(c)(2)(ii) set forth the 
contents currently required for a periodic report: (1) A narrative 
summary and analysis of the information in the report and an analysis 
of the 15-day postmarketing Alert reports submitted during the 
reporting interval; (2) a report describing each adverse experience not 
previously reported; and (3) a history of actions taken since the last 
periodic report. FDA is proposing to amend these regulations to provide 
a more extensive list of contents for a periodic postmarketing adverse 
experience report, as follows:
1. Title Page, Table of Contents, and Introduction
    This section would provide a summary of the periodic report with 
page references to detailed data and information.
2. Applicant's Core Safety Data Sheet
    The applicant's core safety data sheet would be a document prepared 
by the applicant that contains all relevant safety information, 
including adverse drug experiences, which the applicant believes should 
be listed for the drug in all countries where the drug is marketed. It 
may be used by the applicant as the reference document by which an 
adverse drug experience is judged to be expected or unexpected for 
purposes of this postmarketing periodic report. For all other 
determinations of whether an adverse drug experience is expected or 
unexpected, the definition in Secs. 314.80(a) or 600.80(a) would apply.
    FDA recognizes that the postmarketing periodic report may be 
submitted by the applicant to multiple countries and the product may 
have different approved labels in the different countries. The use of 
the applicant's core safety data sheet as the reference document for 
determining whether an adverse drug experience is expected or not may 
result in some overreporting of unexpected adverse events that actually 
are expected by the U.S. approved product label. This is because the 
approved label for the United States may have more safety information 
included in it than the manufacturer's core safety data sheet.
    An applicant may also use the approved U.S. label as the reference 
by which expected and unexpected adverse drug experiences are 
determined for the postmarketing periodic report. If an applicant 
chooses to use the approved U.S. label for this purpose, it must 
clearly be stated in this section of the report. In all instances, if 
an adverse event is not listed in the U.S. label, but is in the 
manufacturer's core safety data sheet, this shall be clearly noted in 
the ``Overall safety evaluation'' (see section II.E.8. of this 
document).
    This section would also highlight clearly any changes and the 
reasons for the changes in the applicant's core safety data sheet since 
the previous postmarketing periodic report.
3. The Product's Marketing Status
    This section would contain, in tabular form, a chronological 
history of the marketing status of the product worldwide (all 
regulatory and marketing decisions affecting the product) from the date 
it was first approved through its current status. Approvals or 
applications voluntarily withdrawn for safety reasons would have to be 
included. The product would be listed by chemical (U.S. Adopted Names, 
international nonproprietary names, or proper name in accordance with 
``Chemical Abstracts Nomenclature Standards'') and brand name(s).
4. Regulatory Actions for Safety Reasons
    This section would identify in narrative form the reasons for 
significant regulatory authority or manufacturer-initiated actions 
taken anywhere in the world, or to be taken imminently, for safety 
reasons during the reporting period. This would include, for example, 
application withdrawal or license suspension or failure to renew, 
distribution restrictions, clinical trial suspension, labeling changes 
due to significant safety concerns, dosage modifications, or 
pharmaceutical changes.
5. Patient Exposure
    This section would include the product's domestic and foreign 
marketing distribution data during the reporting period. This 
information would be used to calculate the extent of patient exposure. 
The method used by the manufacturer to estimate patient exposure would 
always be described and would include the total number of dosage units 
of each dosage form and strength or potency (e.g., 100,000/5-milligram 
tablets, 50,000/10-milliliter vials).
6. Individual Case Histories
    These reports would be presented in line listing format with the 
following 10 columns: country, source, age, gender, dose, duration of 
treatment (prior to event), time to onset, description of reaction (as 
reported), outcome (e.g., fatal, resolved), other comments (e.g., 
manufacturer's report number). This format is consistent with that 
suggested by CIOMS. In addition, a tabular summary of the number of 
adverse events by body system may be included. The individual case 
reports would consist of adverse drug experiences that are: (a) 
Serious, unexpected reports from published or unpublished clinical 
studies where it has been concluded that there is a reasonable 
possibility that the drug or licensed biological product caused the 
adverse experience; (b) serious, expected or unexpected spontaneous 
adverse drug experience reports and nonserious, unexpected spontaneous 
adverse experience reports received directly by the applicant or 
licensed manufacturer from the initial reporter or received by the 
applicant or licensed manufacturer from a drug regulatory authority, 
both U.S. or foreign; and (c) serious, expected or unexpected 
individual published case histories and nonserious, unexpected 
individual published case histories. This section would end with an 
analysis by the reporter, in narrative form, of the cases submitted. 
The applicant or licensed manufacturer would also attach to the end of 
the postmarketing periodic report a completed FDA Form 3500A for all 
U.S. spontaneous reports of adverse experiences except those not to be 
included in the periodic report as specified in proposed 
Secs. 314.80(c)(1)(i) and (c)(1)(ii) and 600.80(c)(1)(i) and 
(c)(1)(ii), or those sent by FDA to the applicant or licensed 
manufacturer.
7. Safety Studies
    This section would analyze and discuss fully and critically all 
toxicological, clinical, and epidemiological studies containing 
important safety information.
8. Overall Safety Evaluation
    This section would provide critical analysis of the safety 
information provided in the periodic report as it pertains to serious 
unexpected reactions, increased frequencies of known toxicity, 
reactions listed in the manufacturer's core safety data sheet but not 
included in the U.S. label, drug or licensed biological product 
interactions, overdose, drug or licensed biological product abuse, 
experiences during pregnancy or lactation, chronic treatment, pediatric 
or geriatric treatment, and new safety issues. For each of these areas, 
any absence of significant information would be reported. The 
evaluation would indicate whether the safety profile of the product 
remains consistent with cumulative experience to date and with the 
previous manufacturer's core safety data sheet. The evaluation would 
specify any action recommended and the reasons for such 
recommendations.
9. Other Information
    This section would consist of important information received after 
the data lock-point. It may include significant new cases or followup 
data that affect the interpretation or evaluation of existing reports.
10. FDA Form 3500A
    This section would consist of a completed FDA Form 3500A for each 
spontaneous U.S. adverse drug experience not reported under paragraphs 
(c)(1)(i) and (c)(1)(ii) in Secs. 314.80 and 600.80.
11. Location of Adverse Experience Records
    This section would identify the current address(es), including 
street, city, State, and zip code, where all adverse experience reports 
and records are maintained.
    This revised list of contents for periodic postmarketing adverse 
experience reports is generally consistent with the international 
system of standardized postmarketing periodic reporting procedures and 
formats proposed by the CIOMS II Working Group. This standardization 
would allow applicants and licensed manufacturers to prepare a single 
postmarketing periodic report of adverse experiences for regulatory 
authorities worldwide. The agency also believes that the proposed rule 
would improve reporting and would enhance FDA's ability to monitor 
potential postmarketing safety problems.
    As a result of this proposed revised list of contents for periodic 
postmarketing adverse experience reports, FDA is proposing to remove 
Secs. 314.80(c)(2)(iii) and 600.80(c)(2)(iii). These sections state 
that periodic reporting does not apply to information obtained from 
postmarketing studies, reports in the scientific literature, and 
foreign marketing experience. The proposed revised list of contents 
would include such information.

F. IND Amendments

    FDA regulations governing the use of investigational drugs in 
clinical investigations are contained in part 312 (21 CFR part 312). In 
order to conduct a clinical investigation using an investigational 
drug, a sponsor must first submit an IND, described in Sec. 312.23, 
which contains, among other things, a description of the drug, the 
results of preclinical studies intended to show that the drug can be 
introduced into humans with reasonable safety, and a proposed protocol 
for the investigation. This protocol provides a description of all 
aspects of the study, including the identity and qualifications of the 
investigators conducting the study, procedures and criteria for 
selecting subjects, the amount of the drug to be administered, the 
duration of use, the observations to be made to assess the effects of 
the drug, and the clinical procedures, laboratory tests, and other 
measures carried out to minimize risk to the patient. After the IND 
becomes effective and the investigational drug is being administered to 
human subjects, the sponsor is required under Sec. 312.32 to make both 
telephone and written safety reports on serious and unexpected adverse 
experiences associated with the administration of the drug, as well as 
written reports only, on other serious adverse events associated with 
administration of the drug. Under current Sec. 312.33, the sponsor is 
also required to submit an annual report containing significant safety 
and other information. If FDA concludes that a study would place 
subjects at unreasonable and significant risk, FDA may place a study on 
clinical hold. This means that the drug may not be administered to 
subjects until the hold is lifted (see Sec. 312.42). FDA may also 
terminate the study under Sec. 312.44 based on such safety concerns.
    FDA is concerned that these IND reporting requirements may not be 
adequate to protect against some unexpected adverse events. For 
example, there is a potential for such events to be disguised by 
patient conditions that might lead the investigator to conclude that 
the experimental drug was not implicated in those events. The agency 
believes that certain modifications in the way clinical investigations 
are conducted and reported may help to ensure that drug toxicity is 
detected as early as possible. A recent internal task force that 
examined an incident that involved a fatal drug toxicity that was not 
detected in early trials has recommended improvements in IND reporting 
that the agency is incorporating into this proposal for public 
consideration. These improvements, as explained below, are intended to 
provide more frequent and more complete evaluations of potentially 
serious adverse effects so that drug-related events can be detected 
earlier by sponsors, investigators, and FDA.
    A clinical study of a nucleoside analog, FIAU, resulted in several 
instances of severe liver injury and five deaths, beginning in June 
1993. The study involved 15 subjects with chronic hepatitis B virus 
infection. FIAU had been considered a highly promising agent without 
recognized serious toxicity. This incident prompted FDA to establish a 
task force to see whether the data available prior to the study gave 
any suggestion of the serious toxicity that emerged. The task force 
examined data from the 1993 FIAU study as well as data from previous 
studies on FIAU and a closely related drug conducted by another 
sponsor. The data from these previous studies was, or should have been, 
available to the sponsor of the 1993 FIAU study. The task force was 
also to determine whether some differences in process or behavior by 
investigators and sponsors might have made it possible or more likely 
to have anticipated the toxicity. The proposed IND amendments contained 
in this document are largely the result of recommendations by the task 
force (Ref. 3).
    Focusing on hepatic and pancreatic adverse events, the task force 
reviewed the data and data analyses that were available to 
investigators, sponsors, and FDA at the start of the study to determine 
whether improvements in the rules governing design, analysis, and 
reporting of data from clinical studies were warranted. The task force 
found a number of observations and events that suggested an association 
between FIAU and hepatic and/or pancreatic abnormalities. However, none 
of these events was attributed by the sponsors or investigators to 
FIAU. Rather, each event, even when recognized as temporally related to 
a study, was attributed by investigators and sponsors to other factors, 
such as concomitant drug administration and/or concurrent illness. The 
task force found that an overview of the data, in which deaths and 
serious adverse experiences were analyzed cumulatively, and, with the 
hypothesis that the events were drug related, was not produced and thus 
was not available for use by the sponsors, the principal investigators, 
or FDA reviewers. Rather, the analyses performed focused on each 
individual event and determined a plausible explanation, other than 
drug toxicity, for each occurrence. The task force recommended that, to 
detect similar patterns of events reflecting toxicity in future 
studies, sponsors should conduct cumulative analyses with a systematic 
consideration of the possibility that the adverse events are caused by 
the investigational drug.
    The proposed IND amendments would apply to all investigational 
studies conducted under part 312. However, FDA invites comments from 
the public and industry on whether any or all of the proposed 
requirements should apply only to certain IND's, whose selection could 
be determined by application of criteria that could be included in 
these regulations, or only to certain phases of drug testing.
1. Clinical Study Design
    FDA is proposing to amend the requirements governing IND format and 
content in Sec. 312.23. Under current Sec. 312.23(a)(6), an IND must 
contain the protocols for each planned study, including information 
such as a statement of the study's objectives and purpose, the criteria 
for patient selection and exclusion, a description of the study design, 
the method for determining the dose(s) to be administered and the 
duration of individual patient exposure to the drug, and a description 
of clinical procedures, laboratory tests, or other measures to be taken 
to monitor the effects of the drug in human subjects and to minimize 
risk.
    In several instances, FDA's FIAU task force found that deaths and 
serious hepatic and pancreatic injuries that appear in retrospect to 
have been related to FIAU were attributed by investigators and sponsors 
to the subjects' underlying disease or to other drugs the subjects were 
taking for their conditions. The task force made several 
recommendations intended to improve the likelihood that clinical 
studies will identify, early in drug development, drug toxicity that 
mimics the underlying disease or the toxicity of concomitant 
medications. These recommendations include: (1) Choosing study designs 
and safety endpoints that increase a study's ability to distinguish 
drug toxicity from underlying disease or other drug toxicity; (2) 
prospectively identifying observations that will trigger certain 
actions by investigators; and (3) summarizing safety data at regular 
intervals with systematic considerations of the possibility that 
adverse events are drug related. The proposed rule would create new 
Sec. 312.23(a)(6)(iii)(h) to require that the protocols describe any 
adverse clinical or laboratory outcomes in the study that are to be 
immediately reported to the sponsor. These reportable events might 
include death, any life-threatening event, or any other serious event 
that might reflect potential drug toxicity, as suggested by preclinical 
data, and include abnormal laboratory results falling outside of a 
specified range. The identified events and abnormal laboratory values 
are to include those that focus attention on toxicity that may target 
the same organs and body systems as the underlying disease or 
concomitant medications. Under the proposal, these events would be 
reported to the sponsor even if they are potentially attributable to 
the patient's underlying disease or concomitant medications. Proposed 
Sec. 312.23(a)(6)(iii)(h) would also require instructions for 
investigators, such as reporting requirements, remeasurement or 
challenge procedures, or discontinuation of the drug in response to 
identified events.
    The task force also recommended that sponsors consider the use of a 
control group (for example, placebo, active control, or historical 
control) in studies that focus on safety when the underlying disease 
process is likely to produce adverse events that might be confused with 
drug toxicity. The task force concluded that such controls would help 
detect some adverse events. Consequently, proposed 
Sec. 312.23(a)(6)(iii)(i) states that sponsors should consider the use 
of a formal control group when the underlying disease is likely to 
produce adverse events that might be confused with drug toxicity.
    The task force also recommended that sponsors attempt to estimate 
the expected incidence of death and serious adverse events in the study 
population that arise from the underlying disease or concomitant 
medications used to treat the disease. This recommendation is reflected 
in proposed new Sec. 312.23(a)(6)(iii)(j) that would require sponsors 
to provide such estimates. Under the proposal, any deaths or adverse 
events that exceed the estimates would create the presumption that the 
events are associated with use of the investigational drug, and the 
sponsor would be required to submit a written safety report to FDA.
    The task force found that the followup periods in some of the FIAU 
and related studies were too short to detect some of the adverse events 
that occurred because significant adverse events sometimes occurred 
weeks to months after dosing with FIAU ended.The task force recommended 
that all protocols contained in the IND include an explicit description 
of the length and type of followup to be performed so that the agency 
may review the followup procedures (task force report at 57). 
Accordingly, FDA is proposing to add new Sec. 312.23(a)(6)(iii)(k) to 
require that the protocol section of an IND specify and justify the 
length and type of followup for subjects after the conclusion of 
dosing. The justification may be brief; for example, a reference to a 
study of a similar drug with the same followup period. The followup 
period would ensure that clinical studies are adequately designed to 
detect drug toxicity that occurs after the conclusion of drug dosing. 
The sponsor would propose an appropriate followup period based on 
preclinical data, experience with other members of the drug class, the 
drug's mechanism of action, and prior human experience. The intensity 
of the followup may change with time; e.g., a full evaluation might be 
scheduled for 2 weeks postdosing, with a telephone followup for 
possible serious events at a later time. Ordinarily, in Phase 1 and 2 
studies, telephone followup should occur at 3 months after the dosing 
is completed, but alternative timeframes and procedures can be proposed 
by the sponsor. For some drugs, like FIAU, a review of available data 
may suggest that the minimum followup period should be longer than 3 
months.
    Current regulations in Sec. 312.56 require sponsors to review and 
evaluate the evidence relating to a drug's safety and effectiveness as 
it is obtained from investigators. The regulations also require 
sponsors to report safety information to FDA. The task force observed 
that in the FIAU study sponsors may not have had available adequate 
resources to evaluate safety data reported by investigators. The 
proposed rule would amend Sec. 312.56(c) to require sponsors, in 
addition to reviewing and evaluating safety and effectiveness 
information, to develop a safety monitoring and evaluation program 
before starting clinical trials. This provision is intended to ensure 
that sponsors have or will develop adequate resources to evaluate 
safety data reported by investigators and is consistent with the task 
force's recommendations (see task force report at 57). Consistent with 
this proposed requirement, FDA is also proposing in new 
Sec. 312.23(a)(3)(v) that an IND contain a description of any safety 
monitoring and evaluation program. This description would be in 
addition to the introductory statement and general investigational plan 
that are required under current regulations.
2. Safety Reports
    FDA is proposing several amendments to the requirements for IND 
safety reports in Sec. 312.32. FDA is proposing to alter the period for 
submitting written safety reports, under Sec. 312.32(c)(1)(i) and 
(d)(3), from 10 working days to 15 calendar days, and for submitting 
safety reports by telephone, under Sec. 312.32(c)(2), from 3 working 
days to 7 calendar days. FDA is also proposing to allow telephone 
safety reports to be made by facsimile transmission as well as orally 
by telephone. These changes will give sponsors additional time to 
gather appropriate data to help interpret the reports before submitting 
these reports. FDA believes the extended time period would be 
sufficient to alert the agency to potential safety problems, especially 
because of the new investigational reporting requirements the agency is 
proposing.
    Proposed Sec. 312.32(c) would also permit sponsors to submit IND 
safety reports to the agency by using FDA Form 3500A. If FDA determined 
that insufficient data were submitted on FDA Form 3500A, the agency 
could require additional narrative data to be submitted. As explained 
elsewhere in this proposal, this amendment is consistent with the 
proposal to use this form for postmarketing reporting of human drug and 
licensed biological product adverse experiences.
    FDA is also proposing to amend the disclaimer contained in 
Sec. 312.32(e) to emphasize that safety information submitted to FDA 
are not to be considered admissions of causation or liability. The 
proposal would substitute the word ``part'' for ``section'' so that the 
revised disclaimer would clearly apply to all safety information 
submitted under part 312. Summaries of such safety information would 
not constitute a statement or admission that there was a causal link 
between the administration of the drug and the subsequent adverse 
event.
3. Semiannual Reports
    FDA is proposing to amend the periodic reporting requirements in 
Sec. 312.33 by adding, in addition to the annual report, a semiannual 
death and serious adverse experiences report. This change is intended 
to ensure that reports of deaths and other serious adverse experiences 
in all clinical studies are collected and reviewed in a timely and 
comprehensive manner, and that the possibility of drug relatedness is 
always considered.
    Under current regulations, sponsors must report deaths and serious 
and unexpected adverse experiences within 3 or 10 working days only if 
the events are associated with the use of the drug. ``Associated with 
the use of the drug'' is defined to mean that there is a reasonable 
possibility that the experience may have been caused by the drug (see 
Sec. 312.32(a)). Deaths and a summary of serious adverse experiences 
that occur in a clinical trial that the sponsor concludes are not 
associated with use of the drug must be reported only in an IND annual 
report. The task force found that many adverse experiences occurring 
during the FIAU study that appear, in retrospect, to have been drug 
related were not reported in safety reports, although, at times, they 
were reported in the annual report as attributable to causes other than 
FIAU.
    The proposed rule, therefore, would create a new ``semiannual 
report'' to require, among other things, the submission of reports of 
all deaths, serious adverse experiences, and study discontinuations 
resulting from an adverse experience, whether expected or unexpected 
and whether or not there was thought to be a possibility that the death 
or adverse experience was caused by the drug. In these twice yearly 
reports, sponsors would also report all deaths and serious adverse 
experiences that occurred during the trial or within the prescribed 
followup period. The report would include data not only from studies 
conducted under the IND, but also data from all premarketing studies of 
the drug conducted worldwide, with an analysis of all unexpected 
deaths, serious adverse experiences, and study discontinuations thought 
to be related to the study drug from foreign postmarketing clinical 
trials and from foreign postmarketing spontaneous or required reporting 
systems. Serious adverse events should include laboratory changes that 
result in discontinuation or that are identified in the study protocol 
as reportable events. Sponsors would present these data both for the 6-
month reporting interval and cumulatively, and submit an analysis of 
the data. The agency would expect the analysis to conform generally to 
the evaluation of deaths, serious adverse experiences, and 
discontinuations in the section entitled ``Integrated Summary of Safety 
Information'' in FDA's ``Guideline for the Format and Content of the 
Clinical and Statistical Sections of New Drug Applications.'' FDA also 
recommends that the sponsor employ, in preparing the analysis, at least 
one individual who had no involvement in conducting the clinical study. 
The proposal would also require a sponsor to conduct a ``worst-case'' 
analysis of the safety data, presuming that observed adverse events 
were the result of toxicity from the investigational drug, and then 
attempt to refute this presumption, with appropriate data and 
evaluations (task force report at 59). The analysis should include 
estimates of the rate of an analyzed event occurring spontaneously in 
the population and specific analyses of cases.
    The sponsor would submit the semiannual report for the 6-month 
period following the day the IND goes into effect, and for each 6-month 
period thereafter, until the end of the followup period specified in 
the protocol. The report would be due within 60 days of the end of the 
reporting period. The semiannual safety report that is due during the 
same period as the annual report would be submitted with the annual 
report.
    The task force recommended (task force report at 59) that FDA 
require the submission of all available autopsy reports and medical 
reports concerning all deaths reported in these semiannual reports, 
because, in at least one instance during the FIAU study, the cause of 
death originally reported was not fully consistent with the autopsy and 
terminal medical reports later obtained for that subject. Proposed 
Sec. 312.33(b)(2) would require the submission of these reports and 
would require the sponsor to clarify any inconsistencies between these 
reports and the cause of death reported to FDA by the sponsor. FDA is 
proposing this requirement to help ensure that reports covering deaths 
submitted to the agency are complete and accurate.
    Under proposed Sec. 312.33(b)(3), at the request of the sponsor, or 
on its own initiative, FDA may modify certain semiannual reporting 
requirements where, for example, the clinical study endpoint is 
mortality or where the study is blinded and full compliance with the 
reporting requirement would require breaking the blind. FDA is 
proposing this provision because studies vary concerning the nature and 
seriousness of the disease to be treated, the number of subjects 
exposed to the drug, and the general pace at which the drug's 
development proceeds.
4. Special Safety Summary
    In new Sec. 312.37(a), FDA also proposes an additional mechanism to 
allow the agency to obtain safety data on investigational drugs and 
summaries of these data not otherwise obtained through other reporting 
requirements if, and when, these data are necessary. Most 
investigational drugs do not present unusual safety concerns, so that 
the safety data contained in the 6-month and annual reports, as well as 
the IND safety reports submitted under Sec. 312.32, would provide 
adequate information to allow FDA to observe drug safety. Some drugs, 
however, may raise significant safety concerns either anticipated or 
unanticipated, so that more comprehensive data on events that do not 
meet the definition of a serious adverse reaction as well as those that 
do are needed. Events that might trigger this heightened scrutiny 
include agency experience with similar drugs, animal toxicity study 
results, and information derived from IND safety, annual, or semiannual 
reports. As recommended by the task force (task force report at 59 and 
60), the proposed regulation is drafted in general language to allow 
the agency, in consultation with the sponsor, flexibility in 
determining when a report should be required and what information it 
should contain. This flexibility is considered necessary because the 
specifics of the safety summary may vary from study to study. FDA 
anticipates that the safety summary will generally not only contain the 
results of the cumulative analysis of deaths and serious adverse 
experiences contained in the 6-month report, but also an analysis of 
related events of lesser seriousness.
    Although the task force recommended that FDA require safety 
summaries unless an exemption had been granted to the sponsor, FDA is 
proposing to require safety summaries only for those studies or 
products where the agency has determined that a specific need for them 
exists. FDA would generally expect safety summaries to be submitted 
within 30 days after they are requested; however, the agency recognizes 
that in cases where large amounts of data are required to be summarized 
and those data are not readily available or easily summarized, a longer 
period of time may be necessary to prepare the summary.
5. Final Clinical Study Report
    Information about FIAU risks and benefits that the sponsor might 
have derived from the process of collecting and analyzing study results 
was delayed or never developed because final reports were not required 
for the earlier clinical studies of FIAU and FIAC (a closely related 
nucleoside analog). Thus, FDA is proposing in Sec. 312.37(b) to require 
sponsors to submit, when required by FDA, a final report or study 
summary of a clinical study. FDA anticipates that final reports usually 
will not be necessary. Instituting requirements for semiannual 
reporting of deaths, serious adverse experiences, and discontinuations, 
and for summarization of all safety data will largely fulfill the need 
for more careful monitoring and analysis of potential drug toxicity 
during drug testing. In some cases, however, it may still be valuable 
to have available an analysis of the results of particular trials; 
e.g., to provide data on the likely effectiveness of a drug for 
purposes of weighing risks against likely benefits to study subjects. 
The proposal wouldrequire final clinical study reports to be submitted 
within 90 days of a request from FDA, but provides for exceptions under 
extraordinary circumstances.
6. Clinical Holds
    Section 312.42 currently allows FDA to delay a proposed clinical 
investigation or to suspend an ongoing investigation under certain 
circumstances. Under the proposal, FDA would amend Sec. 312.42 to allow 
the agency to place an investigation on clinical hold if the sponsor 
fails to submit a special safety summary or final clinical study 
report. If the same or a closely related drug is the subject of a 
concurrent investigation, conducted by the same sponsor, proposed 
Sec. 312.42(b)(1)(v) would require safety summaries from all 
investigations or the agency could place any of the investigations on 
clinical hold. FDA believes this is appropriate because data from all 
studies involving the drug or closely related drugs may help FDA 
evaluate the safety of each study.
7. Termination
    FDA is also proposing in Sec. 312.44(b)(1)(viii) to amend the 
regulations regarding termination so that failure to submit a 
semiannual report would be grounds for terminating an IND. Failure to 
submit an annual report is already grounds for terminating an IND, and 
FDA is aware of no reason why semiannual and annual reports should be 
treated differently in this matter.
    FDA considers that failure to implement an adequate safety 
monitoring and evaluation program, as described in proposed 21 CFR 
312.56(c), would be grounds for either a clinical hold under 
Sec. 312.42 or a termination of the IND under Sec. 312.44, since 
failure to have a program in place would mean that ``[h]uman subjects 
are or would be exposed to an unreasonable and significant risk of 
illness or injury,'' which is currently grounds for either a clinical 
hold or termination.
8. Review of Ongoing Investigations
    FDA is also proposing to amend Sec. 312.64(b) to require 
investigators to submit safety data to sponsors necessary to allow 
sponsors to comply with the other proposed safety reporting 
requirements, such as the proposed semiannual report. The proposed 
amendment would require the investigator to comply with safety 
reporting requirements established in the protocol for the study. 
Current Sec. 312.64(b) requires investigators to report adverse effects 
if they may reasonably be regarded as caused by, or probably caused by, 
the drug. If the adverse effects are alarming, they are to be reported 
to the sponsor immediately. These provisions are being retained as 
minimal requirements which must be met, even if the protocol does not 
require the events to be reported.

G. Written Procedures for Monitoring Adverse Experiences

    FDA is also proposing to amend Secs. 310.305(a) and 314.80(b) for 
marketed human drug products and Sec. 600.80(b) for licensed biological 
products to require applicants or manufacturers, packers, and 
distributors to develop written procedures for the surveillance, 
receipt, evaluation, and reporting of adverse experiences to FDA. This 
requirement would improve postmarketing surveillance by applicants or 
manufacturers and would enhance an applicant's or manufacturer's 
ability to evaluate and report adverse experiences to the agency. FDA 
believes that this provision would not impose a new burden on 
applicants and manufacturers, because it codifies a practice that is 
already customary and usual in the pharmaceutical industry for handling 
adverse experiences. Based on field inspections, FDA is aware that many 
manufacturers already have written procedures for the receipt, 
evaluation, and reporting of adverse experiences to FDA. The agency 
also notes that the current good manufacturing practice (CGMP) 
regulations for finished pharmaceuticals, which apply to manufacturers 
of all marketed human drug and biological products, require written 
procedures describing the handling of all written and oral complaints 
regarding a drug product (21 CFR 211.198).
    Furthermore, the agency's ``Guideline For Postmarketing Reporting 
of Adverse Drug Experiences'' (Ref. 4), which provides guidance on 
adverse drug experiences reported under Secs. 310.305 and 314.80, 
states (at page 17) that:
    Each applicant should develop standardized, formal procedures 
for the surveillance, receipt, evaluation, and reporting of ADE's to 
FDA. * * * All applicants should develop procedures that allow 
expedited adverse experience report handling, and the applicant 
should keep on file documentation of due diligence.
    Elsewhere in this issue of the Federal Register FDA is announcing 
the availability of a guideline entitled ``Guideline for Adverse 
Experience Reporting for Licensed Biological Products.'' This guideline 
discusses the reports required by Sec. 600.80 and provides guidance 
concerning appropriate means of meeting the reporting requirements.

H. Resubmission of Reports Received From FDA

    Under the MedWatch program, FDA will transmit reports of 
spontaneously reported serious adverse experiences received by the 
agency to the applicant, manufacturer, packer, or distributor (as 
appropriate) on an expedited basis. Consequently, FDA is proposing to 
revise Secs. 310.305(c), 314.80(b), and 600.80(b) to state that 
applicants or manufacturers, packers, and distributors should not 
resubmit to the agency reports of adverse experiences that the agency 
has forwarded to them. In addition, FDA is proposing to revise 
Secs. 314.80(c)(1)(i) and 600.80(c)(1)(i) to remove the phrase 
``regardless of source'' from the description of which adverse 
experiences are reported to FDA. These revisions are intended to reduce 
duplicate reporting of adverse experiences to the agency, consistent 
with the reporting instructions in new FDA Form 3500A. FDA notes, 
however, that applicants or manufacturers, packers, and distributors 
receiving reports forwarded to them by FDA are required to handle these 
reports as they would any others and that followup, if obtained, is to 
be sent to the agency as specified in the regulation. These followup 
reports should be included, where appropriate, in the postmarketing 
adverse experience periodic report.
    FDA is also proposing that applicants and licensed manufacturers 
incorporate into any safety analysis (i.e., periodic reports, increased 
frequency reports) the expedited reports received from FDA, whether or 
not additional followup information was obtained, and any information 
received through Freedom of Information requests.

I. Other Revisions to the Reporting Requirements

    FDA is proposing to remove Secs. 314.80(c)(2)(iii) and 
600.80(c)(2)(iii). These paragraphs state that periodic reporting for 
non-15-day Alert reports does not apply to adverse drug experience 
information obtained from postmarketing studies and reports in the 
scientific literature and from foreign marketing experience. FDA is 
proposing to remove these paragraphs because this information would now 
be required under the proposed revisions to the contents of a periodic 
report.
    Current regulations, at Sec. 314.80(c)(1)(ii), require applicants 
and, at Sec. 600,80(c)(1)ii), licensed manufacturers to ``review 
periodically (at least as often as the periodic reporting cycle)'' the 
frequency of reports of adverse experiences and report any significant 
increase in frequency to FDA. Similarly, current Sec. 310.305(c)(4) 
requires manufacturers, packers,and distributors to ``review 
periodically (at least once each year)'' the frequency of reports of 
adverse experiences and report any significant increase in frequency to 
FDA. In order to provide consistency with the proposed semiannual 
reporting requirements for periodic adverse experience reports under 
Secs. 314.80 and 600.80, FDA is proposing to amend Sec. 310.305 to 
require manufacturers, packers, and distributors to review 
periodically, at least twice each year, the frequency of adverse 
experience reports for the purposes of making increased frequency 
reports to FDA.
    FDA is also proposing to amend Secs. 310.305(c) and 314.80(c) by 
reorganizing, renumbering, and retitling the paragraphs in these 
sections to distinguish between postmarketing 15-day Alert reports, 
followups to postmarketing 15-day Alert reports, and increased 
frequency reports. The proposed amendments would also distinguish 
between the reporting intervals for postmarketing 15-day Alert reports 
and the revised intervals proposed for postmarketing periodic reports.
    FDA is also proposing to amend Secs. 310.305(c)(1) through (c)(4) 
and 314.80(c)(1)(i), through (c)(1)(iv) to alter the period for 
submitting postmarketing ``15-day'' Alert reports from 15 working days 
to 15 calendar days. This change should decrease misunderstandings with 
the reporting requirements as all timeframes would now be stated in 
terms of calendar days. In addition, this change would increase 
consistency between the premarketing and postmarketing reporting 
requirements.
    FDA is also proposing to amend Secs. 310.305(c)(2), 
314.80(c)(1)(ii), and 600.80(c)(1)(ii) to require applicants or 
manufacturers, packers, and distributors who have been unable to obtain 
additional information about adverse experiences that are the subject 
of postmarketing 15-day Alert reports to maintain records of their 
attempts to seek additional information. These proposed revisions will 
help ensure that applicants or manufacturers are making good faith 
efforts to investigate adverse experiences that are the subject of 
postmarketing 15-day Alert reports.
    Finally, FDA is proposing to amend Secs. 310.305(d)(3)(ii) and 
314.80(f)(3)(ii) to instruct applicants or manufacturers, packers, and 
distributors that, before using an alternative reporting form instead 
of FDA Form 3500A, they must obtain approval from MedWatch: The FDA 
Medical Products Reporting Program, 5600 Fishers Lane, Rockville, MD 
20852-9787. Current regulations require prior approval from the 
Division of Epidemiology and Surveillance for human drug products.

J. Distribution Reports

    As stated earlier, the proposed rule would change the reporting 
interval for licensed biological product distribution reports to be 
consistent with the suggested CIOMS standardized reporting period for 
postmarketing adverse drug experience periodic reports. Licensed 
biological product distribution reports would be based on the 
international birth date and data lock-point. The proposal would also 
remove Sec. 600.81 and move the regulatory requirements for licensed 
biological product distribution reports to Sec. 600.80(c)(3).

K. Multiple Reports

    FDA is proposing to amend Sec. 600.80(g) concerning multiple 
reports by adding information pertaining to a licensed biological 
product for which a licensed manufacturer holds more than one 
biological product license. This revision would be consistent with the 
requirements in Sec. 314.80(g).

L. Guidelines

    FDA is proposing to amend Secs. 314.80(j) and 600.80(j) to indicate 
where guidelines for the submission of adverse experience reports may 
be obtained. In addition, FDA is adding this information in 
Sec. 310.305(g) for the submission of adverse experience reports for 
prescription drugs without an approved application. For human drug 
products, the guidelines may be obtained from the CDER Executive 
Secretariat Staff (HFD-8), Center for Drug Evaluation and Research, 
Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 
and for licensed biological products from the Congressional and 
Consumer Affairs Branch (HFM-12), Center for Biologics Evaluation and 
Research, Food and Drug Administration, 1401 Rockville Pike, suite 
200N, Rockville, MD 20852-1448.

M. Proposed Implementation Scheme

    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. All applications for human drug or licensed 
biological products approved on or after the effective date of any 
final regulation would be subject to the periodic reporting time 
periods based on the international birth date. All human drug and 
licensed biological product applications approved before the effective 
date of any final regulation would use the U.S. approval date as the 
international birth date.

III. Request for Comments

    Interested persons may, on or before January 25, 1995, 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.

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. 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, 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 economic costs imposed on the industry as a result of this 
proposed rule are the costs associated with reporting deaths, serious 
adverse experiences, or clinical study discontinuations. Reporting 
burdens on the industry resulting from FDA regulations are analyzed 
under the Paperwork Reduction Act of 1980. Based on an estimated total 
of 480,602 annual burden hours, FDA has estimated that the total annual 
reporting cost to the industry as a result of this proposed rule would 
be $ 24,030,100 (the estimated per hour cost to the industry is $ 50). 
In addition, the rule may increase certain nonpaperwork activities. For 
example, added costs may result if the formal control groups suggested 
in Sec. 312.23(a)(6)(iii)(i) prompts additional clinical trial control 
arms, or if the implementation of the followup plan required in 
Sec. 312.23(a)(6)(iii)(k) provokes more elaborate monitoring 
procedures. At this time, FDA cannot predict the extent of these 
actions, but welcomes public comment on issues regarding the scope or 
cost of these activities.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. 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.

VI. Paperwork Reduction Act of 1980

    This proposed rule contains information collection requirements 
which are subject to review by the Office of Management and Budget 
(OMB) under the Paperwork Reduction Act of 1980. The title, 
description, and respondents of the information collection requirements 
are shown below.
    Title: Adverse Experience Reporting Requirements For Human Drug and 
Licensed Biological Products.
    Description: FDA is proposing to amend its current adverse 
experience reporting requirements to replace current Form FDA-1639 with 
new FDA Form 3500A; to revise certain definitions and reporting periods 
and formats; to require applicants or manufacturers, packers, and 
distributors to develop written procedures for monitoring and reporting 
adverse experiences; and to make other revisions to provide uniformity 
to the reporting regulations. These changes would simplify and 
facilitate the reporting of adverse events and product problems under a 
single form and help harmonize international adverse event reporting 
requirements. In addition, FDA is proposing to amend the sponsor 
reporting requirements in part 312.
    Description of Respondents: Businesses or other for profit and 
small businesses or organizations.
    The burden hours for Secs. 310.305 and 314.80 are approved under 
OMB information collection number 0910-0230. The burden hours for 
Sec. 600.80 have been submitted to OMB for approval and can be found 
elsewhere in this issue of the Federal Register. FDA estimates no 
change in the burden hours that have already been approved. OMB has 
approved use of the new form, under OMB information collection number 
0910-0291, through December 1994. The new recordkeeping requirements 
under Sec. 310.305(c)(2), 314.80(c)(1)(ii), and 600.80(c)(1)(ii), that 
applicants or manufacturers, packers, and distributors maintain records 
of unsuccessful attempts to obtain additional followup information on 
15-day ``Alert reports,'' would be negligible and would result in no 
change in the burden hours that have already been approved.
    The new requirements under Secs. 310.305(a), 314.80(b), and 
600.80(b), that applicants or manufacturers, packers, and distributors 
develop written procedures for the surveillance, receipt, evaluation, 
and reporting of adverse experiences, would not impose a new burden 
because they codify a practice that is already customary and usual in 
the pharmaceutical industry for handling adverse experiences.
    The more extensive list of contents for the periodic postmarketing 
adverse experience report, in proposed Secs. 314.80(c)(2)(ii) and 
600.80(c)(2)(ii), would result in an increased reporting burden on the 
industry. As indicated in the accompanying chart, the proposed periodic 
reporting requirements would require, on an average, 19 additional 
hours for respondents to prepare.
    The proposal would also increase the reporting requirements for 
sponsors under part 312. As indicated in the accompanying chart, the 
proposed amendments to part 312 would result in an increase of 167,900 
burden hours on the industry.

                                     Estimated Total Annual Reporting Burden                                    
----------------------------------------------------------------------------------------------------------------
                                     Number of     Responses per   Total annual      Hours per                  
            Section                respondents      respondent      responses        response       Total hours 
----------------------------------------------------------------------------------------------------------------
312.23(a)(3) and (a)(6).........           1,623               1           1,623               4           6,492
312.33(b).......................           1,517             2.6           3,944              40         157,760
312.37(a).......................             152               1             152              16           2,432
312.37(b).......................             152               1             152               8           1,216
314.80(c)(2)....................             528           30.50          16,106              19         306,014
600.80(c)(2)....................              63            5.58             352              19           6,688
                                                                                                 ---------------
      Total.....................                                                                         480,602
----------------------------------------------------------------------------------------------------------------

    As required by section 3504(h) of the Paperwork Reduction Act of 
1980, FDA has submitted a copy of this proposed rule to OMB for its 
review of these information collection requirements. Other 
organizations and individuals desiring to submit comments regarding the 
burden estimate or any aspects of these information collection 
requirements, including suggestions for reducing the burden, should 
direct them to FDA's Dockets Management Branch (address above) and to 
the Office of Information and Regulatory Affairs, OMB, rm. 3208, New 
Executive Office Bldg., Washington, DC 20503, Attn: Desk Officer for 
FDA.

VII. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. to 4 p.m., Monday through Friday.

    1. ``International Reporting of Adverse Drug Reactions,'' Final 
Report of the CIOMS Working Group, 1990.
    2. ``International Reporting of Periodic Drug Safety Update 
Summaries,'' Final Report of the CIOMS Working Group II, 1992.
    3. ``Fialuridine: Hepatic and Pancreatic Toxicity,'' FDA Task 
Force Report, November 12, 1993.
    4. ``Guideline for Postmarketing Reporting of Adverse Drug 
Experiences,'' FDA, Center for Drug Evaluation and Research, March 
1992.

List of Subjects

21 CFR Part 20

    Confidential business information, Courts, Freedom of information, 
Government employees.

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, Reporting and recordkeeping requirements, Safety.

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 20, 
310, 312, 314, and 600 be amended as follows:

PART 20--PUBLIC INFORMATION

    1. The authority citation for 21 CFR part 20 continues to read as 
follows:

    Authority: Secs. 201-903 of the Federal Food, Drug, and Cosmetic 
Act (21 U.S.C. 321-393); secs. 301, 302, 303, 307, 310, 311, 351, 
352, 354-360F, 361, 362, 1701-1706, 2101 of the Public Health 
Service Act (42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263, 
263b-263n, 264, 265, 300u-300u-5, 300aa-1); 5 U.S.C. 552; 18 U.S.C. 
1905.

Sec. 20.112  [Amended]

    2. Section 20.112 Voluntary drug experience reports submitted by 
physicians and hospitals is amended in paragraph (a) by removing the 
words ``Form FDA-1639'' and adding in their place ``FDA Form 3500''.

PART 310--NEW DRUGS

    3. 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).

    4. Section 310.305 is amended by adding a new sentence at the end 
of the concluding text of paragraph (a); by revising paragraphs (b), 
(c), (d)(3)(ii), and (d)(4); by removing in paragraph (d)(1) the words 
``Form FDA-1639 (Adverse Reaction Report)'' and adding in their place 
``FDA Form 3500A''; by removing in paragraph (d)(2), the introductory 
text of paragraph (d)(3), and paragraph (d)(3)(i) the words ``Form FDA-
1639'' and adding in their place ``FDA Form 3500A''; by removing in 
paragraph (f)(1) the words ``paragraph (c)(5)'' and adding in their 
place the words ``paragraph (c)(4)''; and by redesignating paragraph 
(g) as paragraph (h) and by adding new paragraph (g) 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) * * * Manufacturers, packers, and distributors shall also 
develop written procedures for the surveillance, receipt, evaluation, 
and reporting of adverse drug experiences to FDA.
    (b) Definitions. The following definitions of terms apply to this 
section:
    (1) FDA means the Food and Drug Administration.
    (2) Adverse drug experience means any adverse event associated with 
the use of a drug in humans, whether or not considered drug related, 
including the following: An adverse event occurring in the course of 
the use of a drug product in professional practice; an adverse event 
occurring from drug overdose; an adverse event occurring from drug 
withdrawal; and any failure of expected pharmacological action.
    (3) Disability means a substantial disruption of a person's ability 
to carry out normal life functions.
    (4) Increased frequency means an increase in the rate of occurrence 
of a particular adverse drug experience, e.g., an increased number of 
reports of particular adverse drug experience after appropriate 
adjustment for drug exposure.
    (5) Life-threatening means that the patient was, in the view of the 
initial reporter, at immediate risk of death from the adverse drug 
experience as it occurred. It does not include an adverse drug 
experience that, had it occurred in a more serious form, might have 
caused death. For example, product-induced hepatitis that resolved 
without evidence of hepatic failure would not be considered life-
threatening even though hepatitis of a more severe nature can be fatal. 
Similarly, an allergic reaction resulting in angioedema of the face 
would not be life-threatening, although angioedema of the larynx, 
allergic bronchospasm, or anaphylaxis can be fatal.
    (6) Serious means an adverse drug experience occurring at any dose 
that is fatal or life-threatening, results in persistent or significant 
disability/incapacity, requires or prolongs inpatient hospitalization, 
necessitates medical or surgical intervention to preclude permanent 
impairment of a body function or permanent damage to a body structure, 
or is a congenital anomaly.
    (7) Unexpected means an adverse drug experience that is not listed 
in the current labeling for the drug product and includes an event that 
may be symptomatically and pathophysiologically related to an event 
listed in the labeling, but differs from the event because of greater 
severity or specificity. For example, under this definition, hepatic 
necrosis would be unexpected (by virtue of greater severity) if the 
labeling only referred to elevated hepatitic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (by virtue of greater specificity) if the labeling only 
listed cerebral vascular accidents.
    (c) Reporting requirements. Each person identified in paragraph 
(c)(1) of this section shall report to FDA adverse drug experience 
information as described in this section and shall submit one copy of 
each report to the Division of Epidemiology and Surveillance (HFD-730), 
Center for Drug Evaluation and Research, Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857.
    (1) Postmarketing 15-Day ``Alert reports''. (i) Any person whose 
name appears on the label of a marketed prescription drug product as 
its manufacturer, packer, or distributor shall report to FDA each 
adverse drug experience received or otherwise obtained that is both 
serious and unexpected as soon as possible, but in any case, within 15 
calendar days of initial receipt of the information. Each report shall 
be accompanied by a copy of the current labeling for the drug product.
    (ii) A person identified in paragraph (c)(1)(i) of this section is 
not required to submit a 15-day ``Alert report'' for an adverse drug 
experience obtained from a postmarketing study (whether or not 
conducted under an investigational new drug application) unless the 
applicant concludes that there is a reasonable possibility that the 
drug caused the adverse experience.
    (2) Postmarketing 15-Day ``Alert reports''--followup. Each person 
identified in paragraph (c)(1)(i) of this section shall promptly 
investigate all serious, unexpected adverse drug experiences that are 
the subject of these 15-day postmarketing Alert reports and shall 
submit followup reports within 15 calendar days of receipt of new 
information or as requested by FDA. If additional information is not 
obtainable, records should be maintained of the unsuccessful steps 
taken to seek additional information.
    (3) Increased frequency report. Each person identified in paragraph 
(c)(1)(i) of this section shall review periodically (at least twice 
each year) the frequency of reports of adverse drug experiences that 
are both serious and expected and reports of therapeutic failure (lack 
of effect), received or otherwise obtained, and report any significant 
increase in frequency as soon as possible, but in any case within 15 
calendar days of determining that a significant increase in frequency 
exists. Reports of a significant increase in frequency are required to 
be submitted in narrative form (including the time period on which the 
increased frequency is based, the method of analysis, and the 
interpretation of the results) rather than using FDA Form 3500A.
    (4) Submission of reports. In order to avoid unnecessary 
duplication in the submission of, and followup to, reports required in 
this section, including reports required by paragraph (c)(3) of 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. If a packer or distributor elects to 
submit these adverse drug experience reports to the manufacturer rather 
than to FDA, it shall submit each report to the manufacturer within 3 
calendar days of its receipt by the packer or distributor, and the 
manufacturer shall then comply with the requirements of this section 
even if its name does not appear on the label of the drug product. 
Under this circumstance, the packer or distributor shall maintain a 
record of this action which shall include:
    (i) A copy of each drug experience report.
    (ii) Date the report was received by the packer or distributor.
    (iii) Date the report was submitted to the manufacturer.
    (iv) Name and address of the manufacturer.
    (5) Each report submitted to FDA under this section shall bear 
prominent identification as to its contents, i.e., ``15-day Alert 
report,'' ``15-day Alert report--followup,'' or ``Increased frequency 
report.''
    (6) A person identified in paragraph (c)(1)(i) of this section 
should not resubmit to FDA reports forwarded to that person by FDA; 
however, all followup information must be submitted to FDA.
    (d) * * *
    (3) * * *
    (ii) The format is agreed to in advance by MedWatch: The FDA 
Medical Products Reporting Program.
    (4) Ten copies or fewer of FDA Form 3500A and/or a copy of the 
instructions for completing the form may be obtained from the Division 
of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation 
and Research, Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857. More than 10 copies of the form may be obtained by 
writing to the Consolidated Forms and Publications Distribution Center, 
Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 20785.
* * * * *
    (g) Guideline. FDA has prepared under Sec. 10.90(b) of this chapter 
a guideline for the submission of reports of adverse drug experiences 
and suggested followup investigation of reports. Copies of this 
guideline may be obtained from the CDER Executive Secretariat Staff 
(HFD-8), Center for Drug Evaluation and Research, Food and Drug 
Administration, 7500 Standish Pl., Rockville, MD 20855.
* * * * *

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

    5. The authority citation for 21 CFR part 312 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 
352, 353, 355, 356, 357, 371); sec. 351 of the Public Health Service 
Act (42 U.S.C. 262).

    6. Section 312.23 is amended by adding new paragraph (a)(3)(v) and 
paragraphs (a)(6)(iii)(h) through (a)(6)(iii)(k) to read as follows:

Sec. 312.23  IND content and format.

    (a) * * *
    (3) * * *
    (v) A description of the safety monitoring and evaluation program 
developed by the sponsor in order to evaluate safety data reported by 
investigators.
* * * * *
    (6) * * *
    (iii) * * *
    (h) A description of any adverse clinical or laboratory outcomes in 
the study that are to be reported by the investigators to the sponsor 
immediately. This would ordinarily include any death, any life-
threatening event, any serious event that might reflect potential 
toxicity, as suggested by preclinical data, laboratory values that 
exceed specified limits, or any markedly abnormal laboratory value. The 
identified events and abnormal laboratory values are to include those 
that focus attention on toxicity that may target the same organs and 
body systems as the underlying disease or concomitant medications for 
the disease. The events are to be reported to the sponsor even if they 
are potentially attributable to the patient's underlying disease or to 
other medications the patient may have received. This section of the 
protocol shall include instructions for the investigator encountering 
such an event, such as reporting requirements, a remeasurement or 
challenge procedure, or discontinuation of the study drug.
    (i) Sponsors should consider use of a formal control group (for 
example, placebo, active, documented historical) in studies that focus 
on safety when the underlying disease is likely to produce serious 
adverse events that might be confused with drug toxicity.
    (j) The sponsor shall estimate the expected incidence of deaths and 
serious adverse experiences in the study population that may arise from 
the underlying disease or from medications used to treat the underlying 
disease. Deaths or serious adverse experiences that exceed these 
estimates would create a presumption that the events are associated 
with the use of the investigational drug.
    (k) The sponsor shall determine and include in each protocol an 
appropriate followup period and appropriate followup procedures based 
on preclinical data, experience with other members of the drug class, 
the drug's mechanism of action, and prior human experience. The sponsor 
shall include a brief description of the rationale used in selecting 
the followup period and procedures. The intensity of the followup may 
change with time; e.g., a full evaluation might be scheduled for 2 
weeks after the end of drug dosing, with a telephone followup at a 
later time. Ordinarily, in Phase 1 and 2 studies, there should be at 
least telephone followup for 3 months after drug dosing is completed, 
but alternative timeframes and procedures can be proposed by the 
sponsor. In some cases, available information may dictate followup 
periods longer than 3 months.
* * * * *
    7. Section 312.32 is amended in paragraph (a) by revising the 
second sentence in the definition for ``Serious adverse experience,'' 
paragraph (c)(1)(i), the first sentence in paragraph (c)(2), paragraph 
(d)(3), and in paragraph (e) by removing the word ``section'' and 
replacing it with the word ``part'' to read as follows:

Sec. 312.32  IND safety reports.

    (a) * * *
    Serious adverse experience * * * A serious adverse drug experience 
means an experience occurring at any dose that is fatal or life-
threatening, results in permanent or significant disability/incapacity, 
requires or prolongs inpatient hospitalization, necessitates medical or 
surgical intervention to preclude permanent impairment of a body 
function or permanent damage to a body structure, or is a congenital 
anomaly. * * *
* * * * *
    (c) IND safety reports--(1) Written reports. (i) The sponsor shall 
notify FDA and all participating investigators in a written IND safety 
report of any adverse experience associated with use of the drug that 
is both serious and unexpected. This includes notification of any death 
or other serious adverse experience that exceeds the estimate of the 
expected incidence of deaths and serious adverse experiences required 
under Sec. 312.23(a)(6)(iii)(j). Such notification shall be made as 
soon as possible and in no event later than 15 calendar days after the 
sponsor's initial receipt of the information. Each written notification 
may be submitted on FDA Form 3500A or in a narrative form and shall 
bear prominent identification of its contents, i.e., ``IND Safety 
Report.'' Each written notification to FDA shall be transmitted to the 
FDA division of the Center for Drug Evaluation and Research or the 
Center for Biologics Evaluation and Research that has responsibility 
for review of the IND. If FDA determines that insufficient data were 
submitted on FDA Form 3500A, the agency may require further narrative 
data to be submitted.
* * * * *
    (2) Telephone safety reports. The sponsor shall also notify FDA by 
telephone, either orally or by facsimile transmission, of any 
unexpected fatal or life-threatening experience associated with the use 
of the drug no later than 7 calendar days after the sponsor's initial 
receipt of the information. * * *
* * * * *
    (d) * * *
    (3)If the results of a sponsor's investigation show that an adverse 
experience not initially determined to be reportable under paragraph 
(c) of this section is so reportable, the sponsor shall report such 
experience in a written safety report as soon as possible after the 
determination is made, but in no event longer than 15 calendar days.
* * * * *
    8. Section 312.33 is revised to read as follows:

Sec. 312.33  Annual and semiannual reports.

    (a) Annual reports. A sponsor shall within 60 days of the 
anniversary date that the IND went into effect, submit a brief report 
of the progress of the investigation that includes:
    (1) Individual study information. A brief summary of the status of 
each study in progress and each study completed during the previous 
year. The summary is required to include the following information for 
each study:
    (i) The title of the study (with any appropriate study identifiers 
such as protocol number), its purpose, a brief statement identifying 
the patient population, and a statement as to whether the study is 
completed.
    (ii) The total number of subjects initially planned for inclusion 
in the study, the number entered into the study to date, the number 
whose participation in the study was completed as planned, and the 
number who dropped out of the study for any reason.
    (iii) If the study has been completed, or if interim results are 
known, a brief description of any available study results.
    (2) Summary information. Information obtained during the previous 
year's clinical and nonclinical investigations, including:
    (i) A narrative or tabular summary showing the most frequent and 
most serious adverse experiences by body system.
    (ii) A summary of all IND safety reports submitted during the past 
year.
    (iii) A list of subjects who died during participation in the 
investigation, with the cause of death for each subject.
    (iv) A list of subjects who dropped out during the course of the 
investigation in association with any adverse experience, whether or 
not thought to be drug related.
    (v) A brief description of what, if anything, was obtained that is 
pertinent to an understanding of the drug's actions, including, for 
example, information from controlled trials, and information about 
bioavailability.
    (vi) A list of the preclinical studies (including animal studies) 
completed or in progress during the past year and a summary of the 
major preclinical findings.
    (vii) A summary of any significant manufacturing or microbiological 
changes made during the past year.
    (3) A description of the general investigational plan for the 
coming year to replace that submitted 1 year earlier. The general 
investigational plan shall contain the information required under 
Sec. 312.23(a)(3)(iv).
    (4) If the investigator brochure has been revised, a description of 
the revision and a copy of the new brochure.
    (5) A description of any significant Phase 1 protocol modifications 
made during the previous year and not previously reported to the IND in 
a protocol amendment.
    (6) A brief summary of significant foreign marketing developments 
with the drug during the past year, such as approval of marketing in 
any country or withdrawal or suspension from marketing in any country.
    (7) If desired by the sponsor, a log of any outstanding business 
with respect to the IND for which the sponsor requests or expects a 
reply, comment, or meeting.
    (b) Semiannual reports. A sponsor shall submit a report of the 
progress of the investigation with respect to safety issues for the 6-
month period following the day the IND goes into effect, and for each 
6-month period thereafter, until the end of the followup period 
specified in the protocol. The report shall be due within 60 days of 
the end of the reporting period. The semiannual safety report that is 
due during the same period as the annual report required under 
paragraph (a) of this section shall be submitted with the annual 
report. These semiannual reports shall include:
    (1) A summary and analysis of all deaths, all serious adverse 
experiences, and all study discontinuations resulting from an adverse 
experience that occurred during the study or within the prescribed 
followup period, whether the deaths or adverse experiences were 
expected or unexpected and whether or not there is thought to be a 
possibility that the death or adverse experience or study 
discontinuation was caused by the drug. This summary shall include data 
not only from studies conducted under the IND, but also data from all 
premarketing studies of the drug conducted worldwide, with an analysis 
of all unexpected deaths, serious adverse experiences, and study 
discontinuations thought to be related to the study drug from foreign 
postmarketing clinical trials and from foreign postmarketing 
spontaneous or required reporting systems. For purposes of this 
section, serious adverse events shall include laboratory changes 
identified in the study protocol as reportable events or that result in 
discontinuation. The sponsor shall present in the summary both the data 
that accumulated during the reporting period and cumulatively. The 
sponsor shall also submit an analysis of the data that assumes that the 
investigational drug is responsible for the deaths, serious adverse 
experiences, and study discontinuations, and refute, as feasible, this 
presumption with appropriate data and evaluations. The expected 
incidence of deaths and serious adverse experiences in the study 
population that may arise from the underlying disease or from 
medications used to treat the underlying disease that was estimated in 
the protocol should be considered in this evaluation.
    (2) All available autopsy reports and terminal medical reports 
concerning all deaths reported in this summary, with a discussion of 
any inconsistencies between autopsy and medical reports and the cause 
of death reported to FDA by the sponsor.
    (3) At the request of the sponsor, or on its own initiative, FDA 
may modify the requirements of paragraph (b) of this section. A sponsor 
requesting such a modification should submit to the division 
responsible for review of the IND a written request for modification 
and justification for such modification. FDA shall issue a written 
response to the sponsor either granting or denying, in whole or in 
part, the request for modification.
(Collection of information requirements approved by the Office of 
Management and Budget under control number 0910-0014)
    9. Section 312.37 is added to read as follows:

Sec. 312.37  Special safety summary and final clinical study report.

    (a) Special safety summary. Upon request of FDA, a sponsor shall 
prepare and submit special summaries of safety data regarding the 
investigational drug. These summaries may include safety data available 
to the sponsor from previous studies of the drug and of closely related 
drugs identified in consultation with FDA. Examples of types of events 
that may be requested to be summarized include, among others, deaths, 
serious adverse experiences, study discontinuations for safety reasons, 
patients who reach or exceed safety endpoints as defined in the 
protocol, and any unusual or extreme changes in study subjects. The 
special safety summary shall be submitted within 30 days after a 
request by the agency unless the sponsor demonstrates that 
extraordinary circumstances warrant a later date and the agency has 
agreed to that later date.
    (b) Final clinical study report. Upon request by FDA, a sponsor 
shall submit a final report on a clinical study. The final report shall 
be submitted within 90 calendar days after a request by the agency 
unless the sponsor demonstrates that extraordinary circumstances 
warrant a later date and the agency has agreed to that later date.
    10. Section 312.42 is amended by adding paragraph (b)(1)(v) to read 
as follows:

Sec. 312.42  Clinical holds and requests for modification.

* * * * *
    (b) * * *
    (1) * * *
    (v) The sponsor has failed to submit a special safety summary or 
final clinical study report, as required by Sec. 312.37, for the drug 
that is the subject of the investigation. This provision applies to 
special safety summaries and final clinical study reports from other 
investigations on the same drug and special safety summaries and final 
clinical study reports requested by FDA for investigations on closely 
related drugs conducted by the sponsor.
* * * * *
    11. Section 312.44 is amended by revising paragraph (b)(1)(viii) to 
read as follows:

Sec. 312.44  Termination.

* * * * *
    (b) * * *
    (1) * * *
    (viii) The sponsor fails to submit an accurate and timely annual or 
semiannual safety report of the investigations in accordance with 
Sec. 312.33.
* * * * *
    12. Section 312.56 is amended by revising paragraph (c) to read as 
follows:

Sec. 312.56  Review of ongoing investigations.

* * * * *
    (c) Before the initiation of clinical studies, the sponsor shall 
develop a safety monitoring and evaluation program to evaluate safety 
data reported by the investigator(s). The sponsor shall review and 
evaluate the evidence relating to the safety and effectiveness of the 
drug as it is obtained from the investigator(s). The sponsor shall make 
such reports to FDA regarding information relevant to the safety of the 
drug as required under Secs. 312.32 and 312.37. The sponsor shall make 
annual and semiannual safety reports in accordance with Sec. 312.33.
* * * * *
    13. Section 312.64 is amended by adding two sentences at the end of 
paragraph (b) to read as follows:

Sec. 312.64  Investigator reports.

* * * * *
    (b) * * * An investigator shall report to the sponsor all adverse 
clinical and laboratory outcomes that are required to be reported under 
the protocol for the study. These reports shall be made within the time 
period specified within the protocol.
* * * * *

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN 
ANTIBIOTIC DRUG

    14. 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).

    15. Section 314.80 is amended in paragraph (a) by alphabetically 
adding definitions for ``Data lock-point,'' ``Disability,'' 
``International birth date,'' and ``Life-threatening,'' and by revising 
the definition of ``Serious;'' by adding two new sentences at the end 
of paragraph (b); by revising paragraph (c), the second sentence in 
paragraph (d)(1), paragraphs (f)(1), (f)(3)(ii), and (f)(4), and the 
last sentence in paragraph (l); by removing in paragraphs (f)(2) and 
the introductory text of paragraph (f)(3) the words ``Form FDA-1639'' 
and adding in their place the words ``FDA Form 3500A''; and by adding a 
new sentence at the end of paragraph (j) to read as follows:

Sec. 314.80  Postmarketing reporting of adverse drug experiences.

    (a) * * *
* * * * *
    Data lock-point means the date designated as the cutoff date for 
data to be incorporated into a specific postmarketing adverse drug 
experience periodic report. Data available to the applicant after this 
date will not be incorporated into the report, unless it represents 
important information.
    Disability means a substantial disruption of a person's ability to 
carry out normal life functions.
* * * * *
    International birth date means the date that the first regulatory 
authority in the world approved the human drug product for marketing.
    Life-threatening means that the patient was, in the view of the 
initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience 
that, had it occurred in a more serious form, might have caused death. 
For example, product-induced hepatitis that resolved without evidence 
of hepatic failure would not be considered life-threatening even though 
hepatitis of a more severe nature can be fatal. Similarly, an allergic 
reaction resulting in angioedema of the face would not be life-
threatening, even though angioedema of the larynx, allergic 
bronchospasm, or anaphylaxis can be fatal.
    Serious means an adverse drug experience occurring at any dose that 
is fatal or life-threatening, results in persistent or significant 
disability/incapacity, requires or prolongs inpatient hospitalization, 
necessitates medical or surgical intervention to preclude permanent 
impairment of a body function or permanent damage to a body structure, 
or is a congenital anomaly.
* * * * *
    (b) * * * Applicants should not resubmit to FDA adverse product 
experience reports forwarded to the applicant by FDA; however, they 
should submit all followup information to FDA. Applicants shall also 
develop written procedures for the surveillance, receipt, evaluation, 
and reporting of adverse drug experiences.
    (c) Reporting requirements. The applicant shall report to FDA 
adverse drug experience information, as described in this section. The 
applicant shall submit two copies of each report described in this 
section to the Central Document Room, Park Bldg., rm. 2-14, 12420 
Parklawn Dr., Rockville, MD 20857. FDA may waive the requirement for 
the second copy in appropriate instances.
    (1)(i) Postmarketing 15-day ``Alert reports''. The applicant shall 
report each adverse drug experience that is both serious and unexpected 
as soon as possible but in any case within 15 calendar days of initial 
receipt of the information. These reports shall be submitted on FDA 
Form 3500A.
    (ii) Postmarketing Fifteen-day ``Alert reports''--followup. The 
applicant shall promptly investigate all adverse drug experiences that 
are the subject of these postmarketing 15-day Alert reports and shall 
submit followup reports within 15 calendar days of receipt of new 
information or as requested by FDA. If additional information is not 
obtainable, records should be maintained of the unsuccessful steps 
taken to seek additional information. These postmarketing 15-day Alert 
reports and followups to them shall be submitted under separate cover 
and may not be included, except for summary or tabular purposes, in a 
postmarketing adverse drug experience periodic report.
    (iii) Increased frequency report. The applicant shall review 
periodically (at least as often as the periodic reporting cycle) the 
frequency of reports of adverse drug 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 calendar days of 
determining that a significant increase in frequency exists. Upon 
written notice, FDA may require that applicants review the frequency of 
reports of serious, expected adverse drug experiences at intervals 
different than the periodic reporting cycle. Reports of a significant 
increase in frequency are required to be submitted in narrative form 
(including the time period on which the increased frequency is based, 
the method of analysis, and the interpretation of the results), rather 
than using FDA Form 3500A. 15-day Alert reports based on increased 
frequency are required to be submitted under separate cover and may not 
be included, except for summary purposes, in a periodic report.
    (iv) Submission of reports. The requirements of paragraphs 
(c)(1)(i), (c)(1)(ii), and (c)(1)(iii) of this section, concerning the 
submission of postmarketing 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 of reports required by paragraphs (c)(1)(i), (c)(1)(ii), and 
(c)(1)(iii) of this section, obligations of a nonapplicant may be met 
by submission of all reports of serious adverse drug experiences to the 
applicant. If a nonapplicant elects to submit adverse drug experience 
reports to the applicant rather than to FDA, it shall submit each 
report to the applicant within 3 calendar days of its receipt by the 
nonapplicant, and the applicant shall then comply with the requirements 
of this section. Under this circumstance, the nonapplicant shall 
maintain a record of this action which shall include:
    (A) A copy of the drug experience report.
    (B) Date the report was received by the nonapplicant.
    (C) Date the report was submitted to the applicant.
    (D) Name and address of the applicant.
    (v) Report identification. Each report submitted under this 
paragraph shall bear prominent identification as to its contents, i.e., 
``15-day Alert report,'' ``15-day Alert report--followup,'' or 
``Increased frequency report.''
    (2) Periodic adverse drug experience reports. (i) The applicant 
shall report every 6 months each adverse drug experience not reported 
under paragraphs (c)(1)(i) and (c)(1)(ii) of this section. The periodic 
reporting term shall be based upon the international birth date of the 
human drug product. The first 6-month anniversary of the international 
birth date after the application is approved in the United States is 
the data lock-point for the first periodic reporting term. Each 
subsequent 6-month anniversary of the international birth date is the 
data lock-point for subsequent periodic reporting terms for that 
particular product. Periodic reports shall be submitted to FDA within 
45 days after the data lock-point. Upon written notice, FDA may require 
that the applicant submit reports under this section at times other 
than those stated. An applicant who wishes to submit periodic reports 
at different intervals must submit to FDA a request for a waiver under 
Sec. 314.90. Followup information to adverse drug experiences submitted 
initially in a periodic report may be submitted in the next periodic 
report. If the applicant does not receive any adverse experience 
reports during the reporting period, the applicant shall, in place of a 
periodic report, send a copy of the current approved U.S. labeling and 
a letter identifying the product, the application number, and the 
reporting period, stating that no adverse drug experience reports were 
received.
    (ii) Reports. Each periodic report shall contain:
    (A) Title page, table of contents, and introduction. The 
introduction shall be a summary of the periodic report with page 
references to detailed data and information.
    (B) Applicant's core safety data sheet. The applicant's core safety 
data sheet shall be a document prepared by the applicant that contains 
all relevant safety information, including adverse drug experiences, 
which the applicant believes should be listed for the drug in all 
countries where the drug is marketed. It may be used by the applicant 
as the reference document by which an adverse drug experience is judged 
to be expected or unexpected for purposes of this postmarketing 
periodic report. For all other determinations of whether an adverse 
drug experience is expected or unexpected, the definition in paragraph 
(a) of this section shall apply.
    (1) FDA recognizes that the postmarketing periodic report may be 
submitted by the applicant to multiple countries and the product may 
have different approved labels in the different countries. The use of 
the applicant's core safety data sheet as the reference document for 
determining whether an adverse drug experience is unexpected or not may 
result in some overreporting of unexpected adverse events that actually 
are expected by the U.S. approved product label. This is because the 
approved label for the United States may have more safety information 
included in it than the manufacturer's core safety data sheet. If an 
adverse event is not listed in the U.S. label, but is in the 
manufacturer's core safety data sheet, this shall be clearly noted in 
the ``Overall safety evaluation'' (see paragraph (c)(2) (ii)(H) of this 
section). This section also shall highlight clearly any changes and the 
reasons for the changes in the applicant's core safety data sheet since 
the previous postmarketing periodic report.
    (2) An applicant may also use the approved U.S. label as the 
reference by which expected and unexpected adverse drug experiences are 
determined for the postmarketing periodic report. If an applicant 
chooses to use the approved U.S. label for this purpose, it shall 
clearly be stated in this section of the report.
    (C) The product's marketing status. This section shall contain a 
table containing a chronological history of the marketing status of the 
product worldwide (all regulatory decisions affecting the product and 
all market launches) from the date it was first approved through its 
current status. Approvals or applications voluntarily withdrawn for 
safety reasons shall be included at a minimum. The product shall be 
listed by chemical (or proper name) and brand name(s).
    (D) Regulatory actions for safety reasons. This section shall 
contain a narrative identifying the reasons for significant regulatory 
authority or manufacturer-initiated actions taken anywhere in the 
world, or to be taken imminently, for safety reasons during the 
reporting period. This includes, for example, application withdrawal or 
license suspension or failure to renew, distribution restrictions, 
clinical trial suspension, labeling changes due to significant safety 
concerns, dosage modifications, or pharmaceutical changes.
    (E) Patient exposure. This section shall include the product's 
domestic and foreign marketing distribution data during the reporting 
period. This shall be used to calculate the extent of patient exposure. 
The method used by the manufacturer to estimate patient exposure shall 
always be described and shall include the total number of dosage units 
of each dosage form and strength or potency (e.g., 100,000/5-milligram 
tablets, 50,000/10-milliliter vials).
    (F) Individual case histories. This section shall consist of 
individual case reports of adverse drug experiences thought possibly 
associated with the use of the drug that are:
    (1) Serious, unexpected reports from published or unpublished 
clinical studies where the applicant has concluded that there is a 
reasonable possibility that the drug caused the adverse experience;
    (2) Serious, expected or unexpected spontaneous adverse drug 
experience reports and nonserious, unexpected spontaneous adverse drug 
experience reports (causality always assumed in spontaneous reports) 
received directly by the applicant from the initial reporter or 
received by the applicant from a drug regulatory authority, both U.S. 
or foreign; and
    (3) Serious, expected or unexpected, individual published case 
histories and nonserious, unexpected individual published case 
histories.
    (4) All of these reports in paragraphs (c)(2)(ii)(F)(1) through 
(c)(2)(ii)(F)(3) of this section shall be presented in line listing 
format with the following 10 columns: country, source, age, gender, 
dose, duration of treatment (prior to event), time to onset, 
description of reaction (as reported), outcome (e.g., fatal, resolved), 
other comments (e.g., manufacturer's report number). This format is 
consistent with that suggested by CIOMS. In addition, a tabular summary 
of the number of adverse events by body system may be included. This 
section shall end with an analysis by the reporter, in narrative form, 
of the cases submitted. The applicant shall also attach to the end of 
the postmarketing periodic report a completed FDA Form 3500A for all 
U.S. spontaneous reports of adverse drug experiences except those 
reported under paragraphs (c)(1)(i) and (c)(1)(ii) of this section, or 
those sent by FDA to the applicant.
    (G) Safety studies. This section shall contain an analysis and full 
critical discussion of all toxicological, clinical, and epidemiological 
studies containing important safety information.
    (H) Overall safety evaluation. This section shall contain a 
critical analysis and full discussion of the safety information 
provided in the periodic report as it pertains to serious unexpected 
reactions, increased frequencies of known toxicity, reactions listed in 
the manufacturer's core safety data sheet but not included in the U.S. 
label, drug interactions, overdose, drug abuse, experiences during 
pregnancy or lactation, chronic treatment, pediatric or geriatric 
treatment, and new safety issues. The applicant shall indicate when any 
significant information has not been obtained. The evaluation shall 
indicate whether the safety profile of the product remains consistent 
with cumulative experience to date and with the previous manufacturer's 
core safety data sheet. The evaluation shall specify any action 
recommended and the reasons for such recommendations.
    (I) Other information. This section shall include important 
information received after the data lock-point.
    (J) FDA Form 3500A. An FDA Form 3500A shall be used for each 
spontaneous U.S. adverse drug experience not reported under paragraphs 
(c)(1)(i) and (c)(1)(ii) of this section.
    (K) Location of adverse experience records. The current addresses 
where all adverse experience reports and records are maintained.
    (d) * * *
    (1) * * * The 15-day reporting requirements in paragraph 
(c)(1)(iii) of this section (i.e., a significant increase in frequency 
of a serious, expected adverse drug experience, or of a therapeutic 
failure) apply only to the reports found in scientific and medical 
journals either as case reports or as the result of a formal clinical 
trial. * * *
* * * * *
    (f) Reporting FDA Form 3500A. (1) Except as provided in paragraphs 
(c)(1)(iii) and (f)(3) of this section, the applicant shall complete 
FDA Form 3500A for each report of an adverse drug experience.
* * * * *
    (3) * * *
    (ii) The format is agreed to in advance by MedWatch: The FDA 
Medical Products Reporting Program.
    (4) Ten copies or fewer of FDA Form 3500A and/or a copy of the 
instructions for completing the form may be obtained from the Division 
of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation 
and Research, Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857. More than 10 copies of the form may be obtained by 
writing to the Consolidated Forms and Publications Distribution Center, 
Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 20785.
* * * * *
    (j) * * * Copies of this guideline may be obtained from the CDER 
Executive Secretariat Staff (HFD-8), Center for Drug Evaluation and 
Research, Food and Drug Administration, 7500 Standish Pl., Rockville, 
MD 20857.
* * * * *
    (l) * * * For purposes of this provision, the term ``applicant'' 
also includes any person reporting under paragraph (c)(1)(iv) of this 
section.
* * * * *

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    16. 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 of the 
Public Health Service Act (42 U.S.C. 216, 262, 263, 263a, 264).

    17. Section 600.80 as added in a final rule published elsewhere in 
this issue of the Federal Register is amended in paragraph (a) by 
alphabetically adding definitions for ``Data lock-point,'' 
``Disability,'' ``International birth date,'' and ``Life-threatening;'' 
by revising the definition of ``Serious;'' by adding two new sentences 
at the end of paragraph (b); by revising paragraph (c), the third 
sentence in paragraph (d)(1), paragraph (g), and the last sentence in 
paragraph (m); and by adding a new sentence at the end of paragraph (j) 
to read as follows:

Sec. 600.80  Postmarketing reporting of adverse experiences.

    (a) * * *
* * * * *
    Data lock-point means the date designated as the cutoff date for 
data to be incorporated into a specific postmarketing adverse 
experience periodic report. Data available to the licensed manufacturer 
after this date will not be incorporated into the report, unless it 
represents important information.
    Disability means a substantial disruption of a person's ability to 
carry out normal life functions.
* * * * *
    International birth date means the date that the first regulatory 
authority in the world approved the biological drug product for 
marketing.
    Life-threatening means that the patient was, in the view of the 
initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience 
that, had it occurred in a more serious form, might have caused death. 
For example, product-induced hepatitis that resolved without evidence 
of hepatic failure would not be considered life-threatening even though 
hepatitis of a more severe nature can be fatal. Similarly, an allergic 
reaction resulting in angioedema of the face would not be life-
threatening, even though angioedema of the larynx, allergic 
bronchospasm, or anaphylaxis can be fatal.
    Serious means an adverse drug experience occurring at any dose that 
is fatal or life-threatening, results in persistent or significant 
disability/incapacity, requires or prolongs inpatient hospitalization, 
necessitates medical or surgical intervention to preclude permanent 
impairment of a body function or permanent damage to a body structure, 
or is a congenital anomaly.
* * * * *
    (b) * * * Licensed manufacturers should not resubmit to FDA adverse 
product experience reports forwarded to the licensed manufacturer by 
FDA; however, they should submit all followup information to FDA. 
Licensed manufacturers shall also develop written procedures for the 
surveillance, receipt, evaluation, and reporting of adverse 
experiences.
    (c) Reporting requirements. The licensed manufacturer shall report 
to FDA adverse experience information, as described in this section. 
The licensed manufacturer shall submit two copies of each report 
described in this section for nonvaccine biological products to the 
Center for Biologics Evaluation and Research (HFM-210), Food and Drug 
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448. Submit all vaccine adverse experience reports to: Vaccine Adverse 
Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD 20849-
1100. FDA may waive the requirement for the second copy in appropriate 
instances.
    (1)(i) Postmarketing 15-day ``Alert reports''. The licensed 
manufacturer shall report each adverse experience that is both serious 
and unexpected as soon as possible, but in any case within 15 calendar 
days of initial receipt of the information. These reports shall be 
submitted for nonvaccine biological products on FDA Form 3500A, and, 
for vaccines, on a VAERS form.
    (ii) Postmarketing 15-day ``Alert reports''--followup. The licensed 
manufacturer shall promptly investigate all adverse experiences that 
are the subject of these postmarketing 15-day Alert reports and shall 
submit followup reports within 15 calendar days of receipt of new 
information or as requested by FDA. If additional information is not 
obtainable, records should be maintained of the unsuccessful steps 
taken to seek additional information. These postmarketing 15-day Alert 
reports and followups to them shall be submitted under separate cover 
and may not be included, except for summary or tabular purposes, in a 
postmarketing adverse experience periodic report.
    (iii) Increased frequency report. The licensed manufacturer shall 
review periodically (at least as often as the periodic reporting cycle) 
the frequency of reports of adverse biological product 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 calendar 
days of determining that a significant increase in frequency exists. 
Upon written notice, FDA may require that licensed manufacturers review 
the frequency of reports of serious, expected adverse biological 
experiences at intervals different than the periodic reporting cycle. 
Reports of a significant increase in frequency are required to be 
submitted in narrative form (including the time period on which the 
increased frequency is based, the method of analysis, and the 
interpretation of the results), rather than using the form designated 
by FDA. 15-day Alert reports based on increased frequency are required 
to be submitted under separate cover and may not be included, except 
for summary purposes, in a periodic report.
    (iv) Submission of reports. The requirements of paragraphs 
(c)(1)(i), (c)(1)(ii), and (c)(i)(iii) of this section, concerning the 
submission of postmarketing 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. However, in order to avoid unnecessary duplication in 
the submission to FDA of reports required by paragraphs (c)(1)(i), 
(c)(1)(ii), and (c)(1)(iii) of this section, obligations of a 
manufacturer other than the licensed manufacturer, including a licensed 
manufacturer of the product other than in its final form, may be met by 
submission of all reports of serious adverse experiences to the 
licensed manufacturer of the final product. If a manufacturer, other 
than the licensed manufacturer, elects to submit reports to the 
licensed manufacturer rather than to FDA, it shall submit each report 
to the licensed manufacturer within 3 calendar days of its receipt, and 
the licensed manufacturer shall then comply with the requirements of 
this section. Under this circumstance, the manufacturer shall maintain 
a record of this action which shall include:
    (A) A copy of all adverse biological product experience reports 
submitted to the licensed manufacturer.
    (B) Date the report was received by the manufacturer other than the 
licensed manufacturer.
    (C) Date the report was submitted to the licensed manufacturer.
    (D) Name and address of the licensed manufacturer.
    (v) Report identification. Each report submitted under this 
paragraph shall bear prominent identification as to its contents, i.e., 
``15-day Alert report,'' ``15-day Alert report--followup,'' or 
``Increased frequency report.''
    (2)(i) Periodic adverse experience reports. The licensed 
manufacturer shall report every 6 months each adverse experience not 
reported under paragraphs (c)(1)(i) and (c)(1)(ii) of this section. The 
periodic reporting term shall be based upon the international birth 
date of the biological product. The first 6-month anniversary of the 
international birth date after the application is approved in the 
United States is the data lock- point for the first periodic reporting 
term. Each subsequent 6-month anniversary of the international birth 
date is the data lock-point for subsequent periodic reporting terms for 
that particular product. Periodic reports shall be submitted to FDA 
within 45 days after the data lock-point. Upon written notice, FDA may 
require that the licensed manufacturer submit reports under this 
section at times other than those stated. A licensed manufacturer who 
wishes to submit periodic reports at different intervals must submit to 
FDA a request for a waiver under Sec. 600.90. Followup information to 
adverse experiences submitted in a periodic report may be submitted in 
the next periodic report. If the licensed manufacturer does not receive 
any adverse experience reports during the reporting period, the 
licensed manufacturer shall, in place of a periodic report, send a copy 
of the current approved U.S. labeling and a letter identifying the 
product, the application number, and the reporting period, stating that 
no adverse experience reports were received.
    (ii) Reports. Each periodic report shall contain:
    (A) Title page, table of contents, and introduction. The 
introduction shall be a summary of the periodic report with page 
references to detailed data and information.
    (B) Licensed manufacturer's core safety data sheet. The licensed 
manufacturer's core safety data sheet shall be a document prepared by 
the licensed manufacturer that contains all relevant safety 
information, including adverse experiences, which the licensed 
manufacturer believes should be listed for the licensed biological 
product in all countries where the licensed biological product is 
marketed. It may be used by the licensed manufacturer as the reference 
document by which an adverse experience is judged to be expected or 
unexpected for purposes of this postmarketing periodic report. For all 
other determinations of whether an adverse experience is expected or 
unexpected, the definition in paragraph (a) of this section shall 
apply.
    (1) FDA recognizes that the postmarketing periodic report may be 
submitted by the licensed manufacturer to multiple countries and the 
product may have different approved labels in the different countries. 
The use of the licensed manufacturer's core safety data sheet as the 
reference document for determining whether an adverse drug experience 
is unexpected or not may result in some overreporting of unexpected 
adverse events that actually are expected by the U.S. approved product 
label. This is because the approved label for the United States may 
have more safety information included in it than the licensed 
manufacturer's core safety data sheet. If an adverse event is not 
listed in the U.S. label, but is in the licensed manufacturer's core 
safety data sheet, this shall be clearly noted in the ``Overall safety 
evaluation'' (see paragraph (c)(2)(ii)(H) of this section). This 
section also shall highlight clearly any changes and the reasons for 
the changes in the licensed manufacturer's core safety data sheet since 
the previous postmarketing periodic report.
    (2) A licensed manufacturer may also use the approved U.S. label as 
the reference by which expected and unexpected adverse experiences are 
determined for the postmarketing periodic report. If a licensed 
manufacturer chooses to use the approved U.S. label for this purpose, 
it shall clearly be stated in this section of the report.
    (C) The product's marketing status. This section shall contain a 
table containing a chronological history of the marketing status of the 
product worldwide (all regulatory decisions affecting the product and 
all market launches) from the date it was first approved through its 
current status. Approvals or applications voluntarily withdrawn for 
safety reasons shall be included at a minimum. The product shall be 
listed by chemical (or proper name) and brand name(s).
    (D) Regulatory actions for safety reasons. This section shall 
contain a narrative identifying the reasons for significant regulatory 
authority or manufacturer-initiated actions taken anywhere in the 
world, or to be taken imminently, for safety reasons during the 
reporting period. This includes, for example, licensed application 
withdrawal or license suspension or failure to renew, distribution 
restrictions, clinical trial suspension, labeling changes due to 
significant safety concerns, dosage modifications, or pharmaceutical 
changes.
    (E) Patient exposure. This section shall include the product's 
domestic and foreign marketing distribution data during the reporting 
period. This shall be used to calculate the extent of patient exposure. 
The method used by the licensed manufacturer to estimate patient 
exposure shall always be described and shall include the total number 
of dosage units of each dosage form and strength or potency (e.g., 
100,000/5-milligram tablets, 50,000/10-milliliter vials).
    (F) Individual case histories. This section shall consist of 
individual case reports of adverse experiences thought possibly 
associated with the use of the licensed biological product that are:
    (1) Serious, unexpected reports from published or unpublished 
clinical studies where the licensed manufacturer has concluded that 
there is a reasonable possibility that the licensed biological product 
caused the adverse experience;
    (2) Serious, expected or unexpected spontaneous adverse experience 
reports and nonserious, unexpected spontaneous adverse experience 
reports (causality always assumed in spontaneous reports) received 
directly by the licensed manufacturer from the initial reporter or 
received by the licensed manufacturer from a drug regulatory authority, 
both U.S. or foreign; and
    (3) Serious, expected or unexpected, individual published case 
histories and nonserious, unexpected individual published case 
histories.
    (4) All of these reports under paragraphs (c)(2)(ii)(F)(1) through 
(c)(2)(ii)(F)(3) of this section shall be presented in line listing 
format with the following 10 columns: country, source, age, gender, 
dose, duration of treatment (prior to event), time to onset, 
description of reaction (as reported), outcome (e.g., fatal, resolved), 
other comments (e.g., manufacturer's report number). This format is 
consistent with that suggested by CIOMS. In addition, a tabular summary 
of the number of adverse events by body system may be included. This 
section shall end with an analysis by the reporter, in narrative form, 
of the cases submitted. The licensed manufacturer shall also attach to 
the end of the postmarketing periodic report a completed FDA Form 3500A 
or VAERS form for all U.S. spontaneous reports of adverse experiences 
except those reported under paragraphs (c)(1)(i) and (c)(1)(ii) of this 
section, or those sent by FDA to the licensed manufacturer.
    (G) Safety studies. This section shall contain an analysis and full 
critical discussion of all toxicological, clinical, and epidemiological 
studies containing important safety information.
    (H) Overall safety evaluation. This section shall contain a 
critical analysis and full discussion of the safety information 
provided in the periodic report as it pertains to serious unexpected 
reactions, increased frequencies of known toxicity, reactions listed in 
the manufacturer's core safety data sheet but not included in the U.S. 
label, licensed biological product interactions, overdose, licensed 
biological product abuse, experiences during pregnancy or lactation, 
chronic treatment, pediatric or geriatric treatment, and new safety 
issues. The licensed manufacturer shall indicate when any significant 
information has not been obtained. The evaluation shall indicate 
whether the safety profile of the product remains consistent with 
cumulative experience to date and with the previous licensed 
manufacturer's core safety data sheet. The evaluation shall specify any 
action recommended and the reasons for such recommendations.
    (I) Other information. This section shall include important 
information received after the data lock-point.
    (J) FDA Form 3500A or VAERS Form. An FDA Form 3500A or VAERS form 
(for vaccines)shall be used for each spontaneous U.S. adverse 
experience not reported under paragraphs (c)(1)(i) and (c)(1)(ii) of 
this section.
    (K) Location of adverse experience records. The current addresses 
where all adverse experience reports and records are maintained.
    (3) Distribution reports. The licensed manufacturer shall submit 
information about the quantity of the product distributed under the 
product license, including the quantity distributed to distributors. 
The interval between distribution reports shall be 6 months. The 
reporting term shall be based upon the international birth date of the 
biological product. The first 6-month anniversary of the international 
birth date after the application is approved in the United States is 
the data lock-point for the first reporting term. Each subsequent 6-
month anniversary of the international birth date is the data lock-
point for subsequent reporting terms for that particular product. 
Distribution reports shall be submitted to FDA within 45 calendar days 
after the data lock-point. Upon written notice, FDA may require that 
the licensed manufacturer submit distribution reports under this 
section at times other than every 6 months. The distribution report 
shall consist of the bulk lot number (from which the final container 
was filled), the fill lot numbers for the total number of dosage units 
of each strength or potency distributed (e.g., 50,000/10-milliliter 
vials), the label lot number (if different from fill lot number), 
labeled date of expiration, number of doses in fill lot/label lot, date 
of release of fill lot/label lot released for distribution at that 
time. If any significant amount of a fill lot/label lot is returned, 
include this information. Disclosure of financial or pricing data is 
not required. As needed, FDA may require submission of more detailed 
product distribution information. Upon written notice, FDA may require 
that the licensed manufacturer submit reports under this section at 
times other than those stated. A licensed manufacturer that wishes to 
submit reports at times other than those stated should submit a request 
for a waiver under Sec. 600.90.
    (d) * * *
    (1) * * * The 15-day reporting requirements in paragraph 
(c)(1)(iii) of this section (i.e., a significant increase in frequency 
of a serious, expected adverse experience or of a therapeutic failure) 
apply only to reports found in scientific and medical journals either 
as the results of formal clinical trial, or from epidemiologic studies 
or analyses of experience in a monitored series of patients. * * *
* * * * *
    (g) Multiple reports. A licensed manufacturer should not include in 
reports under this section any adverse experience that occurred in 
clinical trials if they were previously submitted as part of the 
license application. If a report applies to a licensed biological 
product for which a licensed manufacturer holds more than one 
biological product license, the licensed manufacturer should submit the 
report for the license that was first approved. If a report refers to 
more than one biological product marketed by a licensed manufacturer, 
the licensed manufacturer should submit the report to the license for 
the product listed first in the report.
* * * * *
    (j) * * * Copies of this guideline may be obtained from the 
Congressional and Consumer Affairs Branch (HFM-12), Center for 
Biologics Evaluation and Research, Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20852-1448.
* * * * *
    (m) * * * For purposes of this provision, this paragraph also 
includes any person reporting under paragraph (c)(1)(iv) of this 
section.

Sec. 600.81  [Removed]

    18. Section 600.81  Distribution reports (as added in a final rule 
published elsewhere in this issue of the Federal Register) is removed.

    Dated: October 13, 1994.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 94-26483 Filed 10-26-94; 8:45 am]
BILLING CODE 4160-01-F