[Federal Register Volume 62, Number 194 (Tuesday, October 7, 1997)]
[Rules and Regulations]
[Pages 52237-52253]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-26255]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

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

[Docket No. 93N-0181]
RIN 0910-AA97


Expedited Safety Reporting Requirements for Human Drug and 
Biological Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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

SUMMARY: The Food and Drug Administration (FDA) is amending its 
expedited safety reporting regulations for human drug and biological 
products to provide consistency with the elements of FDA Form 3500A for 
use in pre- and postmarketing safety reporting;

[[Page 52238]]

implement definitions, reporting periods, formats, and standards as 
recommended by the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) and by the World Health Organization's Council for 
International Organizations of Medical Sciences (CIOMS); require 
applicants, manufacturers, packers, and distributors, as well as 
licensed manufacturers and other manufacturers of biological products, 
to develop written procedures for postmarketing safety monitoring and 
reporting; state that FDA Form 3500A reports that FDA forwards to any 
person subject to the postmarketing safety reporting requirements are 
not required to be resubmitted to the agency; and make other revisions 
to the regulations to provide uniformity with definitions and 
procedures used in expedited pre- and postmarketing safety reporting 
for human drug and biological products. These changes simplify and 
facilitate expedited safety reporting and enhance agencywide 
consistency in the collection of postmarketing safety data.

DATES: This regulation is effective April 6, 1998. Submit written 
comments on the information collection provisions of this final rule by 
December 8, 1997.

ADDRESSES: Submit written comments on the information collection 
provisions of this final rule to the Dockets Management Branch (HFA-
305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:
    For information concerning human drug products: Audrey A. Thomas, 
Center for Drug Evaluation and Research (HFD-7), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-5625.
    For information concerning human biological products: Valerie A. 
Butler, Center for Biologics Evaluation and Research (HFM-17), Food and 
Drug Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 
20852-1448, 301-594-3074.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In the Federal Register of October 27, 1994 (59 FR 54046), FDA 
published a proposed rule to amend the regulations for expedited and 
periodic pre- and postmarketing safety reporting for human drug and 
biological products (hereinafter referred to as the October 1994 
proposal). FDA also proposed to amend the requirements for clinical 
study design and conduct and annual sponsor reporting in the 
investigational new drug application (IND) regulations.
    As explained in the October 1994 proposal, the amendments to the 
safety reporting regulations are intended to provide consistency with 
certain standardized definitions, procedures, and formats developed by 
ICH and CIOMS (59 FR 54046 at 54047). In the Federal Register of July 
9, 1993 (58 FR 37408), FDA published an ICH draft guideline entitled 
``Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting'' (hereinafter referred to as the draft ICH E2A 
guideline). The public was given an opportunity to comment on the draft 
ICH E2A guideline. After consideration of the comments received and 
revisions to the draft guideline, ICH finalized the guideline. In the 
Federal Register of March 1, 1995 (60 FR 11284), FDA published the ICH 
final guideline (hereinafter referred to as the final ICH E2A 
guideline). Although the final ICH E2A guideline pertains to expedited 
safety reporting during the preapproval phase of drug development, for 
consistency and simplicity many of the definitions, reporting periods, 
formats, and standards also could apply to FDA's expedited 
postmarketing safety reporting requirements.
    In this final rule, FDA is amending its regulations for expedited 
safety reporting to implement certain definitions, reporting periods, 
and formats recommended in the final ICH E2A guideline. FDA is 
considering other recommendations in the final ICH E2A guideline that 
were not included in the October 1994 proposal and plans to propose 
additional amendments to its expedited safety reporting regulations 
shortly (e.g., pre- and postmarketing reporting of adverse drug 
reactions rather than adverse drug experiences, submission of expedited 
safety reports to FDA from clinical investigations based on the opinion 
of either the sponsor or investigator).
    FDA is delaying finalization of the proposed amendments to the 
periodic postmarketing safety reporting regulations (59 FR 54046). The 
proposed amendments were based, for the most part, on recommendations 
developed by the CIOMS Working Group II (Ref. 1). ICH also developed 
recommendations, based on the CIOMS Working Group II proposals, for 
periodic postmarketing safety reporting. In the Federal Register of May 
19, 1997 (62 FR 27470), FDA published an ICH final guideline entitled 
``Clinical Safety Data Management: Periodic Safety Update Reports for 
Marketed Drugs'' (hereinafter referred to as the ICH E2C guideline). 
FDA will finalize the proposed amendments to the periodic postmarketing 
safety reporting regulations after consideration of the provisions of 
the ICH E2C guideline.
    In light of the comments the agency received, FDA has reconsidered 
the proposed amendments to the requirements for clinical study design 
and conduct and annual sponsor reporting under the IND (59 FR 54046). 
In general, the comments opposed the proposed amendments because the 
current IND regulations protect the safety of the public in all but the 
most unusual cases. Based on these general comments and others specific 
to each of the proposed amendments, the agency has decided to withdraw 
the proposed amendments to the IND requirements for clinical study 
design and conduct and annual sponsor reporting. The agency will, 
instead, develop a guidance document providing recommendations on study 
design and monitoring of investigational drugs used to treat serious 
and potentially fatal illnesses, with particular attention to detection 
of adverse events that are similar to those caused by the underlying 
disease. In developing the draft guidance document, FDA will consider 
comments submitted in response to the proposed amendments and will 
provide opportunity for public input on the document prior to its 
implementation. Thus, in this final rule, FDA is withdrawing the 
proposed amendments to the IND regulations (part 312 (21 CFR part 312)) 
at Secs. 312.23, the second sentence of 312.32(c)(1)(i), 312.33, 
312.37, 312.42, 312.44, 312.56, and 312.64 (59 FR 54046 at 54057 to 
54059).
    In the Federal Register of June 25, 1997 (62 FR 34166), FDA 
published a final rule to amend its regulations on expedited reporting 
of postmarketing adverse experiences to revoke the requirement for 
increased frequency reports as expedited reports for human drug and 
licensed biological products. Thus, in this final rule, FDA is 
withdrawing the proposed amendments to the increased frequency 
reporting requirements published in the October 1994 proposal.

II. Background

    In the Federal Register of June 3, 1993 (58 FR 31596), FDA 
announced the availability of a new form for reporting single cases of 
adverse events and product problems with medications, devices, and 
other FDA-regulated medical products (hereinafter referred to as the 
June 1993 notice). This form is available in two versions: FDA Form 
3500 is for use by health care professionals and consumers for

[[Page 52239]]

voluntary reporting; FDA Form 3500A is for use by any person subject to 
FDA's mandatory safety reporting regulations. Adverse events associated 
with vaccines continue to be reported to FDA and the Centers for 
Disease Control and Prevention using the Vaccine Adverse Event 
Reporting System (VAERS) form.
    Under the existing regulations, manufacturers, packers, and 
distributors; applicants of approved new and abbreviated marketing 
applications for drugs and antibiotics; and licensed manufacturers and 
other manufacturers of biological products must submit expedited 
reports of postmarketing adverse drug experiences under 21 CFR 310.305, 
314.80, 314.98, and 600.80. Sponsors of IND's must also submit 
expedited reports, under Sec. 312.32, for adverse experiences 
associated with the use of an investigational human drug or biological 
product. Currently, there is no standard form for these IND expedited 
safety reports.
    FDA Forms 3500 and 3500A are part of FDA's Medical Products 
Reporting Program (MedWatch) and are designed to facilitate safety 
reporting for most FDA-regulated human medical products by the entire 
health care community, including manufacturers, distributors, user 
facilities, and health care professionals. FDA issued the new forms to 
simplify and consolidate safety reporting for human drug products, 
biologics, and medical devices, as well as other FDA-regulated medical 
products. The new forms eliminate redundant or nonessential elements 
from past reporting forms and clarify those areas that have caused 
confusion.
    In developing FDA Forms 3500 and 3500A, and in developing the 
revisions to the expedited safety reporting regulations that are the 
subject of this final rule, the agency considered several ICH and CIOMS 
recommendations. 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. In addition, several CIOMS working groups have 
served to coordinate and standardize the international reporting of 
suspected postmarketing adverse drug reactions by pharmaceutical 
manufacturers to regulatory authorities. FDA believes the changes 
recommended by CIOMS and ICH will result in more effective and 
efficient safety reporting to regulatory authorities worldwide.

III. Description of the Final Rule

    This final rule amends parts 20, 310, 312, 314, and 600 (21 CFR 
parts 20, 310, 312, 314, and 600) to revise definitions, requirements, 
and procedures for expedited pre- and postmarketing safety reporting. 
This rulemaking finalizes many of the expedited safety reporting 
provisions as proposed in the October 1994 proposal. In addition, this 
final rule reflects amendments to the October 1994 proposal that were 
made in response to comments (discussed in section IV of this 
document), including comments recommending greater consistency with the 
ICH E2A guideline and uniformity between pre- and postmarketing safety 
reporting definitions. This final rule also incorporates minor 
revisions for clarity and further consistency. The major provisions of 
the final rule are summarized as follows:
    1. FDA Forms 3500/3500A. As proposed, the final rule permits 
sponsors to submit IND safety reports, under Sec. 312.32(c)(1)(i), on 
FDA Form 3500A rather than in a narrative format, and replaces, at 
Secs. 310.305 and 314.80, Form FDA-1639 with FDA Form 3500A for use in 
postmarketing safety reporting for human drug products. The final rule 
also replaces, at Sec. 20.112, Form FDA-1639 with FDA Form 3500 for 
voluntary drug experience reporting by physicians and hospitals. The 
final rule, like the proposed rule, instructs applicants, 
manufacturers, packers, and distributors to obtain approval from FDA's 
MedWatch office before using an alternative reporting format for 
postmarketing safety reporting under Secs. 310.305(d)(3)(ii) and 
314.80(f)(3)(ii). Pre- and postmarketing safety reporting of foreign 
events may continue to be reported to FDA on the CIOMS I form (Ref. 2). 
After consideration of the comments, the final rule, unlike the 
proposed rule, permits use of the CIOMS I form for this purpose without 
prior FDA approval.
    2. Definitions. In response to comments, the proposed definition of 
``serious'' at Secs. 310.305(b), 312.32(a), 314.80(a), and 600.80(a) 
has been revised to make it consistent with the definition of 
``serious'' in the final ICH E2A guideline and with the definition of 
``serious'' used in FDA Form 3500A. To provide uniformity between the 
pre- and postmarketing definitions of ``serious,'' the following 
information has been removed from the current definition of ``serious 
adverse experience'' at Sec. 312.32(a) and added as a reporting 
requirement to the IND safety reporting regulations at 
Sec. 312.32(c)(1)(i):
    With respect to results obtained from tests in laboratory 
animals, a serious adverse drug experience includes any experience 
suggesting a significant risk for human subjects, including any 
finding of mutagenicity, teratogenicity, or carcinogenicity.
This revision represents an organizational change that does not impose 
a new burden because sponsors are already required to report such 
information to FDA.
    In response to comments, the final rule also amends the proposed 
definitions of ``disability'' and ``life-threatening'' at 
Secs. 310.305(b), 314.80(a), and 600.80(a) for consistency with the 
final ICH E2A guideline and for clarity. In addition, the definition of 
``disability'' has been added to the ``definitions'' section of the 
premarketing safety reporting regulations at Sec. 312.32(a), and the 
definition of ``life-threatening'' has been removed from the 
``telephone safety report'' section of the premarketing safety 
reporting regulations at Sec. 312.32(c)(2) and added to the 
``definitions'' section of these regulations at Sec. 312.32(a). For 
further clarity and consistency in reporting adverse drug experiences 
that are life-threatening, FDA has decided to replace, at 
Secs. 310.305(b), 312.32(a), 314.80(a), and 600.80(a), the word 
``serious'' with ``severe'' so that the first sentence of the 
definition of ``life-threatening'' includes the following: ``* * *, 
i.e., [Life-threatening] does not include a reaction that, had it 
occurred in a more severe form, might have caused death.'' As explained 
in the final ICH E2A guideline, ``severe'' refers to the intensity 
(severity) of a specific event (e.g., mild, moderate, or severe 
myocardial infarction); the event itself may be of relatively minor 
medical significance such as a severe headache. The term ``serious,'' 
however, is based on patient/event outcome or action criteria usually 
associated with events that pose a threat to a patient's life or 
functioning (e.g., an event that results in death or that is life-
threatening or requires inpatient hospitalization) (60 FR 11284 at 
11285). FDA has also decided to remove the following sentence from this 
definition: ``For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life-threatening 
even though drug-induced hepatitis can be fatal.'' Use of hepatitis as 
an example for life-threatening may be confusing because viral 
transmission of certain types of hepatitis through blood products could 
be life-

[[Page 52240]]

 threatening. To harmonize pre- and postmarketing safety reporting 
definitions, FDA has decided to withdraw the examples listed in the 
proposed postmarketing definition of ``life-threatening'' at 
Secs. 310.305(b), 314.80(a), and 600.80(a). The agency has decided, 
instead, to revise the guidances associated with this final rule to 
include examples of life-threatening adverse drug experiences (CDER's 
``Guideline for Postmarketing Reporting of Adverse Drug Experiences,'' 
March 1992 and CBER's ``Guideline for Adverse Experience Reporting for 
Licensed Biological Products,'' October 1993).
    In this final rule, FDA is incorporating minor changes to the 
definition of ``unexpected'' adverse drug experience at 
Secs. 310.305(b), 312.32(a), 314.80(a), and 600.80(a) to provide 
uniformity between pre- and postmarketing safety reporting definitions 
and consistency with the ICH E2A guideline.
    The definition of ``unexpected'' adverse drug experience at 
Secs. 310.305(b), 314.80(a), and 600.80(a) currently states:
    * * * 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 hepatic 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.
To clarify what must be reported to the agency as an ``unexpected 
adverse drug experience,'' FDA is amending this definition by adding 
the following sentence:
    ``Unexpected,'' as used in this definition, refers to an adverse 
drug experience that has not been previously observed (i.e., 
included in the labeling) rather than from the perspective of such 
experience not being anticipated from the pharmacological properties 
of the pharmaceutical product.
This amendment is consistent with the discussion of ``expectedness of 
an adverse drug reaction'' in the final ICH E2A guideline:
    The purpose of expedited reporting is to make regulators, 
investigators, and other appropriate people aware of new, important 
information on serious reactions. Therefore, such reporting will 
generally involve events previously unobserved or undocumented, and 
a guideline is needed on how to define an event as ``unexpected'' or 
``expected'' (expected/ unexpected from the perspective of 
previously observed, not on the basis of what might be anticipated 
from the pharmacological properties of a medicinal product).
    The definition of ``unexpected adverse experience'' at 
Sec. 312.32(a) currently states:
    * * * any adverse experience that is not identified in nature, 
severity, or frequency in the current investigator brochure; or, if 
an investigator brochure is not required, that is not identified in 
nature, severity, or freuquency [sic] in the risk information 
described in the general investigational plan or elsewhere in the 
current application, as amended.
For clarity and consistency, FDA is amending this definition to conform 
with the definition of ``unexpected'' at Secs. 310.305(b), 314.80(a), 
and 600.80(a) by removing the references to frequency, replacing the 
word ``nature'' with the word ``specificity,'' adding examples of 
unexpected adverse drug experiences, and making other minor revisions. 
The revised definition at Sec. 312.32(a) states:
    Unexpected adverse drug experience: Any adverse drug experience, 
the specificity or severity of which is not consistent with the 
current investigator brochure; or if an investigator brochure is not 
required or available, the specificity or severity of which is not 
consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as 
amended. For example, under this definition, hepatic necrosis would 
be unexpected (by virtue of greater severity) if the investigator 
brochure only referred to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (by virtue of greater specificity) if the investigator 
brochure only listed cerebral vascular accidents. ``Unexpected,'' as 
used in this definition, refers to an adverse drug experience that 
has not been previously observed (e.g., included in the investigator 
brochure) rather than from the perspective of such experience not 
being anticipated from the pharmacological properties of the 
pharmaceutical product.
    3. IND Safety Reports. As proposed, the final rule revises the time 
period for submitting written IND safety reports, under 
Sec. 312.32(c)(1) and (d)(3), from 10 working days to 15 calendar days, 
and revises the time period for submitting telephone IND safety 
reports, under Sec. 312.32(c)(2), from 3 working days to 7 calendar 
days. The final rule also permits telephone safety reports to be made 
by facsimile transmission under Sec. 312.32(c)(2). The final rule, as 
proposed with minor revisions for clarity, also states, at 
Sec. 312.32(c)(1)(i), that FDA may require sponsors to submit 
additional data.
    In response to comments, FDA is making minor revisions to its IND 
safety reporting regulations to provide greater consistency with the 
final ICH E2A guideline. Currently, the requirement at Sec. 312.32(b) 
states:
    The sponsor shall promptly review all information relevant to 
the safety of the drug obtained or otherwise received by the sponsor 
from any source, foreign or domestic, including information derived 
from clinical investigations, animal investigations, commercial 
marketing experience, reports in the scientific literature, and 
unpublished scientific papers.
To clarify the phrase ``any source,'' FDA is adding ``epidemiological 
investigations'' and ``foreign regulatory authorities that have not 
already been previously reported to the agency by the sponsor'' to the 
list of examples in Sec. 312.32(b). This revision does not impose a new 
burden because sponsors are already required to review all information 
relevant to the safety of the drug obtained or otherwise received by 
the sponsor from any source, foreign or domestic. The amendment 
clarifies for sponsors the type of safety information that must be 
examined for determination of whether information should be submitted 
to the agency in IND safety reports. This revision is consistent with 
the final ICH E2A guideline (60 FR 11284 at 11285 and 11286):
    [Expedited reporting] applies to reports from spontaneous 
sources and from any type of clinical or epidemiological 
investigation, independent of design or purpose.
The agency does not expect sponsors to search adverse drug experience 
data bases generated by regulatory authorities for safety information 
or to submit to FDA adverse drug experience reports submitted to them 
by FDA.
    FDA is also amending its IND safety reporting regulations at 
Sec. 312.32(c)(1)(i), as noted above, by adding, with minor revisions, 
language that is being moved from the current definition of ``serious 
adverse experience'' at Sec. 312.32(a):
    any finding from tests in laboratory animals that suggests a 
significant risk for human subjects including reports of 
mutagenicity, teratogenicity, or carcinogenicity.
This revision represents an organizational change that does not impose 
any new burden because sponsors are currently required to report such 
information to FDA. For clarity and consistency, FDA is amending 
Sec. 312.32(c)(1)(i) to state that reports from animal studies and 
epidemiological studies must be submitted in a narrative format rather 
than on FDA Form 3500A because FDA Form 3500A has been designed for 
reporting of adverse experience information from an individual patient.
    4. Postmarketing 15-day Alert and Followup Reports. As proposed, 
the final rule revises, at Secs. 310.305(c), 314.80(c), and 600.80(c), 
the time period for submitting postmarketing Alert reports from 15 
working days to 15 calendar days. For clarity, the final rule is being 
amended, at Sec. 310.305(c)(1)(i),

[[Page 52241]]

to state that the 15 calendar day timeframe for reporting adverse drug 
experiences on marketed prescription drugs for human use without 
approved new drug applications (NDA's) begins upon initial receipt of 
the information by the person whose name appears on the label. In 
addition, the final rule at Secs. 310.305(c)(2), 314.80(c)(1)(ii), and 
600.80(c)(1)(ii), as proposed, advises any person subject to the 
reporting requirements under Secs. 310.305(c), 314.80(c), and 
600.80(c), who has been unable to obtain additional information for 
adverse drug experiences that are the subject of postmarketing 15-day 
Alert reports, to maintain records of their unsuccessful attempts to 
seek additional information. For clarity, the final rule is being 
amended, at Sec. 310.305(c)(2), to state that 15-day Alert reports and 
followups to them must be submitted under separate cover.
    The final rule specifies, like the proposed rule, at 
Secs. 310.305(c)(6), 314.80(b), and 600.80(b), that no one subject to 
this rule is required to resubmit to the agency reports of adverse drug 
experiences that the agency has forwarded to them. For clarity, the 
final rule is being amended, at Secs. 310.305(c)(6), 314.80(b), and 
600.80(b), to emphasize that followup reports must be submitted for 
reports received from the agency. The final rule also requires, at 
Secs. 310.305(a), 314.80(b), and 600.80(b), any person subject to the 
reporting requirements under Secs. 310.305(c), 314.80(c), and 600.80(c) 
to develop written procedures for the postmarketing surveillance, 
receipt, evaluation, and reporting of adverse drug experiences to FDA. 
In response to comments, the final rule permits persons subject to the 
reporting requirements under Secs. 310.305(c), 314.80(c), and 600.80(c) 
to submit reports of serious adverse drug experiences to a 
manufacturer, applicant, or licensed manufacturer of a final biological 
product instead of FDA in 5 calendar days, instead of 3 calendar days 
as proposed.
    In this final rule, FDA is also amending the postmarketing 
expedited reporting regulations, at Secs. 314.80(c)(1)(i) and 
600.80(c)(1)(i), by replacing, in the first sentence, the phrase 
``regardless of source'' with the phrase ``whether foreign or 
domestic.'' This amendment is consistent with Secs. 314.80(b) and 
600.80(b) which describe adverse drug experience information that must 
be reviewed by applicants and licensed manufacturers:
    Each applicant (Any person having a product license) * * * shall 
promptly review all adverse drug experience information (pertaining 
to its product) obtained or otherwise received by the applicant 
(licensed manufacturer) from any source, foreign or domestic, 
including * * *.
FDA is making this revision to clarify that 15-day Alert reports are to 
be submitted for appropriate foreign as well as domestic adverse drug 
experiences.
    5. Implementation Schedule. The effective date for this final rule 
has been extended to 180 days after its publication in the Federal 
Register to allow sufficient time for the agency to comply with the 
provisions of the Paperwork Reduction Act of 1995. Any person subject 
to FDA's mandatory safety reporting requirements may comply with the 
provisions of this final rule prior to its effective date.
    6. Guidances. In the Federal Register of February 27, 1997 (62 FR 
8961), FDA published a notice of a guidance document entitled ``Good 
Guidance Practices (GGP's),'' in which FDA announced that notices of 
draft and final guidances will be provided both in the Federal Register 
and on the FDA World Wide Web (WWW) home page (http://www.fda.gov) (62 
FR 8961 at 8965). In this final rule, FDA is amending its postmarketing 
safety reporting regulations at Secs. 314.80(j) and 600.80(j) to remove 
reference to guidelines prepared by the agency for submission of 
reports of adverse drug experiences and suggested followup 
investigation of these reports. FDA is also withdrawing its proposed 
amendments of October 27, 1994, regarding the availability of adverse 
experience reporting guidelines under Secs. 310.305(g), 314.80(j), and 
600.80(j). FDA is making these amendments because the guidance document 
of February 27, 1997, describes processes for timely notification of 
availability of draft and final guidance documents and it is no longer 
necessary for the agency to include reference to these documents in its 
postmarketing safety reporting regulations.
    At the present time, FDA is in the process of revising guidances 
pertaining to this final rule (CDER's ``Guideline for Postmarketing 
Reporting of Adverse Drug Experiences,'' March 1992 and CBER's 
``Guideline for Adverse Experience Reporting for Licensed Biological 
Products,'' October 1993) to provide persons with the agency's current 
thinking on reporting of postmarketing adverse drug experiences. The 
agency will provide notice of availability of any draft or final 
guidance document pertaining to these regulations in the Federal 
Register and on the FDA WWW home page.

IV. Comments on the Proposed Rule

    FDA received 57 comments on the proposed rule from representatives 
of pharmaceutical companies, health care professional and 
pharmaceutical associations, academic and government institutions, and 
individuals. The comments addressed all aspects of the October 1994 
proposal, including those areas that are not being finalized in this 
final rule. In general, the comments endorsed FDA's efforts in the 
proposal to support global harmonization through the adoption of 
certain ICH and CIOMS recommendations. However, many comments described 
areas where the proposed regulations did not conform to the 
international guidelines, and recommended that the proposal be revised 
to be more consistent. The agency also received comments recommending 
uniformity between its pre- and postmarketing safety reporting 
definitions. In response to these comments, FDA, as described in 
section III of this document, is amending its regulations to implement 
additional provisions recommended in the final ICH E2A guideline and to 
provide uniformity in its safety reporting definitions.
    A discussion of the comments pertaining to this final rule and the 
agency's responses follows.

A. Definition of Disability

    FDA proposed to define ``disability,'' in Secs. 310.305(b), 
314.80(a), and 600.80(a), as ``a substantial disruption of a person's 
ability to carry out normal life functions.''
    1. Eight comments requested clarification of this definition. One 
comment asked whether it included missing work because of an adverse 
experience, quitting a job, an inability to get out of bed, or a 
decrease in earning capacity. Another comment asked if it included 
nausea, vomiting, and diarrhea that would keep a person home from work. 
One questioned whether the proposed definition included events such as 
migraine headaches, severe influenza, or accidental trauma (e.g., 
sprained ankle). Another comment contended that if the proposed 
definition is intended to mean the substantial disruption of normal 
life functions, then such a condition would require hospitalization or 
the in-house use of life-support equipment.
    FDA proposed to include the definition of ``disability'' in the 
regulations to enable reporters to determine when a ``serious'' adverse 
drug experience occurs. The extent of a disability required for a 
serious adverse drug experience is described in the

[[Page 52242]]

definition of ``serious'' by the phrase ``* * * results in persistent 
or significant disability/incapacity * * *.'' Thus, only a persistent 
or significant or incapacitating disability is intended. The type of 
disability that would constitute a serious adverse drug experience is 
also described in the final ICH E2A guideline, which states that a 
serious adverse drug experience is based on events that pose a threat 
to a patient's life or functioning and not on events of relatively 
minor medical significance (60 FR 11284 at 11285). Thus, disability is 
not intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
    For clarity, FDA has revised the proposed definition of 
``disability'' by substituting the words ``to conduct'' for the words 
``to carry out.''
    To assure a consistent interpretation of serious adverse drug 
experience in premarketing and postmarketing safety reporting, FDA has 
decided to revise the ``definitions'' section of the IND safety reports 
regulation, at Sec. 312.32(a), by adding the definition of 
``disability'' that is used in the postmarketing safety reporting 
regulations at Secs. 310.305(b), 314.80(a), and 600.80(a).

B. Definition of Life-Threatening

    FDA proposed to define ``life-threatening,'' in Secs. 310.305(b), 
314.80(a), and 600.80(a), as follows:
    [T]hat 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.
    2. Five comments opposed the use of the phrase ``in the view of the 
initial reporter.'' The comments stated that the initial reporter could 
be a lay person whose judgment of what constitutes an ``immediate risk 
of death'' may be contrary to an evaluation by a medically 
knowledgeable source. Several comments suggested alternative language 
for the definition to minimize inaccurate reporting of events. One 
comment requested deletion of the word ``initial.'' Another suggested 
changing the phrase ``initial reporter'' to ``a health care 
professional directly associated with the care of the patient,'' while 
a third recommended changing the word ``reporter'' to ``health care 
provider who reports the adverse experience.''
    FDA declines to amend the proposed definition of ``life-
threatening'' by deleting or revising the phrase ``in the view of the 
initial reporter.'' As explained in the June 1993 notice (58 FR 31596 
and 31604), FDA encourages health care professionals and consumers to 
report adverse drug experiences to manufacturers. FDA Form 3500A 
includes a section for identifying the ``initial reporter'' and for 
indicating the reporter's occupation and whether the person is a health 
care professional. Thus, the manufacturer and FDA will know whether the 
adverse drug experience report came from a lay person or a health care 
professional and can take that information into account when evaluating 
the report.
    Current IND safety reporting regulations for telephone reports 
define a ``life-threatening'' experience at Sec. 312.32(c)(2), as:
    * * * that the patient was, in the view of the investigator, at 
immediate (emphasis added) risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that, had it occurred 
in a more serious form, might have caused death. For example, drug-
induced hepatitis that resolved without evidence of hepatic failure 
would not be considered life-threatening even though drug-induced 
hepatitis can be fatal.
FDA has decided, on its own initiative, to remove the definition of 
``life-threatening'' from the telephone safety reports section, at 
Sec. 312.32(c)(2), and add it to the general ``definitions'' section of 
Sec. 312.32, at Sec. 312.32(a). This action will clarify that reporting 
of life-threatening events apply to both written and telephone IND 
safety reports. FDA has also replaced ``serious'' with ``severe'' in 
the definition of ``life-threatening'' to make it consistent with the 
final ICH E2A guideline. FDA has also decided, on its own initiative, 
to add the words ``or subject'' after ``patient'' in this definition to 
clarify that IND safety reports apply to healthy subjects as well as 
patients. FDA has also removed the last sentence in the definition of 
``life-threatening'' under Sec. 312.32 (and the last two sentences in 
the proposed postmarketing definition of ``life-threatening'' under 
Secs. 310.305(b), 314.80(a), and 600.80(a)), as noted in section III of 
this document, to minimize confusion. The revised definition of ``life-
threatening adverse drug experience'' in the IND safety reporting 
regulations at Sec. 312.32(a) reads as follows:
    Any adverse drug experience that places the patient or subject, 
in the view of the investigator, at immediate risk of death from the 
reaction as it occurred, i.e., it does not include a reaction that, 
had it occurred in a more severe form, might have caused death.

C. Definition of Serious

    FDA proposed to revise the definition of ``serious,'' in 
Secs. 310.305(b), 312.32(a), 314.80(a), and 600.80(a), 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.
    3. Twenty-five comments opposed all or parts of the phrase 
``necessitates medical or surgical intervention to preclude permanent 
impairment of a body function or permanent damage to a body 
structure.'' Nine comments stated that this phrase makes the U.S. 
definition of ``serious'' inconsistent with harmonized safety reporting 
standards such as the ICH E2A and E6 guidelines and with the CIOMS II 
report. One comment said that although the phrase was included to 
provide a consistent definition of what constitutes a serious adverse 
event for all FDA-regulated products, it causes inconsistency between 
United States and international reporting requirements. Another comment 
said that the difference in definitions between the United States and 
the international community will cause confusion and additional expense 
for manufacturers who are complying with the reporting requirements of 
several countries. One comment stated that if the definition is 
finalized as proposed, preparation and submission of a single 
postmarketing periodic report worldwide will not be possible. Another 
comment said that a definition as important as ``serious'' should be 
internationally consistent in order to be easy to learn, quote, and 
recognize in global clinical development and medical safety. One 
comment noted that it would be especially difficult to implement the 
proposed criterion of ``medical/surgical intervention'' during the 
course of an ongoing clinical study.
    Ten comments recommended deletion of the phrase. Eleven comments 
requested clarification of the phrase because it is too vague and 
misinterpretation would result in overreporting or underreporting of 
adverse events. Another comment suggested that the phrase be reworded 
as an ``unusual and potentially serious experience that necessitates 
any medical or surgical intervention.'' One comment recommended 
adopting the approach in the final ICH E2A guideline of including 
``medical and surgical intervention''

[[Page 52243]]

within the area of ``other important medical events.'' The comment 
indicated that the guideline leaves the determination of whether or not 
such an event is serious to medical and scientific judgment.
    As explained in the June 1993 notice (58 FR 31596), FDA Forms 3500 
and 3500A are 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 care 
professionals. This includes reporting of adverse events and product 
problems with human drug products, biologics, and medical devices, as 
well as other FDA-regulated medical products.
    FDA adopted several recommendations from ICH and CIOMS in 
developing the definitions used in the forms and in the proposed 
amendments to the safety reporting regulations for human drug and 
biological products. The agency believes that certain standardized 
definitions, procedures, and formats proposed by ICH and CIOMS will 
result in more effective and efficient safety reporting to regulatory 
authorities worldwide. The agency proposed to amend the definition of 
``serious'' to have a consistent definition of what constitutes a 
serious adverse drug experience for all FDA-regulated products and to 
avoid confusion about what events should be reported to regulatory 
authorities worldwide.
    FDA agrees with the comments that the differences between the 
definition of serious, as proposed, and the definition recommended in 
the final ICH E2A guideline and in the CIOMS II report may create 
confusion about what events to report as serious. Therefore, the agency 
has revised the definition of ``serious'' to be consistent with the 
final ICH E2A guideline (60 FR 11284 at 11285) and FDA Forms 3500 and 
3500A. The revised definition states:
    Any adverse drug experience occurring at any dose that results 
in any of the following outcomes: Death, a life-threatening adverse 
drug experience, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/ 
incapacity, or a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
    The term ``serious'' is defined similarly in the final ICH E2A 
guideline (60 FR 11284 at 11285) as:
    A serious adverse event (experience) or reaction is any untoward 
medical occurrence that at any dose:
      Results in death,
      Is life-threatening,
    * * *
      Requires inpatient hospitalization or prolongation of 
existing hospitalization,
      Results in persistent or significant disability/
incapacity, or
      Is a congenital anomaly/birth defect.
    Medical and scientific judgment should be exercised in deciding 
whether expedited reporting is appropriate in other situations, such 
as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above. These should also usually 
be considered serious.
    Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse.
    The revised definition of ``serious'' is also consistent with 
section B.2 of FDA Forms 3500 and 3500A, which directs persons 
completing the forms to indicate which of the following outcomes is 
attributed to the adverse event: ``death, life-threatening, 
hospitalization--initial or prolonged, disability, congenital anomaly, 
required intervention to prevent permanent impairment/damage, or 
other.''
    In order to make the definition of ``serious'' in the premarketing 
safety reporting regulations at Sec. 312.32(a) uniform with the revised 
definition of ``serious'' in the postmarketing safety reporting 
regulations at Secs. 310.305(b), 314.80(a), and 600.80(a), FDA is 
removing the following sentence from the current definition of 
``serious'' at Sec. 312.32(a), and adding it, with minor revisions, to 
the IND written safety reporting requirements under 
Sec. 312.32(c)(1)(i):
    With respect to results obtained from tests in laboratory 
animals, a serious adverse drug experience includes any experience 
suggesting a significant risk for human subjects, including any 
finding of mutagenicity, teratogenicity, or carcinogenicity.
    4. One comment requested adding the phrase ``including overdose and 
underdose'' after the phrase ``occurring at any dose'' in the 
definition of ``serious'' in order to eliminate confusion. Otherwise, 
the comment claimed, adverse outcomes associated with underdoses may be 
interpreted as a lack of therapeutic effect rather than an adverse drug 
experience.
    FDA declines to amend the definition of ``serious'' to include the 
phrase ``including overdose or underdose.'' Use of the phrase 
``occurring at any dose'' in the revised definition of ``serious'' will 
ensure that serious adverse drug experiences occurring at any dose, 
including an overdose or an underdose, must be reported.
    5. Five comments asked for examples of what is considered serious. 
One comment asked whether intravenous (IV) treatment for dehydration 
without hospital admission or the use of IV antibiotics, blood 
products, or dialysis would be considered serious.
    FDA advises that use of IV fluids, antibiotics, or blood products, 
or dialysis may or may not be serious, depending on why they are being 
used. A decision using medical judgment should be made based on the 
circumstances surrounding each case. As stated in the revised 
definition of ``serious'', other examples include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, and the development of drug dependency or drug abuse.
    6. Five comments requested clarification of the following sentence 
in the preamble to the proposed rule under the discussion of the 
definition of ``serious'': ``FDA notes that a serious adverse 
experience would not include the discontinuation of therapy, changes in 
dosage, or routine treatment with a prescription medication'' (59 FR 
54046 at 54048). One comment stated that the sentence should also be 
included in the codified definition of ``serious'' because the 
qualifiers are extremely important in limiting the range of events not 
considered serious. Three comments asked for clarification of the 
phrase ``routine treatment with a prescription medication.'' One of 
these comments noted that treatment with any new medication could 
potentially be considered a medical intervention and therefore could be 
classified as serious. Another comment requested clarification of the 
phrase ``would not include discontinuation of therapy'' because it 
implies that discontinuation of therapy in response to a clinically 
significant rise in serum aminotransferases or serum creatinine would 
not be considered intervention and therefore would not be serious.
    FDA declines to revise the definition of ``serious'' to include 
examples of events not considered serious. FDA

[[Page 52244]]

clarifies that discontinuation of therapy, changes in dosage, and 
routine treatment with a prescription medication are not in themselves 
serious events but may occur as the result of a serious event.
    7. Several comments discussed the use of the words ``persistent'' 
and ``permanent'' in the definition of ``serious''. One comment 
requested rewording the phrase ``persistent or significant disability'' 
to read ``permanent or persistent disability.'' Another comment 
suggested that the term ``permanent disability'' in the current 
definition of ``serious'' should be retained because replacing 
``permanent'' with ``persistent'' does not further define disability. 
The comment noted that a condition like influenza might be 
significantly incapacitating but may not qualify as a serious event. 
Three comments recommended changing the word ``permanent'' to 
``persistent'' in the phrase ``preclude permanent impairment of a body 
function or permanent damage to a body system.'' One comment requested 
that the phrase ``persistent or significant disability'' be used 
instead of ``permanent or significant disability'' in the definition of 
``serious'' in proposed Sec. 312.32(a) in order to be consistent with 
proposed Secs. 310.305(b), 314.80(a), and 600.80(a).
    As explained in the preamble to the October 1994 proposal (59 FR 
54046 at 54047), FDA is revising the phrase ``is permanently 
disabling'' to ``results in a persistent or significant disability/
incapacity'' in order to clarify that a disability need not be 
permanent to be considered a serious adverse drug experience. Thus, FDA 
declines to substitute the phrase ``permanent or persistent 
disability'' for ``persistent or significant disability'' or retain 
``permanent disability.'' In addition, FDA has corrected the 
typographical error in proposed Sec. 312.32(a) by revising ``permanent 
or significant disability'' to read ``persistent or significant 
disability.''
    8. One comment requested the addition of the word ``immediately'' 
before ``life-threatening'' in the definition of ``serious''. The 
comment stated that although ``immediate'' is stated in the definition 
of ``life-threatening'', it is not indicated on FDA Form 3500 or 3500A. 
As a result, reporters may interpret ``life-threatening'' to mean 
``potentially'' life-threatening rather than ``immediately'' life-
threatening.
    FDA declines to revise the definition of ``serious'' to add the 
word ``immediately'' before ``life-threatening'' because the phrase 
``at immediate risk of death'' is part of the definition of ``life-
threatening adverse drug experience.'' Although the word 
``immediately'' does not appear before the word ``life-threatening'' on 
FDA Forms 3500 and 3500A, the MedWatch ``FDA Desk Guide for Adverse 
Event and Product Problem Reporting'' explains that a life-threatening 
adverse event would be immediate.

D. IND Safety Reports--Written

    FDA proposed to revise the requirements for submitting written IND 
safety reports, under Sec. 312.32(c)(1) and (d)(3), by altering the 
time period for submitting such reports from 10 working days to 15 
calendar days. In addition, FDA proposed to permit sponsors to submit 
written IND safety reports to the agency by using FDA Form 3500A or in 
a narrative format. If a sponsor chose to use FDA Form 3500A, 
additional narrative data might be required if the agency determined 
that insufficient data were submitted on the form.
    9. Three comments expressed support for the 15 calendar days 
timeframe. One comment commended FDA for requiring the same timeframe 
for both pre- and postmarketing expedited reporting. Two other comments 
requested that the timeframe be increased to 20 calendar days, while 
another comment recommended any period longer than 15 calendar days. 
The comments stated that 15 calendar days would not provide enough time 
for the submission of reports or for contacting non-U.S. physicians. 
One comment noted that a longer timeframe would permit better review 
and reporting of serious adverse experiences.
    As explained in the October 1994 proposal (59 FR 54046 at 54051), 
FDA believes that the extended timeframe is sufficient for sponsors to 
gather appropriate data to help initially interpret the reports before 
submitting them to FDA. This timeframe is also consistent with the 15 
calendar day period in the final ICH E2A guideline (60 FR 11284 at 
11286).
    10. Although one comment expressed support for use of FDA Form 
3500A for written IND safety reports because it would provide 
consistency with the form for postmarketing reports, another comment 
requested that the form not be required for these reports because of 
limited space for describing narrative information.
    FDA notes that it is not ``requiring'' use of FDA Form 3500A for 
written IND safety reports. Reporters may use the form or, 
alternatively, may submit these reports in a narrative format. In 
addition, as explained in the June 1993 notice announcing the 
availability of the form, reporters may use additional blank sheets of 
paper, referenced to the section of the form being described, to 
complete any narrative sections of the form.
    In the June 1993 notice (58 FR 31596 at 31598), FDA also stated 
that companies may use the CIOMS I form for reporting foreign events 
after obtaining FDA approval. FDA has decided, based on comments to its 
postmarketing safety reporting regulations (see section IV.F of this 
document), to amend Sec. 312.32(c)(1) to permit use of the CIOMS I form 
for reporting foreign events without prior approval. FDA has decided to 
take this action to expedite reporting of foreign events and harmonize 
its pre- and postmarketing safety reporting regulations.
    11. One comment requested clarification about what sponsors must 
include in a written IND safety report. The comment also requested 
guidance on how often a report should be submitted and whether one is 
required every time a new case is reported.
    Under Sec. 312.32(b), as amended in this final rule, FDA requires 
that the sponsor must promptly review all information relevant to the 
safety of the drug obtained or otherwise received by the sponsor from 
any source, foreign or domestic, including information derived from any 
clinical or epidemiological investigations, animal investigations, 
commercial marketing experience, reports in the scientific literature, 
and unpublished scientific papers, as well as reports from foreign 
regulatory authorities that have not already been previously reported 
to the agency by the sponsor. This requirement qualifies for sponsors 
the type of safety information that must be examined for determination 
of whether the information should be included in IND safety reports.
    As noted earlier, FDA is amending its IND safety reports 
regulations, at Sec. 312.32, by moving, for organizational purposes, 
certain information from the current definition of ``serious adverse 
experience,'' at Sec. 312.32(a), to the written IND safety reports 
section, at Sec. 312.32(c)(1)(i). Under Sec. 312.32(c)(1)(i), as 
revised in this final rule, sponsors must submit written IND safety 
reports to FDA and all participating investigators within 15 calendar 
days after the sponsor's receipt of information on any adverse 
experience associated with the use of the drug that is both serious and 
unexpected; or any finding from tests in laboratory animals that 
suggests a significant risk for human subjects including reports of

[[Page 52245]]

mutagenicity, teratogenicity, or carcinogenicity.
    FDA advises sponsors, as described in greater detail in the final 
ICH E2A guideline (60 FR 11284 at 11285 and 11286), to submit in 
written IND safety reports as much information as possible on a case. 
In some instances, information for final description and evaluation of 
a case report may not be available within 15 calendar days. 
Nevertheless, initial reports should be submitted within this timeframe 
when the following minimum criteria are met: An identifiable patient; a 
suspected medicinal product; an identifiable reporter; and an adverse 
event or outcome that can be identified as serious and unexpected, and 
for which, in clinical investigation cases, there is a reasonable 
suspected causal relationship between the investigational product and 
the adverse event (i.e., the causal relationship cannot be ruled out). 
For reportable events that occur during a ``blinded'' clinical 
investigation, sponsors should only break the blind for the subject in 
question. Sponsors should consult with the FDA review division 
responsible for their IND in situations in which the sponsor believes 
that breaking the blind would compromise their study (e.g., when a 
fatal or other serious outcome is the primary efficacy endpoint in a 
clinical investigation). Reportable events attributed to a specific 
dosage form, formulation, or route of administration should be cross-
referenced to other IND's for the drug. Reportable events associated 
with a particular population or for a specific indication should also 
be cross-referenced to other IND's for the drug.
    FDA expects sponsors to submit written IND safety reports every 
time the sponsor receives or otherwise obtains information about a 
serious and unexpected adverse experience associated with the use of 
the drug until the current investigator brochure or, if the 
investigator brochure is not required, until the risk information 
described in the general investigational plan or elsewhere in the 
current application is amended. This is consistent with the final ICH 
E2A guideline (60 FR 11284 at 11285): ``Until source documents are 
amended, expedited reporting is required for additional occurrences of 
the reaction.''
    12. One comment asked when a written safety report would be due if 
the 15th day occurs on a weekend or holiday.
    FDA advises that if the 15th calendar day occurs on a weekend or 
U.S. Federal holiday, the written safety report would be due the 1st 
working day after the weekend or U.S. Federal holiday.

E. IND Safety Reports--Telephone

    FDA proposed to revise the requirements for submitting IND safety 
reports by telephone, under Sec. 312.32(c)(2), by altering the time 
period for submitting such reports from 3 working days to 7 calendar 
days. FDA also proposed to allow telephone safety reports to be made by 
facsimile transmission.
    13. Two comments expressed support for the 7 calendar day 
timeframe. Other comments requested longer timeframes because 7 days 
does not provide a significant difference from the current time period, 
and because additional time is needed for contacting non-U.S. 
physicians. One comment asked for a timeframe of 10 calendar days, and 
another requested any period longer than 7 calendar days.
    FDA declines to lengthen the timeframe for IND safety reports by 
telephone or facsimile transmission. FDA believes it is important that 
unexpected fatal or life-threatening experiences associated with the 
use of the drug be reported to the agency as expeditiously as possible. 
A 7 calendar day timeframe is reasonable for these types of reports. 
This timeframe is also consistent with recommendations in the final ICH 
E2A guideline (60 FR 11284 at 11286).
    14. Three comments supported FDA's proposal to accept telephone 
safety reports by ``facsimile transmission.'' The comments also 
requested that FDA permit transmission of these reports by other 
electronic mechanisms such as Internet or electronic mail systems.
    In the Federal Register of March 20, 1997 (62 FR 13430), FDA 
published a final rule that permits the agency to accept electronic 
records, electronic signatures, and handwritten signatures executed to 
electronic records as generally equivalent to paper records and 
handwritten signatures executed on paper. FDA stated in this final rule 
that it will announce in the Federal Register when it is prepared to 
accept certain submissions in electronic format only. At the present 
time, FDA is not prepared to accept electronic submission of IND safety 
reports, but is developing a system to accept such submissions in the 
future.
    15. One comment requested that FDA restore the phrase ``in the 
clinical studies conducted under the IND'' to the language in 
Sec. 312.32(c)(2) for telephone safety reports of any unexpected fatal 
or life-threatening experience associated with the use of the drug. The 
phrase did not appear in the October 27, 1994, proposed revisions to 
this section.
    It is FDA's intention not to restrict telephone safety reports of 
any unexpected fatal or life-threatening experience associated with the 
use of the drug to clinical studies conducted under the IND. As stated 
under Sec. 312.32(b), as revised in this final rule, the sponsor shall 
promptly review all information relevant to the safety of the drug 
obtained or otherwise received by the sponsor from any source, foreign 
or domestic, including information derived from any clinical or 
epidemiological investigations, animal investigations, commercial 
marketing experience, reports in the scientific literature, and 
unpublished scientific papers, as well as reports from foreign 
regulatory authorities that have not already been previously reported 
to the agency by the sponsor. Thus, the sponsor is responsible for 
notifying FDA by telephone or facsimile transmission, as soon as 
possible, but in no event later than 7 calendar days, of any unexpected 
fatal or life-threatening experience associated with the use of the 
drug from any source. This requirement is consistent with the final ICH 
E2A guideline (60 FR 11284 at 11286):
    Information obtained by a sponsor or manufacturer on serious, 
unexpected reports from any source should be submitted on an 
expedited basis to appropriate regulatory authorities if the minimum 
criteria for expedited reporting can be met.

F. Postmarketing Alert and Followup Reports

    FDA proposed to amend Secs. 310.305(c), 314.80(c), and 600.80(c) by 
reorganizing, renumbering, and retitling the paragraphs in these 
sections to distinguish between postmarketing 15-day Alert reports and 
followups to these reports. FDA also proposed to distinguish between 
the reporting intervals for postmarketing 15-day Alert reports and the 
intervals proposed for postmarketing periodic reports. In addition, FDA 
proposed to amend Secs. 310.305(c)(1) through (c)(4), 314.80(c)(1)(i) 
through (c)(1)(iv), and 600.80(c)(1)(i) through (c)(1)(iv), to alter 
the time period for submitting postmarketing 15-day Alert reports and 
followup reports from 15 working days to 15 calendar days.
    16. Twelve comments stated that the 15 calendar day timeframe is 
overly burdensome. One comment noted that the change from 15 working 
days to 15 calendar days would result in approximately one-third (6 
days) less time for preparation of reports for submission to FDA. 
Another comment indicated that, although the proposed

[[Page 52246]]

timeframe is in accord with the final ICH E2A guideline, it would cause 
significant disruption in reporting schedules and would probably result 
in incomplete reports. Another comment stated that the revised 
timeframe would not provide international companies with sufficient 
time to receive and translate foreign reports. One comment said that 
the proposed timeframe incorrectly assumes that reporters are 
universally accessible anywhere in the world. Six comments offered 
suggestions for alternative timeframes. Three comments recommended 20 
calendar days, one recommended 21 calendar days, and another 
recommended 22 calendar days. Two of the comments encouraged retention 
of the 15 working day timeframe currently required by FDA.
    FDA declines to revise its proposed 15 calendar day timeframe for 
postmarketing Alert reports. The agency proposed to revise the 
reporting period from 15 working days to 15 calendar days to provide 
consistency in pre- and postmarketing safety reporting timeframes for 
products and to decrease misunderstandings with reporting requirements 
by stating all timeframes in terms of calendar days. This timeframe is 
consistent with the 15 calendar day reporting timeframe in the final 
ICH E2A guideline (60 FR 11284 at 11286) and consistent with the change 
in timeframe set forth in this final rule at Sec. 312.32(c)(1) and 
(d)(3) for IND safety reporting of serious and unexpected experiences. 
This timeframe is sufficient for persons subject to the postmarketing 
safety reporting requirements to gather appropriate data and initially 
interpret reports before submitting them to the agency.
    In this final rule, FDA is amending its postmarketing expedited 
safety reporting regulations, at Sec. 310.305(c)(1)(i), by adding the 
following phrase to the end of the first sentence: ``by the person 
whose name appears on the label.'' FDA is making this revision to 
clarify when the 15 calendar day timeframe begins for marketed 
prescription drugs for human use without approved new drug 
applications. This change is consistent with current language under 
Secs. 314.80(c)(1)(i) and 600.80(c)(1)(i) for marketed prescription 
drugs for human use with approved NDA's and for licensed biological 
products. Under Sec. 314.80(c)(1)(i), 15-day Alert reports must be 
submitted no later than 15 calendar days of initial receipt of 
information by the applicant. Under Sec. 600.80(c)(1)(i), such reports 
must be submitted within the same timeframe based on initial receipt of 
information by the licensed manufacturer.
    17. Two comments requested that they be permitted to use the CIOMS 
I form for reporting foreign events as an alternative to FDA Form 3500A 
without obtaining prior FDA approval. In addition, the comments 
preferred using the CIOMS I form instead of FDA Form 3500A for all 
adverse drug experience reporting worldwide.
    In the June 1993 notice, the agency stated that reporters may use 
the CIOMS I form for reporting foreign events with prior FDA approval. 
FDA has considered the comments and has decided to revise 
Secs. 310.305, 314.80, and 600.80 to permit the use of the CIOMS I form 
for reports of foreign events without first obtaining prior FDA 
approval. FDA is taking this action to expedite the reporting of 
foreign events.
    FDA will continue to require use of FDA Form 3500A for reports of 
domestic events. FDA Form 3500A is more comprehensive than the CIOMS I 
form and includes elements recommended by the final ICH E2A guideline 
that are not part of the CIOMS I form (60 FR 11284 at 11287). For 
example, the following items are included in FDA Form 3500A and 
requested in the ICH E2A guideline but are not included in the CIOMS I 
form: Body weight, the terms ``congenital anomaly'' and ``other'' 
(identifiers of adverse event outcomes), the lot number and dosage 
strength of suspected medicinal product(s), details on the event 
reporter, and the regulatory code number (e.g., IND/NDA number).
    18. One comment requested that FDA accept postmarketing 15-day 
Alert and followup reports through electronic transmission.
    As explained above, FDA has published a final rule to permit the 
agency to accept electronic records, electronic signatures, and 
handwritten signatures executed to electronic records as generally 
equivalent to paper records and handwritten signatures executed on 
paper (62 FR 13430). At the present time, FDA is not prepared to accept 
electronic submission of 15-day Alert reports, but is developing a 
system to accept such submissions in the future.

G. Written Procedures for Monitoring Adverse Drug Experiences

    FDA proposed to amend Secs. 310.305(a), 314.80(b), and 600.80(b) to 
require that any person subject to the reporting requirements under 
Secs. 310.305(c), 314.80(c), and 600.80(c) develop written procedures 
for the surveillance, receipt, evaluation, and reporting of adverse 
drug experiences to FDA.
    19. One comment opposed this amendment. The comment stated that 
these written procedures are customary and usual in the industry and, 
if made part of a regulation, could be potentially burdensome to 
manufacturers and would permit FDA to dictate internal procedures.
    FDA declines to withdraw this proposed amendment. As explained in 
the preamble to the October 1994 proposal (59 FR 54046 at 54053), this 
requirement would improve postmarketing surveillance by applicants and 
manufacturers and would enhance an applicant's and a manufacturer's 
ability to evaluate and report adverse drug experiences to the agency. 
In addition, because such written procedures are usual and customary, 
FDA believes that this provision would not impose a new burden on 
applicants and manufacturers.
    20. One comment stated that it is inappropriate to require packers 
and distributors to develop written procedures for the surveillance, 
receipt, evaluation, and reporting of adverse drug experiences to FDA 
if they elect to submit these reports to the manufacturer.
    Under Secs. 310.305(c)(1)(i), 314.80(c)(1)(iv), and 
600.80(c)(1)(iv), packers and distributors are subject to the reporting 
requirements if their name appears on the label of a marketed 
prescription drug product or licensed biological product. A packer or 
distributor who elects to submit adverse drug experience reports to an 
applicant, manufacturer, or licensed manufacturer of a final biological 
product under Secs. 310.305(c)(4), 314.80(c)(1)(iv), and 
600.80(c)(1)(iv) must include information about making such an election 
in their written procedures, as well as procedures for recordkeeping 
required to be maintained under these regulations. For the reasons 
explained in the October 1994 proposal (59 FR 54046 at 54053), it is 
appropriate to require that these packers and distributors develop 
written procedures to ensure that they comply with these regulations.
    21. One comment requested that FDA specify the minimum requirements 
for a company's written procedures for reporting adverse drug 
experiences.
    FDA declines to specify minimum requirements for written reporting 
procedures. As explained in the October 1994 proposal (59 FR 54046 at 
54053), written procedures for handling adverse drug experiences are 
customary and usual in the pharmaceutical industry. In

[[Page 52247]]

addition, such procedures have been required for many years by FDA's 
current good manufacturing practice (CGMP) regulations for finished 
pharmaceuticals (21 CFR 211.198).

H. Submission of Postmarketing 15-day Alert Reports by Persons Other 
Than Applicants, Manufacturers, and Licensed Manufacturers of a Final 
Biological Product

    Current postmarketing safety reporting regulations, at 
Sec. 310.305(c)(5), permit packers and distributors to submit reports 
of serious adverse drug experiences to the manufacturer instead of FDA. 
Under Sec. 314.80(c)(1)(iii), manufacturers, packers, and distributors 
may submit these reports to the applicant. Under 
Sec. 600.80(c)(1)(iii), packers, distributors, and manufacturers other 
than licensed manufacturers of the final biological product may submit 
these reports to the licensed manufacturer of the final product. 
Currently, these reports must be submitted within 3 working days of 
their receipt. FDA proposed to revise this timeframe to 3 calendar 
days. The manufacturer, applicant, and licensed manufacturer of the 
final biological product would then comply with the requirements 
described in this section by submitting the report to FDA as soon as 
possible, but in no case later than 15 calendar days of initial receipt 
of the information.
    22. Five comments opposed changing 3 working days to 3 calendar 
days because the new timeframe is overly burdensome, especially if the 
period includes holidays or weekends. One comment said that 
manufacturers, packers, distributors, and shared and joint 
manufacturers would probably submit these reports directly to FDA in 
order to utilize the longer timeframe. This would result in duplicative 
reporting to the agency. The comments suggested alternative timeframes. 
Three comments recommended 5 calendar days, one recommended 7 calendar 
days, and another recommended that the current requirement of 3 working 
days be maintained.
    FDA agrees with the comments and has revised the final rule at 
Secs. 310.305(c)(4), 314.80(c)(1)(iv), and 600.80(c)(1)(iv) to permit 
manufacturers, packers, and distributors, as well as manufacturers, 
packers, distributors, shared manufacturers, joint manufacturers, and 
any other participant involved in divided manufacturing of a biological 
product, to submit reports of serious adverse drug experiences to the 
manufacturer, applicant, or licensed manufacturer of the final 
biological product in 5 calendar days.
    23. One comment requested that the regulations state that 
manufacturers should not submit to FDA reports it receives from a 
reporter, if the reporter has submitted the report to FDA.
    FDA declines to revise its regulations to exempt manufacturers from 
submitting safety reports to FDA that it receives from a voluntary 
reporter who has submitted the report to FDA, regardless of whether the 
reporter is a physician, pharmacist, or other health care professional, 
or a consumer. The agency requires manufacturers to submit such reports 
to FDA to ensure that the agency receives all safety reports. However, 
as now stated at Secs. 310.305(c)(6), 314.80(b), and 600.80(b), no one 
subject to the postmarketing safety reporting regulations at 
Secs. 310.305(c), 314.80(c), and 600.80(c) is required to resubmit to 
the agency FDA Form 3500A reports that the agency has forwarded to 
them.

I. General Comments

    24. One comment asked whether the Federal Register notices 
announcing the availability of FDA Forms 3500 and 3500A had been 
withdrawn, revised, or replaced by the October 1994 proposal. The 
comment indicated that the effective date for FDA Form 3500A was put on 
hold pending revision of the regulations for safety reporting.
    The June 1993 notice (58 FR 31596), announced the availability of 
FDA Forms 3500 and 3500A. The use of FDA Form 3500 was effective 
immediately, while the use of FDA Form 3500A was scheduled to be 
effective on November 30, 1993. Manufacturers, medical device 
distributors, and user facilities were encouraged to begin using the 
form immediately. In the Federal Register of December 3, 1993 (58 FR 
64001), FDA extended the effective date for use of FDA Form 3500A until 
FDA issues a final rule amending the regulations to require the use of 
the form. This final rule makes the requirement for use of FDA Form 
3500A effective on April 6, 1998.
    25. Four comments requested that FDA publish guidelines to explain 
the proposed regulations. Two of the comments asked whether a draft 
guideline could be published with an opportunity for public comment 
before publication of the final rule.
    In the Federal Register of March 1, 1995 (60 FR 11284), FDA 
published the final ICH E2A guideline ``Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting.'' 
Concerning the opportunity for comment on guidances, on July 9, 1993 
(58 FR 37408), FDA published the draft ICH E2A guideline for public 
comment.
    As described under section III of this document, FDA is in the 
process of revising guidances pertaining to this final rule and will 
provide opportunity for public comment and notice of availability of 
any draft or final guidance documents in the Federal Register and on 
FDA's WWW home page, under the GGP's (62 FR 8961).
    26. One comment asked whether information on the United Kingdom 
Medicines Control Agency's Medical Dictionary for Drug Regulatory 
Affairs would be incorporated into the final rule.
    This terminology was not discussed in the proposed rule and will 
not be incorporated into this final rule. At the September 1994 CIOMS 
meeting, it was agreed that this terminology would be the basis for the 
development of a new international medical terminology to support 
classification of terms relating to all aspects of drug regulation. In 
July 1997, ICH developed a final consensus guideline on this topic (ICH 
M1). At this time, FDA is considering the ICH M1 document.

V. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) 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.

VI. Analysis of Impacts

    The agency has considered the potential economic impact of this 
final rule under Executive Order 12866, the Regulatory Flexibility Act 
(5 U.S.C. 601-612), as amended by Subtitle D of the Small Business 
Regulatory Fairness Act of 1996 (Pub. L. 104-721), and the Unfunded 
Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Order 12866 
directs agencies to assess all costs and benefits of available 
regulatory alternatives and, when regulation is necessary, to select 
regulatory approaches that maximize net benefits (including potential 
economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this final rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the final 
rule is not a significant regulatory action as defined by the Executive 
Order and so is not subject to review under the Executive Order.

[[Page 52248]]

    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 final rule will not 
have a significant economic impact on a substantial number of small 
entities. According to the Small Business Administration, manufacturers 
of medicinals and botanicals or pharmaceutical preparations with 750 or 
less employees, and manufacturers of diagnostic substances or 
biological products with 500 or less employees are considered a small 
business. As discussed in section VII of this document, modifications 
and additions to the recordkeeping requirements will not result in a 
change in industry's current recordkeeping burden hours. Therefore, 
under the Regulatory Flexibility Act, no further analysis is needed.
    The final rule will also not impose annual expenditures of $100 
million or more on either State, local, and tribal governments in 
aggregate, or on the private sector. Therefore, a written statement and 
economic analysis is not required as prescribed under section 202(a) of 
the Unfunded Mandates Reform Act of 1995.

VII. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title, 
description, and respondent description of the information collection 
provisions are shown below.
    Title: Expedited Safety Reporting Requirements for Human Drug and 
Biological Products; Final Rule.
    Description: FDA is amending its current expedited safety reporting 
requirements to replace current Form FDA-1639 with new FDA Form 3500A; 
to revise certain definitions, reporting periods and formats; to 
require applicants, manufacturers, packers, and distributors, as well 
as licensed manufacturers and other manufacturers of biological 
products to develop written procedures for postmarketing safety 
monitoring and reporting of adverse drug experiences to FDA; and to 
make other revisions to provide uniformity to the expedited pre- and 
postmarketing safety reporting regulations. These changes will simplify 
and facilitate expedited safety reporting and enhance agencywide 
consistency in the collection of postmarketing safety data.
    Respondent Description: Businesses and other for-profit 
organizations, State or local governments, Federal agencies, and 
nonprofit institutions.
    FDA believes that this final rule will not result in any increase 
in paperwork burden as compared to current expedited safety reporting 
requirements. The new requirement under Secs. 310.305(a), 314.80(b), 
and 600.80(b), that persons subject to the postmarketing safety 
reporting requirements develop written procedures for the surveillance, 
receipt, evaluation, and reporting to FDA of adverse drug experiences, 
does not impose a new burden because it codifies a practice that is 
already customary and usual in the pharmaceutical industry for handling 
adverse drug experiences.
    The new recordkeeping requirements under Secs. 310.305(c)(2), 
314.80(c)(1)(ii), and 600.80(c)(1)(ii), that persons subject to the 
postmarketing safety reporting requirements maintain records of 
unsuccessful attempts to obtain additional followup information on 15-
day Alert reports, do not result in a change in the burden. Current 
regulations provide for submission of a followup report describing 
steps taken to seek additional information and the reasons why it could 
not be obtained; FDA estimates that the effort needed to file this 
existing information will be, at worst, no more than the effort that 
would have been required to submit it to FDA.
    The new language in Sec. 312.32(b) explicitly requiring that 
sponsors review: (1) Information derived from any epidemiological 
investigations, or (2) reports from foreign regulatory authorities that 
have not already been previously reported to the agency by the sponsor 
does not impose a new burden because this amendment is only a 
clarification. Sponsors are already required to review all information 
relevant to the safety of the drug obtained or otherwise received by 
the sponsor from any source, foreign or domestic.
    Although the October 1994 proposal provided a 90-day comment period 
under the Paperwork Reduction Act of 1980, FDA is providing an 
additional opportunity for public comment under the Paperwork Reduction 
Act of 1995, which was enacted after the expiration of the comment 
period and applies to this final rule. Therefore, FDA now invites 
comments on: (1) Whether the proposed collection of information is 
necessary for the proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology. Individuals and organizations may submit 
comments on the information collection provisions of this final rule by 
December 8, 1997. Comments should be directed to the Dockets Management 
Branch (address above).
    At the close of the 60-day comment period, FDA will review the 
comments received, revise the information collection provisions as 
necessary, and submit these provisions to OMB for review and approval. 
FDA will publish a notice in the Federal Register when the information 
collection provisions are submitted to OMB, and an opportunity for 
public comment to OMB will be provided at that time. Prior to the 
effective date of this final rule, FDA will publish a notice in the 
Federal Register of OMB's decision to approve, modify, or disapprove 
the information collection provisions. An agency may not conduct or 
sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number.

VIII. References

    The following references have been placed on display at the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. International Reporting of Periodic Drug-Safety Update 
Summaries, Final Report of CIOMS Working Group II, 1992.
    2. International Reporting of Adverse Drug Reactions, Final 
Report of CIOMS Working Group I, 1990.

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.

[[Page 52249]]

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, 21 CFR parts 20, 310, 312, 314, and 600 
are 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; 19 U.S.C. 2531-2582; 21 U.S.C. 1401-1403.

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 paragraph (a); by revising paragraphs (b), (c), (d)(1), (d)(3)(ii), 
and (d)(4); by removing in paragraph (d)(2), the introductory text of 
paragraph (d)(3), and paragraph (d)(3)(i) the words ``Form FDA-1639'' 
or ``FDA-1639'' and adding in their place ``FDA Form 3500A'' 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) * * * Any person subject to the reporting requirements of 
paragraph (c) of this section shall also develop written procedures for 
the surveillance, receipt, evaluation, and reporting of postmarketing 
adverse drug experiences to FDA.
    (b) Definitions. The following definitions of terms apply to this 
section:
    Adverse drug experience. 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 whether accidental or intentional; an adverse event 
occurring from drug abuse; an adverse event occurring from drug 
withdrawal; and any failure of expected pharmacological action.
    Disability. A substantial disruption of a person's ability to 
conduct normal life functions.
    Life-threatening adverse drug experience. Any adverse drug 
experience that places the patient, in the view of the initial 
reporter, at immediate risk of death from the adverse drug experience 
as it occurred, i.e., it does not include an adverse drug experience 
that, had it occurred in a more severe form, might have caused death.
    Serious adverse drug experience. Any adverse drug experience 
occurring at any dose that results in any of the following outcomes: 
Death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/ incapacity, or a congenital 
anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be 
considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
    Unexpected adverse drug experience. Any adverse drug experience 
that is not listed in the current labeling for the drug product. This 
includes events that may be symptomatically and pathophysiologically 
related to an event listed in the labeling, but differ 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 hepatic 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. ``Unexpected,'' as used in 
this definition, refers to an adverse drug experience that has not been 
previously observed (i.e., included in the labeling) rather than from 
the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product.
    (c) Reporting requirements. Each person identified in paragraph 
(c)(1)(i) 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 Pharmacovigilance and Epidemiology (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 no case later than 
15 calendar days of initial receipt of the information by the person 
whose name appears on the label. 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 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. Postmarketing 15-day Alert 
reports and followups to them shall be submitted under separate cover.

[[Page 52250]]

    (3) Submission of reports. To avoid unnecessary duplication in the 
submission of, and followup to, reports required in this section, a 
packer's or distributor's obligations may be met by submission of all 
reports of serious adverse drug experiences to the manufacturer of the 
drug product. 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 5 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 adverse drug experience report;
    (ii) The date the report was received by the packer or distributor;
    (iii) The date the report was submitted to the manufacturer; and
    (iv) The name and address of the manufacturer.
    (4) Each report submitted to FDA under this section shall bear 
prominent identification as to its contents, i.e., ``15-day Alert 
report,'' or ``15-day Alert report-followup.''
    (5) A person identified in paragraph (c)(1)(i) of this section is 
not required to resubmit to FDA adverse drug experience reports 
forwarded to that person by FDA; however, the person must submit all 
followup information on such reports to FDA.
    (d) * * * (1) Except as provided in paragraph (d)(3) of this 
section, each person identified in paragraph (c)(1)(i) of this section 
shall submit each report of a serious and unexpected adverse drug 
experience on an FDA Form 3500A (foreign events may be submitted either 
on an FDA Form 3500A or, if preferred, on a CIOMS I form).
* * * * *
    (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 Pharmacovigilance and Epidemiology (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.
* * * * *

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 312.32 is amended by revising paragraphs (a), (b), 
(c)(1)(i), (c)(2), and (d)(3); by adding in the second sentence of 
paragraph (c)(3) the words ``new drug review'' before the phrase 
``division in the Center for Drug Evaluation and Research'' and the 
words ``the director of the product review division in'' before the 
phrase ``the Center for Biologics Evaluation and Research''; and by 
removing in paragraph (e) the word ``section'' and replacing it with 
the word ``part'', to read as follows:

Sec. 312.32  IND safety reports.

    (a) Definitions. The following definitions of terms apply to this 
section:
    Associated with the use of the drug. There is a reasonable 
possibility that the experience may have been caused by the drug.
    Disability. A substantial disruption of a person's ability to 
conduct normal life functions.
    Life-threatening adverse drug experience. Any adverse drug 
experience that places the patient or subject, in the view of the 
investigator, at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that, had it occurred in 
a more severe form, might have caused death.
    Serious adverse drug experience: Any adverse drug experience 
occurring at any dose that results in any of the following outcomes: 
Death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/ incapacity, or a congenital 
anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be 
considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
    Unexpected adverse drug experience: Any adverse drug experience, 
the specificity or severity of which is not consistent with the current 
investigator brochure; or, if an investigator brochure is not required 
or available, the specificity or severity of which is not consistent 
with the risk information described in the general investigational plan 
or elsewhere in the current application, as amended. For example, under 
this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the investigator brochure only referred to 
elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue 
of greater specificity) if the investigator brochure only listed 
cerebral vascular accidents. ``Unexpected,'' as used in this 
definition, refers to an adverse drug experience that has not been 
previously observed (e.g., included in the investigator brochure) 
rather than from the perspective of such experience not being 
anticipated from the pharmacological properties of the pharmaceutical 
product.
    (b) Review of safety information. The sponsor shall promptly review 
all information relevant to the safety of the drug obtained or 
otherwise received by the sponsor from any source, foreign or domestic, 
including information derived from any clinical or epidemiological 
investigations, animal investigations, commercial marketing experience, 
reports in the scientific literature, and unpublished scientific 
papers, as well as reports from foreign regulatory authorities that 
have not already been previously reported to the agency by the sponsor.
    (c) IND safety reports. (1) Written reports--(i) The sponsor shall 
notify FDA and all participating investigators in a written IND safety 
report of:
    (A) Any adverse experience associated with the use of the drug that 
is both serious and unexpected; or
    (B) Any finding from tests in laboratory animals that suggests a 
significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. Each 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

[[Page 52251]]

Form 3500A or in a narrative format (foreign events may be submitted 
either on an FDA Form 3500A or, if preferred, on a CIOMS I form; 
reports from animal or epidemiological studies shall be submitted in a 
narrative format) and shall bear prominent identification of its 
contents, i.e., ``IND Safety Report.'' Each written notification to FDA 
shall be transmitted to the FDA new drug review division in the Center 
for Drug Evaluation and Research or the product review division in the 
Center for Biologics Evaluation and Research that has responsibility 
for review of the IND. If FDA determines that additional data are 
needed, the agency may require further data to be submitted.
* * * * *
    (2) Telephone and facsimile transmission safety reports. The 
sponsor shall also notify FDA by telephone or by facsimile transmission 
of any unexpected fatal or life-threatening experience associated with 
the use of the drug as soon as possible but in no event later than 7 
calendar days after the sponsor's initial receipt of the information. 
Each telephone call or facsimile transmission to FDA shall be 
transmitted to the FDA new drug review division in the Center for Drug 
Evaluation and Research or the product review division in the Center 
for Biologics Evaluation and Research that has responsibility for 
review of the IND.
* * * * *
    (d) * * *
    (3) If the results of a sponsor's investigation show that an 
adverse drug 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, 
but in no event later than 15 calendar days after the determination is 
made.
* * * * *

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

    7. 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).

    8. Section 314.80 is amended by revising paragraphs (a), (c)(1), 
(f)(1), (f)(3)(ii), and (f)(4) and the introductory text of paragraph 
(c); by adding two new sentences at the end of paragraph (b); by 
removing in paragraph (d)(2) the words ``Epidemiology and 
Surveillance'' and adding in their place the words ``Pharmacovigilance 
and Epidemiology''; by removing in paragraphs (c)(2)(ii)(b), (d)(2), 
(f)(2), and (f)(3) and in the heading for paragraph (f) the words 
``Form FDA-1639'' or ``FDA-1639'' and adding in their place the words 
``FDA Form 3500A''; and by removing paragraph (j) and redesignating 
paragraphs (k) and (l) as paragraphs (j) and (k), respectively, to read 
as follows:

Sec. 314.80  Postmarketing reporting of adverse drug experiences.

    (a) Definitions. The following definitions of terms apply to this 
section:
    Adverse drug experience. 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 whether accidental or intentional; an adverse event 
occurring from drug abuse; an adverse event occurring from drug 
withdrawal; and any failure of expected pharmacological action.
    Disability. A substantial disruption of a person's ability to 
conduct normal life functions.
    Life-threatening adverse drug experience. Any adverse drug 
experience that places the patient, in the view of the initial 
reporter, at immediate risk of death from the adverse drug experience 
as it occurred, i.e., it does not include an adverse drug experience 
that, had it occurred in a more severe form, might have caused death.
    Serious adverse drug experience. Any adverse drug experience 
occurring at any dose that results in any of the following outcomes: 
Death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/ incapacity, or a congenital 
anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be 
considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
    Unexpected adverse drug experience. Any adverse drug experience 
that is not listed in the current labeling for the drug product. This 
includes events that may be symptomatically and pathophysiologically 
related to an event listed in the labeling, but differ 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 hepatic 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. ``Unexpected,'' as used in 
this definition, refers to an adverse drug experience that has not been 
previously observed (i.e., included in the labeling) rather than from 
the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product.
    (b) * * * Applicants are not required to resubmit to FDA adverse 
drug experience reports forwarded to the applicant by FDA; however, 
applicants must submit all followup information on such reports to FDA. 
Any person subject to the reporting requirements under paragraph (c) of 
this section shall also develop written procedures for the 
surveillance, receipt, evaluation, and reporting of postmarketing 
adverse drug experiences to FDA.
    (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, 12229 Wilkins Ave., Rockville, MD 
20852. 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, whether foreign or domestic, as soon as possible but in no 
case later than 15 calendar days of initial receipt of the information 
by the applicant.
    (ii) Postmarketing 15-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. Postmarketing 15-day Alert 
reports and followups to

[[Page 52252]]

them shall be submitted under separate cover.
    (iii) Submission of reports. The requirements of paragraphs 
(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of 
postmarketing 15-day Alert reports, shall also apply to any person 
other than the applicant (nonapplicant) whose name appears on the label 
of an approved drug product as a manufacturer, packer, or distributor. 
To avoid unnecessary duplication in the submission to FDA of reports 
required by paragraphs (c)(1)(i) and (c)(1)(ii) 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, the nonapplicant shall submit each report to the 
applicant within 5 calendar days of receipt of the report 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 each adverse drug experience report;
    (B) The date the report was received by the nonapplicant;
    (C) The date the report was submitted to the applicant; and
    (D) The name and address of the applicant.
    (iv) Report identification. Each report submitted under this 
paragraph shall bear prominent identification as to its contents, i.e., 
``15-day Alert report,'' or ``15-day Alert report-followup.''
* * * * *
    (f) * * * (1) Except as provided in paragraph (f)(3) of this 
section, the applicant shall complete FDA Form 3500A for each report of 
an adverse drug experience (foreign events may be submitted either on 
an FDA Form 3500A or, if preferred, on a CIOMS I form).
* * * * *
    (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 Pharmacovigilance and Epidemiology (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.
* * * * *

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    9. The authority citation for 21 CFR part 600 continues to read as 
follows:

    Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 
353, 355, 360, 360i, 371, 374); secs. 215, 351, 352, 353, 361, 2125 
of the Public Health Service Act (42 U.S.C. 216, 262, 263, 263a, 
264, 300aa-25).

    10. Section 600.80 is amended by revising paragraphs (a), (c)(1), 
(f)(1), and the first sentence of paragraph (g); by adding two new 
sentences at the end of paragraph (b); and by removing paragraph (j) 
and redesignating paragraphs (k), (l), and (m) as paragraphs (j), (k), 
and (l), respectively, to read as follows:

Sec. 600.80  Postmarketing reporting of adverse experiences.

    (a) Definitions. The following definitions of terms apply to this 
section:
    Adverse experience. Any adverse event associated with the use of a 
biological product in humans, whether or not considered product 
related, including the following: An adverse event occurring in the 
course of the use of a biological product in professional practice; an 
adverse event occurring from overdose of the product whether accidental 
or intentional; an adverse event occurring from abuse of the product; 
an adverse event occurring from withdrawal of the product; and any 
failure of expected pharmacological action.
    Blood Component. As defined in Sec. 606.3(c) of this chapter.
    Disability. A substantial disruption of a person's ability to 
conduct normal life functions.
    Life-threatening adverse experience. Any adverse experience that 
places the patient, in the view of the initial reporter, at immediate 
risk of death from the adverse experience as it occurred, i.e., it does 
not include an adverse experience that, had it occurred in a more 
severe form, might have caused death.
    Serious adverse experience. Any adverse experience occurring at any 
dose that results in any of the following outcomes: Death, a life-
threatening adverse experience, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
    Unexpected adverse experience: Any adverse experience that is not 
listed in the current labeling for the biological product. This 
includes events that may be symptomatically and pathophysiologically 
related to an event listed in the labeling, but differ 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 hepatic 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. ``Unexpected,'' as used in 
this definition, refers to an adverse experience that has not been 
previously observed (i.e., included in the labeling) rather than from 
the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product.
    (b) * * * Licensed manufacturers are not required to resubmit to 
FDA adverse product experience reports forwarded to the licensed 
manufacturer by FDA; licensed manufacturers, however, must submit all 
followup information on such reports to FDA. Any person subject to the 
reporting requirements under paragraph (c) of this section shall also 
develop written procedures for the surveillance, receipt, evaluation, 
and reporting of postmarketing adverse experiences to FDA.
    (c) * * *
    (1)(i) Postmarketing 15-day ``Alert reports''. The licensed 
manufacturer shall report each adverse experience that is both serious 
and unexpected, whether foreign or domestic, as soon as possible but in 
no case later than 15 calendar days of initial receipt of the 
information by the licensed manufacturer.
    (ii) Postmarketing 15-day ``Alert reports''--followup. The licensed 
manufacturer shall promptly investigate

[[Page 52253]]

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. 
Postmarketing 15-day Alert reports and followups to them shall be 
submitted under separate cover.
    (iii) Submission of reports. The requirements of paragraphs 
(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of 
postmarketing 15-day Alert reports, shall also apply to any person 
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. To avoid unnecessary duplication in the submission to 
FDA of reports required by paragraphs (c)(1)(i) and (c)(1)(ii) of this 
section, obligations of persons other than the licensed manufacturer of 
the final biological product may be met by submission of all reports of 
serious adverse experiences to the licensed manufacturer of the final 
product. If a person elects to submit adverse experience reports to the 
licensed manufacturer of the final product rather than to FDA, the 
person shall submit each report to the licensed manufacturer of the 
final product within 5 calendar days of receipt of the report by the 
person, and the licensed manufacturer of the final product shall then 
comply with the requirements of this section. Under this circumstance, 
a person who elects to submit reports to the licensed manufacturer of 
the final product 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 of the final product;
    (B) The date the report was received by the person;
    (C) The date the report was submitted to the licensed manufacturer 
of the final product; and
    (D) The name and address of the licensed manufacturer of the final 
product.
    (iv) Report identification. Each report submitted under this 
paragraph shall bear prominent identification as to its contents, i.e., 
``15-day Alert report,'' or ``15-day Alert report-followup.''
* * * * *
    (f) Reporting forms. (1) Except as provided in paragraph (f)(3) of 
this section, the licensed manufacturer shall complete the reporting 
form designated by FDA for each report of an adverse experience (FDA 
Form 3500A, or, for vaccines, a VAERS form; foreign events including 
those associated with the use of vaccines, may be submitted either on 
an FDA Form 3500A or, if preferred, on a CIOMS I form).
* * * * *
    (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. * * *
* * * * *

    Dated: September 25, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-26255 Filed 10-6-97; 8:45 am]
BILLING CODE 4160-01-F