[Federal Register: September 29, 2010 (Volume 75, Number 188)]
[Rules and Regulations]
[Page 59935-59963]
[DOCID:fr29se10-3]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 312 and 320

[Docket No. FDA-2000-N-0108] (formerly Docket No. 00N-1484)
RIN 0910-AG13

Investigational New Drug Safety Reporting Requirements for Human
Drug and Biological Products and Safety Reporting Requirements for
Bioavailability and Bioequivalence Studies in Humans

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Final rule.

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SUMMARY:  The Food and Drug Administration (FDA) is amending its
regulations governing safety reporting requirements for human drug and
biological products subject to an investigational new drug application
(IND). The final rule codifies the agency's expectations for timely
review, evaluation, and submission of relevant and useful safety
information and implements internationally harmonized definitions and
reporting standards. The revisions will improve the utility of IND
safety reports, reduce the number of reports that do not contribute in
a meaningful way to the developing safety profile of the drug, expedite
FDA's review of critical safety information, better protect human
subjects enrolled in clinical trials, subject bioavailability and
bioequivalence studies to safety reporting requirements, promote a
consistent approach to safety reporting internationally, and enable the
agency to better protect and promote public health.

DATES:  This rule is effective March 28, 2011.

FOR FURTHER INFORMATION CONTACT:
    For information on IND safety reporting for human drug products:
Janet Norden, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 6324, Silver
Spring, MD 20993-0002,<PHONE_NUMBER>.
    For information on IND safety reporting for human biological
products: Laura Rich, Center for Biologics Evaluation and Research,
Food and Drug Administration,1401 Rockville Pike, suite 200N,
Rockville, MD 20852-1448,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
    A. Rationale for Rulemaking
    B. The Proposed Rule
II. Overview of the Final Rule
    A. Definitions
    B. Review of Safety Information
    C. Reporting Requirements
III. Comments on the Proposed Rule
    A. Definitions--Proposed Sec.  312.32(a)
    B. Review of Safety Information--Proposed Sec.  312.32(b)
    C. IND Safety Reports (Requirement for Minimum Data Set)--Proposed
Sec.  312.32(c)
    D. Serious and Unexpected SADR--Proposed Sec.  312.32(c)(1)(i)
    E. Alternative Reporting Arrangements
    F. Unblinding
    G. Information Sufficient to Consider Product Administration
Changes--Proposed Sec.  312.32(c)(1)(ii)
    H. Submission of Written Reports--Proposed Sec.  312.32(c)(1)(iii)
    I. Telephone and Facsimile Transmission Safety Reports--Proposed
Sec.  312.32(c)(2)
    J. Investigations of Marketed Drugs--Proposed Sec.  312.32(c)(4)
    K. Followup--Proposed Sec.  312.32(d)
    L. Disclaimer--Proposed Sec.  312.32(e)
    M. Annual Reports
    N. Investigator Reports--Proposed Sec.  312.64(b)
    O. Bioavailability and Bioequivalence Requirements--Proposed Sec.
320.31(d)
    P. Reports to Investigators and IRBs
    Q. Miscellaneous Comments
    R. Initial Analysis of Impacts and Paperwork Burden Estimates
IV. Legal Authority
V. Environmental Impact
VI. Analysis of Impacts
    A. Need for the Regulation
    B. Costs of the Regulation (to Prepare and Submit Safety Reports)
    C. Benefits of the Regulation
    D. Final Regulatory Flexibility Analysis
VII. Paperwork Reduction Act of 1995
VIII. Executive Order 13132: Federalism
IX. References

I. Background

    In the Federal Register of March 14, 2003 (68 FR 12406), FDA issued
a proposed rule to revise its regulations governing pre- and
postmarketing safety

reporting for human drug and biological products\1\, which appear in
parts 310, 312, 314, 320, 600, 601, and 606 (21 CFR parts 310, 312,
314, 320, 600, 601, and 606). The proposed revisions represented a
major effort to clarify and integrate several safety reporting rules
and guidance documents that had been issued by international
organizations and by FDA dating back to the 1990s. The background for
and description of these regulations and guidance documents are
described in the preamble of the proposed rule (68 FR 12406 at 12407 to
12410, Figure 1). The proposal called for the submission of comments by
July 14, 2003. At the request of industry, and to provide all
interested persons additional time to comment, the comment period was
extended until October 14, 2003 (68 FR 36527, June 18, 2003).
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    \1\ For the purposes of this document, unless otherwise
specified, all references to ``drugs'' or ``drug products'' include
human drug products and biological products that are also drugs.
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    FDA received numerous comments in response to the proposed rule,
many of which stated that the proposal would not meet its stated goals
and requested that the agency reevaluate specific aspects of the
proposal. FDA agreed with some of these comments and has reevaluated
and revised aspects of the proposal. To make the rulemaking process
more manageable, FDA has decided to issue revisions to the premarketing
and postmarketing safety reporting regulations in two separate
rulemakings. By separating these rules, the agency has been able to
reevaluate and refine each requirement in the premarketing and
postmarketing settings to better ensure that the rules will achieve
their goals.
    This rule finalizes revisions to the IND safety reporting
regulations found in part 312 and the safety reporting requirements for
bioavailability and bioequivalence studies found in part 320. The
agency is working on revisions to the postmarketing safety reporting
regulations found in parts 310, 314, 600, 601, and 606 separately, and
will address these sections in a future rule. Therefore, revisions to
and comments about postmarketing safety reporting requirements found in
parts 310, 314, 600, 601, and 606 are not addressed in this rulemaking.
This document discusses information relevant to and comments about the
proposed revisions found in parts 312 and 320.

A. Rationale for Rulemaking

    In the proposed rule (68 FR 12406 at 12412 to 12415), FDA described
its goals for the proposed rulemaking. Many of the stated goals were
primarily applicable to postmarketing safety reporting, but revising
and clarifying the IND safety reporting requirements was also a
critical component of FDA's stated efforts to: (1) Improve the overall
quality of safety reporting, thereby strengthening the agency's ability
to review critical safety information, (2) monitor the safety of human
drug and biological products, and (3) harmonize safety reporting
internationally. Each of these is discussed in turn in this document.
    First, the revisions to the IND safety reporting requirements will
improve the overall quality of safety reporting and the agency's
ability to review critical safety information by ensuring that the
information that FDA receives in an IND safety report is relevant and
useful. Under former regulations, there may have been over-reporting of
serious adverse events for which there was little reason to believe
that the drug had caused the event, complicating or delaying FDA's
ability to detect a safety signal. In this final rule, FDA clarifies
definitions, provides examples of the types of evidence that suggest a
causal relationship for purposes of reporting a suspected adverse
reaction to the IND and participating investigators, and revises the
requirements for expedited reporting of serious and unexpected
suspected adverse reactions to the IND. The final rule also allows
sponsors to arrange alternative formats and/or frequencies for
reporting and provides that study endpoints must not be submitted as
IND safety reports except in unusual cases. These revisions not only
have an impact on which reports are sent to FDA and participating
investigators, but also affect the reports that are sent by
investigators to Institutional Review Boards (IRBs). These revisions
and clarifications will minimize reports that do not contribute to
FDA's understanding of the developing safety profile of the drug and
decrease the number of uninterpretable reports (so-called ``noise'') in
the system. In addition, the revisions and clarifications will help to
make clear under what circumstances the study blind should be broken
and when unblinding is unnecessary. Ultimately, these revisions and
clarifications should contribute toward more useful adverse reaction
information and more effective monitoring of clinical trials.
    Second, by requiring expedited reports of certain safety
information that was not reported expeditiously under former IND safety
reporting requirements or bioavailability or bioequivalence
requirements, the final rule will help FDA monitor the safety of human
drug and biological products and better protect human subjects enrolled
in clinical trials. Under the final rule, FDA will receive expedited
reports of:
     Findings from clinical studies, epidemiological studies or
pooled analyses of multiple studies that suggest a significant risk in
humans exposed to the drug,
     Serious suspected adverse reactions that occur at an
increased rate than listed in the protocol or investigator brochure,
and
     Serious adverse events from bioavailability and
bioequivalence studies.
    By receiving these reports expeditiously, FDA will be better able
to monitor and evaluate the drug's safety.
    Finally, FDA had proposed certain revisions to its IND safety
reporting requirements to harmonize the regulations with
recommendations 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), and which have
been adopted by the European Union (EU) (Ref. 1). In the preamble to
the proposed rule (68 FR 12406 at 12415, table 4), FDA detailed the
specific proposed revisions to the definitions and reporting standards
based on international recommendations in the ICH guidance ``E2A
Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting'' (60 FR 11284, March 1, 1995) (ICH E2A guidance).
FDA received numerous comments, described in more detail in section III
of this document, stating that certain of FDA's proposed revisions were
inconsistent with how the provisions are interpreted and implemented in
other member ICH nations. After reviewing the comments and after
discussions with our ICH partners, FDA has revised the definitions and
reporting standards to be as consistent as possible with international
definitions and standards, recognizing that there may be
inconsistencies within ICH documents and among the other member ICH
nations' interpretations of these definitions and standards.

B. The Proposed Rule

    The following describes the proposed revisions to the requirements
in parts 312 and 320. FDA proposed the following revisions to Sec.
312.32 on IND safety reports:
     Replace the defined phrase ``associated with the use of
the drug''

with the term ``suspected adverse drug reaction (SADR),''
     Require submission of expedited reports of ``information
sufficient to consider product administration changes,''
     Make it clear that safety reports of overall findings or
data in the aggregate must be submitted in a narrative format,
     Permit the determination that an SADR is life-threatening
to be based on the opinion of either the investigator or sponsor (as
opposed to only the investigator),
     Require that the sponsor notify FDA and all participating
investigators of each SADR that is both serious and unexpected, based
on the opinion of either the investigator or sponsor (as opposed to
only the sponsor),
     Require a ````minimum data set'' for each report of an
SADR submitted to FDA, and
     Clarify the sources of information that sponsors must
review for safety surveillance and reporting purposes.
    FDA proposed the following revision to Sec.  312.64(b):
     Make it clear that the investigator must report to the
sponsor any serious SADR immediately and any other SADR promptly,
unless otherwise specified in the protocol or investigator's brochure.
    FDA proposed the following revision to Sec.  320.31(d):
     Make bioavailability and bioequivalence studies subject to
IND safety reporting requirements.

II. Overview of the Final Rule

    This final rule amends parts 312 and 320 of FDA regulations by
revising the requirements for IND safety reporting and for
bioavailability and bioequivalence studies. This final rule reflects
revisions the agency made in response to comments on the March 2003
proposal (addressed in detail in section III of this document) and
other revisions, including editorial changes to clarify provisions and
support the agency's plain language initiative (addressed in this
section).

A. Definitions

    The definitions section for the IND safety reporting regulations
(Sec.  312.32(a)) now includes the following five terms:
     Adverse event,
     Life-threatening adverse event or life-threatening
suspected adverse reaction,
     Serious adverse event or serious suspected adverse
reaction,
     Suspected adverse reaction, and
     Unexpected adverse event or unexpected suspected adverse
reaction.
    FDA has revised and clarified terms and definitions that were in
the proposed rule. First, as discussed in detail in section III of this
document, the two terms ``adverse event'' and ``suspected adverse
reaction'' replace the proposed definition of ``suspected adverse drug
reaction (SADR).'' The definitions ``adverse event'' and ``suspected
adverse reaction'' also replace the phrase ``associated with the use of
the drug'' defined in former Sec.  312.32(a). The definitions of the
terms ``adverse event'' and ``suspected adverse reaction'' make clear a
distinction in the degree of evidence of a causal relationship between
the drug and the adverse event within these terms.
    Second, the final rule requires that the determination for
reporting purposes about whether an adverse event or suspected adverse
reaction is ``life-threatening'' or ``serious'' be based on the opinion
of either the investigator or sponsor. FDA had proposed this revision
for the definition of ``life-threatening SADRs,'' and the agency
decided that the determination about whether an adverse event or
suspected adverse reaction is ``serious'' is comparable to the
determination of whether it is life-threatening. Therefore, FDA revised
the definition ``serious adverse event or serious suspected adverse
reaction'' to specify that the determination of seriousness be based on
the opinion of either the investigator or sponsor. In addition, FDA
eliminated the definition of ``disability'' as a separate term and
includes the meaning of the term in the definition of ``serious adverse
event or serious suspected adverse reaction.''
    Third, the final rule makes clear what adverse events or suspected
adverse reactions are considered unexpected. The proposed definition of
``unexpected SADR'' included the following sentence from the then-
current definition for ``unexpected adverse drug experience'' (with
minor clarification): ```Unexpected' as used in this definition, refers
to an SADR that has not been previously observed (e.g., in the
investigator brochure); it does not refer to an SADR that might be
anticipated from the pharmacological properties of the drug product.''
To this clarification, FDA proposed to add the following new sentence:
``SADRs that are mentioned in the investigator's brochure as occurring
with a class of drugs but not specifically mentioned as occurring with
the particular drug are considered unexpected.'' In this final rule,
FDA combined these proposed sentences to read as follows:
```Unexpected,' as used in this definition, also refers to adverse
events or suspected adverse reactions that are mentioned in the
investigator brochure as occurring with a class of drugs or as
anticipated from the pharmacological properties of the drug, but are
not specifically mentioned as occurring with the particular drug under
investigation.'' This revision makes clear that adverse events that
have not been previously observed with the drug under investigation,
but are predicted to occur based on the class of the drug or
pharmacological properties of the drug are considered ``unexpected''
for reporting purposes.

B. Review of Safety Information

    The final rule clarifies what safety information must be reviewed
under Sec.  312.32(b). The proposal would have required sponsors to
review ``reports from foreign regulatory authorities that have not been
previously reported to FDA by the sponsor.'' FDA has deleted the phrase
``that have not been previously reported to FDA by the sponsor,''
because it confuses the review with the reporting requirements. FDA
expects sponsors to review all information, but to avoid duplicate
reporting to the agency. In addition, the final rule clarifies the
agency's expectations for analysis of previous, similar reports (Sec.
312.32(c)(1)).

C. Reporting Requirements

    In Sec.  312.32(c), the final rule clarifies how and when to submit
IND safety reports to FDA and participating investigators, including
the requirement in Sec.  312.32(c)(1)(v) that certain reports be
submitted in a narrative format (proposed Sec.  312.32(c)(1)(iii)). It
provides examples of the kinds of evidence that suggest a causal
relationship between the drug and the adverse event when determining
whether a serious and unexpected adverse event qualifies for expedited
reporting (Sec.  312.32(c)(1)(i)). The final rule also requires that
sponsors submit expedited reports of findings from clinical studies,
epidemiological studies, or pooled analyses of multiple studies that
suggest a significant risk in humans (Sec.  312.32(c)(1)(ii)); findings
from animal or in vitro testing that suggests a significant risk in
humans (Sec.  312.32(c)(1)(iii)); and reports of an increased rate of
occurrence of serious suspected adverse reactions over that listed in
the protocol or investigator brochure (Sec.  312.32(c)(1))(iv)). The
final rule also provides for alternative reporting arrangements (Sec.
312.32(c)(3)) and provides that study endpoints not be reported except
in unusual cases (Sec.  312.32(c)(5)).
    Furthermore, FDA has made it clear in Sec.  312.32(c)(1)(v) that
the period of time for submitting additional data requested by the
agency is 15 calendar

days (i.e., the same period of time that is allowed for submitting
followup information under Sec.  312.32(d)(3)). In addition, the agency
revised several provisions to allow for electronic submission of
reports. First, in Sec.  312.32(c)(1)(v) ``Submission of IND safety
reports,'' FDA renamed and revised proposed Sec.  312.32(c)(1)(iii)
``Submission of written reports.'' Second, FDA revised proposed Sec.
312.32(c)(2) ``Telephone and facsimile transmission safety reports'' to
eliminate the specificity that unexpected fatal or life-threatening
reports be submitted only by telephone or facsimile transmission so
that other means of rapid communication (e.g., e-mail) may be accepted
in the future. FDA also renamed the provision to ``Unexpected fatal or
life-threatening suspected adverse reaction reports.'' Last, in Sec.
320.31(d)(3), FDA revised the proposed requirement for submission of
IND safety reports and unexpected fatal or life-threatening reports
from bioavailability and bioequivalence studies to mirror these
revisions.
    The final rule allows for alternative reporting arrangements, as
provided in former Sec.  312.32(c)(3). However, the agency revised the
statement, ``FDA may request a sponsor to submit IND safety reports in
a format or at a frequency different than that required under this
paragraph'' by replacing the word ``request'' with ``require'' to
reflect the existing process. In addition, the final rule clarifies the
reporting requirements for clinical investigations of drug products
that are marketed in the United States (Sec.  312.32(c)(4)).
    The final rule makes minor editorial changes to Sec.  312.32(d)(2)
to clarify the followup reporting requirements. In addition, the agency
eliminated the redundant submission requirements for information
amendments and annual reports under Sec.  312.32(d)(4) because they are
already contained in Sec. Sec.  312.31 and 312.33.
    The final rule clarifies the requirements for investigators to
submit reports of serious adverse events to the sponsor and clarifies
the requirement for reporting study endpoints that are serious adverse
events (Sec.  312.64(b)).
    Finally, the final rule requires that applicants submit to FDA
reports of serious adverse events from bioavailability and
bioequivalence studies. Proposed Sec.  320.31(d) would have required
that these studies be subject to the proposed IND safety reporting
requirements, thereby requiring all reports under proposed Sec.  312.32
(e.g., reports of serious and unexpected SADRs, reports of information
sufficient to consider product administration changes). FDA has
tailored the rule to require only those reports that FDA believes would
be most informative (i.e., reports of all serious adverse events). FDA
also revised this provision to make it consistent with the final
revisions for submission of IND safety reports and reports of any fatal
or life-threatening adverse event. The final rule requires that reports
must be submitted to the Office of Generic Drugs.
    Table 1 of this document identifies the changes from the proposed
rule in the IND safety reporting requirements that the agency made in
this final rule.

                         Table 1--Changes Made by the Final Rule From the Proposed Rule
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                                               Description of Change See comment or section of this document
      21 CFR Section in Final Rule          (identified in parentheses) for more detailed information regarding
                                                                        the change.
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312.32(a) Adverse event                    Added definition for ``adverse event'' (1)
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312.32(a) Life-threatening adverse event   Made minor editorial revisions for clarity, including
 or life-threatening suspected adverse     language changes to accommodate deletion of ``SADR'' definition and
 reaction                                  use of alternative terminology (2)
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312.32(a) Serious adverse event or         Changed language to accommodate deletion of ``SADR''
 serious suspected adverse reaction        definition and use of alternative terminology (6)
                                           Incorporated the definition from former Sec.   312.32(a) of
                                           ``disability'' within the definition of ``serious'' (III.A.2)
                                           Revised so that the seriousness determination is based on the
                                           opinion of either the sponsor or investigator (6)
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312.32(a) Suspected adverse reaction       Replaced the term ``SADR'' with the term ``suspected adverse
                                           reaction,'' clarifying the meaning of ``reasonable possibility''
                                           within the definition (1)
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312.32(a) Unexpected adverse event or      Revised to make clear that ``unexpected'' adverse events or
 unexpected suspected adverse reaction     suspected adverse reactions include those that may be anticipated
                                           from the pharmacological properties of the drug, or that occur with
                                           members of the drug class, but that have not previously been observed
                                           with the drug under investigation (8)
----------------------------------------------------------------------------------------------------------------
312.32(b) Review of safety information     Made minor editorial changes for clarity and deleted the
                                           phrase ``that have not been previously reported to FDA by the
                                           sponsor'' (II)
----------------------------------------------------------------------------------------------------------------
312.32(c)(1) IND safety reports            Withdrew the proposed requirement for each report of an SADR
                                           to contain a minimum data set and to maintain records of efforts to
                                           obtain a minimum data set (5, 13, and 14)
----------------------------------------------------------------------------------------------------------------
312.32(c)(1)(i) Serious and unexpected     Clarified agency's expectation for analysis of previous,
 suspected adverse reactions               similar reports or any other relevant information (16)
                                           Withdrew the requirement that the causality assessment be
                                           based on the opinion of the investigator or the sponsor (15)
                                           Provided examples of the types of evidence that suggest a
                                           causal relationship between the drug and the adverse event (18 to 21)
----------------------------------------------------------------------------------------------------------------
312.32(c)(1)(ii) Findings from other       Revised proposed reports of ``Information sufficient to
 studies                                   consider product administration changes'' to clarify agency
                                           expectations of reports from clinical studies, epidemiological
                                           studies or pooled analyses of multiple studies that suggest a
                                           significant risk in humans (23 to 25)
----------------------------------------------------------------------------------------------------------------

312.32(c)(1)(iii) Findings from animal     Revised proposed reports of ``Information sufficient to
 or in vitro testing                       consider product administration changes'' to clarify agency
                                           expectations of reports from animal or in vitro testing that suggests
                                           a significant risk in humans (26 to 29)
----------------------------------------------------------------------------------------------------------------
312.32(c)(1)(iv) Increased rate of         Added the requirement for reports of any clinically important
 occurrence of serious suspected adverse   increase in the rate of a serious suspected adverse reaction over
 reactions                                 that listed in the protocol or investigator brochure (32)
----------------------------------------------------------------------------------------------------------------
312.32(c)(1)(v) Submission of IND safety   Revised to allow for electronic submission of IND safety
 reports                                   reports and clarified time period for reporting additional data or
                                           information requested by FDA (II)
----------------------------------------------------------------------------------------------------------------
312.32(c)(2) Unexpected fatal or life-     Revised to eliminate the specificity that unexpected fatal or
 threatening suspected adverse reaction    life-threatening suspected adverse reaction reports be submitted only
 reports                                   by telephone or facsimile transmission and renamed the requirement
                                           (II)
----------------------------------------------------------------------------------------------------------------
312.32(c)(3) Reporting format or           Replaced ``request'' with ``require'' (20)
 frequency
----------------------------------------------------------------------------------------------------------------
312.32(c)(4) Investigations of marketed    Clarified requirements for investigations of marketed drugs
 drugs                                     (31)
----------------------------------------------------------------------------------------------------------------
312.32(c)(5) Reporting study endpoints     Added requirement that study endpoints (e.g., mortality or
                                           major morbidity) must be reported according to the protocol instead
                                           of as IND safety reports except when there is evidence suggesting a
                                           causal relationship between the drug and the event (19 and 21)
----------------------------------------------------------------------------------------------------------------
312.32(d) Followup                         Deleted provision that required safety information to be
                                           submitted in an information amendment or annual report and made minor
                                           editorial changes for clarity (III.K)
----------------------------------------------------------------------------------------------------------------
312.64(b) Investigator reports             Clarified requirements for investigator reports (35 and 36)
----------------------------------------------------------------------------------------------------------------
320.31(d) Applicability of requirements    Revised to require that persons conducting bioavailability
 regarding an ``Investigational New Drug   and bioequivalence studies report all serious adverse events (II)
 Application''                             Revised to make consistent with requirements for submission
                                           of IND safety reports and reports of any fatal or life-threatening
                                           adverse event (II)
----------------------------------------------------------------------------------------------------------------

III. Comments on the Proposed Rule

    The agency received 110 comments in the docket for the March 14,
2003, proposed rule on premarket and postmarket safety reporting
revisions. Comments were received from prescription and nonprescription
drug manufacturers and related companies; trade organizations
representing drug manufacturers and other interested parties; blood
banks and transfusion facilities; international organizations and non-
U.S. agencies; professional associations and organizations;
consultants; contract research organizations; academic institutions;
health care and consumer advocacy organizations, individual physicians,
pharmacists, and consumers; and others.
    To make it easier to identify comments and our responses, the word
``Comment,'' in parentheses, appears before the comment's description,
and the word ``Response,'' in parentheses, appears before our response.
We have numbered each comment to help distinguish between different
comments. Similar comments are grouped together under the same number.
The number assigned to each comment is purely for organizational
purposes and does not signify the comment's value or importance or the
order in which it was received. Comments addressing the proposed
requirements for IND safety reporting and bioavailability and
bioequivalence studies and the agency's responses follow:

A. Definitions--Proposed Sec.  312.32(a)

1. Suspected Adverse Drug Reaction (SADR)
    FDA proposed to add the term ``suspected adverse drug reaction
(SADR)'' and define the term as follows: ``A noxious and unintended
response to any dose of a drug product for which there is a reasonable
possibility that the product caused the response. In this definition,
the phrase `a reasonable possibility' means that the relationship
cannot be ruled out.''
    (Comment 1) Nearly all of the comments overwhelmingly opposed the
agency adopting the proposed definition of SADR and strongly encouraged
the agency to abandon the proposed definition for many reasons,
including the following:
     Many comments did not agree that ``reasonable
possibility'' should be defined as ``the relationship cannot be ruled
out.'' Most comments stated that this interpretation makes the
definition overly broad and will lead to reporting almost every
serious, unexpected adverse event because no event could ever be
completely ruled out.
     Many comments stated that although the proposed definition
was similar to the definition contained in the ICH E2A guidance, the
agency's interpretation was inconsistent with the guidance. The ICH E2A
guidance makes clear that a causality assessment is required for
clinical investigations and that a ``reasonable causal relationship''
is meant to convey in general that there are facts (evidence) or
arguments to suggest a causal relationship. The comments expressed
concern that the agency's interpretation of ``reasonable possibility''
would lead to inconsistencies in globally conducted studies and
reports.
     Many comments asserted that the significantly increased
numbers of expedited reports that could result from the proposed
definition might dilute real safety signals, making them harder to
detect. The lengthy in depth investigations needed to rule out the
increased number of false positive associations would take away
resources from other safety surveillance efforts and potentially lead
to a delay in identification of real signals.

     Several comments expressed concern that the proposed
definition would have a negative impact on the conduct of clinical
trials. In addition to sharply increasing the number of reports of
cases from clinical trials that would need to be sent to FDA in an
expedited manner, sponsors and investigators would have to break the
blind for nearly all subjects with serious, unexpected SADRs because
the relationship between drug and the event could not definitively be
ruled out. Increased unblinding would compromise the integrity of well-
regulated clinical investigations, lead to fewer patients completing a
trial, necessitate larger patient enrollment, and lengthen the timeline
for new product development, possibly leading to higher costs for
marketed drugs. One comment expressed concern that, to minimize
unblinding, studies would be designed to exclude patients with serious
medical conditions who are likely to experience serious adverse events
during the study period, thereby limiting the applicability of study
results.
    Many comments also stated that the proposed definition would result
in significant increases in meaningless individual expedited reports
being sent to already overburdened IRBs and investigators. The comments
pointed out that an unintended effect of the increase in volume of
reports may be to reduce an investigator's and IRB's vigilance in
detecting adverse events.
     Several comments expressed concern that the proposed
definition would dilute the utility of drug product labeling because
many more events would be regarded as ``drug related'' even though the
likelihood of a true causal relationship is minimal.
     Several comments stated that the ``S'' abbreviation for
``suspected'' in SADR could be confused with the ``S'' abbreviation for
``serious'' in SAE (serious adverse event).
    The majority of the comments recommended that reporting adverse
events from clinical trials should be based on a scientific or medical
judgment that there is a possible causal relationship between the drug
and the event, rather than simply being unable to unequivocally exclude
a drug's role. The comments suggested several alternatives to the
agency's proposed definition, including the following:
     Several comments recommended that the definition of an
adverse reaction encompass all of the concepts presented within the ICH
E2A guidance, which are supported by CIOMS and presented in the
European Union Clinical Trial Directive. Comments recommended that the
definition of reasonable possibility be technically consistent with the
ICH E2A guidance definition and clearly delineate the concept of
``reasonable causal relationship'' as conveying in general that there
are facts (evidence) or arguments to suggest a causal relationship.
     Some comments supported retaining FDA's former definition
of ``associated with the use of the drug'' as ``there is a reasonable
possibility that the experience may have been caused by the drug.''
    Three comments supported adopting the proposed definition because
they considered it an inclusive, conservative approach to adverse event
reporting.
    (Response) Based on the comments, and on review of definitions and
terminology used in the ICH E2A guidance and in former Sec.  312.32,
the agency has decided not to adopt the proposed definition for
``suspected adverse drug reaction (SADR).'' The agency agrees with the
comments stating that there should be a causality assessment applied
and that the threshold for reporting should be that there is a
``reasonable possibility'' that the drug caused the adverse event. The
agency also believes that it is important to use definitions that are
clear and consistent, and in harmony with those used internationally.
    The agency believes that the comments raised legitimate concerns
that the proposed definition was too broad and could have a negative
impact on clinical trials, IRBs, investigators, signal detection, and
drug labeling. Instead of adopting the proposed definition, the agency
has adopted the terms for ``adverse event'' and ``suspected adverse
reaction'' in the definition section of this final rule, which
addresses these concerns. The definitions of these terms should
contribute to harmonization of safety reporting to regulatory
authorities worldwide because they are consistent with the concepts and
definitions adopted by the ICH E2A guidance and CIOMS. The terms are
defined as follows:
     ``Adverse event'' means any untoward medical occurrence
associated with the use of a drug in humans, whether or not considered
drug related. (For the purposes of this definition, ``untoward'' means
unfavorable, negative, or harmful).
    ``Suspected adverse reaction'' means any adverse event for which
there is a reasonable possibility that the drug caused the adverse
event. For the purposes of IND safety reporting, ``reasonable
possibility'' means there is evidence to suggest a causal relationship
between the drug and the adverse event. Suspected adverse reaction
implies a lesser degree of certainty about causality than adverse
reaction, which means any adverse event caused by a drug.
    These definitions reflect the varying degrees of certainty that are
part of a causality assessment. For example:
     An adverse event (also referred to as an ``adverse
experience'') is any event observed or reported that is associated with
the use of the drug, without regard to causality.
     A suspected adverse reaction is a subset of all adverse
events in which there is a reasonable possibility that the drug caused
the event.
     An adverse reaction, described within the definition, is a
subset of all suspected adverse reactions for which there is reason to
conclude that the drug caused the event.
    With this change from the proposed definition, the basis that the
agency has established for assessing the degree of certainty about
causality between a drug and an adverse event for the purposes of
expedited IND safety reporting has not changed from former Sec.
312.32(c). The sponsor must continue to evaluate the evidence and use
its judgment to determine whether an adverse event meets the definition
of suspected adverse reaction and qualifies for expedited reporting
under Sec.  312.32(c). The agency has also clarified the requirements
for reporting a serious and unexpected suspected adverse reaction under
Sec.  312.32(c)(1)(i) to assist sponsors with making this determination
(see Comment 18 of this document).
    Finally, the agency has concluded that abbreviations are
potentially confusing (e.g., the ``S'' abbreviation for ``suspected''
in SADR could be mistaken for an abbreviation of the term ``serious'').
Although the agency has retained the term ``suspected'' in ``suspected
adverse reaction,'' our preferred approach is to avoid use of any
abbreviation (e.g., ``SAR'' for ``suspected adverse reaction''). The
agency believes that sponsors are familiar with the term ``suspected''
and its use by the European Commission and CIOMS (e.g., the acronym
``SUSAR'' means ``suspected, unexpected, serious adverse reaction'' in
guidance documents and working group reports (for example, see Ref.
1)).
    Because the agency is not adopting the proposed definition of
``suspected adverse drug reaction (SADR),'' other proposed definitions
(e.g., ``serious SADR,'' ``life-threatening SADR'') and requirements
that used this terminology have been revised in this final rule to use
the terms ``adverse event'' or ``suspected adverse reaction'' as
appropriate.

2. Disability
    The proposed rule included a definition of the term ``disability''
to mean a substantial disruption of a person's ability to conduct
normal life functions. Because the term ``disability'' appeared only
within the definition of ``serious SADR'' in the proposed rule, the
agency eliminated the definition of ``disability'' as a separate term
in this final rule. Instead, the agency revised the definition of
``serious adverse event or serious suspected adverse reaction'' in this
final rule to incorporate the definition of ``disability'' by replacing
the phrase ``a persistent or significant disability/incapacity'' with
``a persistent or significant incapacity or substantial disruption of
the ability to conduct normal life functions.'' Thus, in the final
rule, the term disability is replaced by the proposed definition in the
one place where it appeared, and the definition itself has been
deleted.
3. Life-Threatening Suspected Adverse Drug Reaction (SADR)
    FDA proposed the term ``life-threatening suspected adverse drug
reaction (SADR)'' to mean any SADR that, in the view of the
investigator or sponsor, places the patient or subject at immediate
risk of death from the SADR as it occurred. It does not include an SADR
that, had it occurred in a more severe form, might have caused death.
    (Comment 2) Several comments agreed with FDA's proposal to add the
term ``or sponsor'' to the definition of life-threatening SADR. SADRs
would be reported as life-threatening if either the investigator or
sponsor considered them to be life-threatening. However, several
comments expressed concern with FDA's proposal. The comments stated
that a trained investigator is most qualified to make the sometimes
subjective assessment of whether an event is life-threatening and that
this determination often is best made by the health-care professional
or the reporter who is in direct contact with the patient. These
comments also stated that sponsors may exercise medical and scientific
judgment in deciding whether expedited reporting is appropriate. One
comment stated that allowing a sponsor to determine severity would
change the nature of the assessment and result in increased reporting
of events assessed by those with often incomplete information. One
comment pointed out that FDA's rationale for expanding the role of the
sponsor is not supported by the quote from the ICH E2A guidance in the
preamble to the proposed rule (68 FR 12406 at 12419) because the ICH
E2A guidance quote refers to causality assessment, not assessment of
seriousness.
    (Response) The agency agrees with the comments that support
expanding this definition to include reporting of an adverse event as
life-threatening if either the investigator or the sponsor considers it
to be life-threatening. The agency believes that, in some cases, the
sponsor may not agree with the investigator's assessment that an
adverse event does not qualify as life-threatening. In such cases,
because these events are critically important for the identification of
significant safety problems, the agency believes that broadening the
definition to allow sponsors to also make this assessment is prudent
and appropriate. While the agency agrees with the comment that pointed
out that the preamble to the proposed rule misinterpreted the quote
from the ICH E2A guidance, we nonetheless believe that the revision to
the definition is consistent with the overall intent of the ICH E2A
guidance.
    (Comment 3) Several comments disagreed with the agency's position
articulated in the preamble to the proposed rule that reasons for any
differences of opinion between the investigator and sponsor regarding a
determination that an SADR is life-threatening would be included in the
IND safety report (68 FR 12406 at 12419). The comments argued that this
adds no value and is not appropriate or necessary in all cases. In
addition, comments stated that obtaining the investigator's view when
he or she deems the event non-life-threatening would be difficult.
    (Response) The agency agrees that reasons for differences of
opinion between the sponsor and investigator are not always important
and, therefore, not necessary to include in the IND safety report in
all cases. Therefore, in this final rule, the agency does not require
including the reasons for differences of opinion in the IND safety
report. However, it is important that any adverse event or suspected
adverse reaction considered life-threatening by either the sponsor or
the investigator be reported as such.
    (Comment 4) Some comments suggested that FDA clarify the definition
of life-threatening to take into account the role of other study staff
making safety observations. The comments suggested that the definition
be clarified to state that investigators or sponsors must evaluate
information communicated to them or recorded by their qualified staff
or agents and transmit reportable information to the sponsor or FDA.
One comment recommended that the definition be modified to include
contractors as well as sponsors.
    (Response) The agency does not agree that the recommended revisions
to the definition are necessary because taking the observations of
staff into account is inherent in the obligations of the investigator.
Any qualified study staff could make pertinent safety observations, and
it is the investigator's responsibility in supervising the conduct of
the clinical investigation (see Sec. Sec.  312.53 and 312.60) to report
adverse experiences to the sponsor in accordance with Sec.  312.64.
Further information on the supervisory responsibilities of
investigators can be obtained in the agency's guidance for industry
entitled ``Investigator Responsibilities: Protecting the Rights,
Safety, and Welfare of Study Subjects'' (74 FR 55052, October 26,
2009).\2\ The agency does not believe that it is necessary to change
the definition to include contractors because, under Sec.  312.52, a
contract research organization that assumes any obligation of a sponsor
must comply with the applicable regulation.
---------------------------------------------------------------------------

    \2\ Draft and final guidances for the Center for Drug Evaluation
and Research (CDER)-related information are posted on the Internet
at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/default.htm. The Center for Biologics Evaluation and
Research (CBER)-related information is posted at http://www.fda.gov/
BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
Guidances/default.htm (21 U.S.C. 371(h), 21 CFR 10.115).
---------------------------------------------------------------------------

4. Minimum Data Set
    Under Sec.  312.32(a), FDA proposed the term ``minimum data set''
to mean that ``the report includes an identifiable patient, an
identifiable reporter, a suspect drug product, and an SADR.''
    (Comment 5) Two comments requested further clarification regarding
the meaning of ``identifiable'' with respect to the kind and amount of
information needed to meet the criteria for an ``identifiable patient''
and ``identifiable reporter.'' One comment questioned whether patient
characteristics, such as age or gender, would be adequate, or if the
ability to contact the patient is necessary.
    (Response) As discussed in comments 13 and 14 of this document,
because the four elements of the minimum data set are generally readily
available in the clinical trial setting, the agency has determined that
the definition and the requirement are unnecessary and has decided not
to require a minimum data set for IND safety reports as proposed in
Sec.  312.32(c). Because the agency is not adopting this definition in
the IND safety reporting requirements, the comments requesting
clarification about

the elements of the definition are no longer relevant.
5. Serious SADR
    FDA proposed to define ``serious SADR'' in the same way as the
then-current definition of ``serious adverse drug experience'' under
Sec.  312.32(a) as follows: ``Serious SADR means any SADR that results
in any of the following outcomes: Death, a life-threatening SADR,
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 SADR 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
hospitalization, or the development of drug dependency or drug abuse.''
    (Comment 6) One comment suggested that the definition of ``serious
SADR'' be revised to expressly allow the sponsor to determine if an
adverse event is serious, in the absence of a reporter's assessment of
seriousness.
    (Response) For reasons similar to those stated in Comment 2 of this
document (definition of life-threatening), the agency agrees that the
definition of ``serious adverse event or serious suspected adverse
reaction'' should be revised to allow the determination that an adverse
event or suspected adverse reaction is ``serious'' if either the
investigator or sponsor considers it serious. Therefore, the agency has
revised this definition to add the phrase ``in the view of either the
investigator or sponsor.''
6. Unexpected SADR
    FDA proposed that the definition of ``unexpected SADR'' be the same
as the then-current definition for ``unexpected adverse drug
experience'' under Sec.  312.32(a), except that the following sentence
was added to make clear which SADRs are considered unexpected: ``SADRs
that are mentioned in the investigator's brochure as occurring with a
class of drugs but not specifically mentioned as occurring with the
particular drug are considered unexpected.''
    (Comment 7) One comment stated that in the proposed definition, the
``severity'' standard is vague, leaving the determination of
``expectedness'' to the investigator's judgment.
    (Response) Unless a sponsor-investigator is responsible for the
clinical trial, the sponsor, rather than the investigator, generally
determines if a suspected adverse reaction is unexpected for reporting
purposes. However, the agency acknowledges that judgment is needed to
decide if the severity of a suspected adverse reaction is greater than
described in the investigator brochure. The definition of ``unexpected
adverse event or unexpected suspected adverse reaction'' in the final
rule includes an example of a suspected adverse reaction that would be
considered unexpected by virtue of its greater severity than other
suspected adverse reactions mentioned in the investigator brochure
(i.e., hepatic necrosis would be considered unexpected where the
investigator brochure includes elevated hepatic enzymes or hepatitis).
    (Comment 8) Another comment recommended that FDA provide guidance
on what should be considered ``expected'' for regulatory reporting
purposes, in particular, what safety information to include in the
investigator brochure and what subset of such information would be
considered ``expected'' (i.e., only those for which a causal
relationship is suspected, reasonably established, or inferred based on
evidence). Some comments stated that if the basis for evaluating
expectedness is that an event is listed in the investigator's brochure,
sponsors may add long lists of adverse events, thereby delaying
important safety reports from being submitted to FDA. One comment
recommended that FDA require that, until the applicable reference
safety information document is officially updated (e.g., reprinted and
distributed) to include a new serious, suspected adverse reaction
(thereby making it expected), all subsequent reports of similar serious
adverse drug reactions be submitted expeditiously as an IND safety
report. Another comment suggested adopting use of the Developmental
Core Safety Information (DCSI) document, proposed by a CIOMS Working
Group, as the reference for ``expectedness'' instead of the
investigator brochure because the DCSI document contains only those
adverse events that, after careful analysis are believed by the company
to be likely related to the drug (Refs. 2 and 3).
    (Response) The purpose of the investigator brochure is to provide
the investigator with information (clinical and nonclinical) about the
investigational drug that is relevant to study of the drug in human
subjects. The investigator brochure should include the information that
is important for the investigator, who is administering the drug to
human subjects, to know and understand. The investigator brochure is
required to include information about the drug substance and
formulation, pharmacological and toxicological effects of the drug in
animals (and in humans, if known), pharmacokinetics and biological
disposition of the drug in animals (and in humans, if known),
information relating to safety and effectiveness in humans obtained
from prior clinical studies, and information about possible risks and
side effects to be anticipated on the basis of prior experience with
the drug under investigation or with related drugs, and precautions or
special monitoring to be done as part of the investigational use of the
drug (see Sec.  312.23(a)(5)).
    In general, the investigator brochure lists those adverse events
that have been observed with the investigational drug and for which a
causal relationship with the drug is suspected or confirmed. It is not
appropriate for sponsors to add long lists of adverse events that are
unlikely to have been caused by the drug to the investigator brochure
because such lists could dilute the importance of clinically meaningful
risk information and as a result, may put subjects at risk. The sponsor
needs to exercise judgment when deciding if the threshold has been
reached for adding a newly observed adverse event to the investigator
brochure. This decision usually depends on the strength of the evidence
from individual or multiple cases and previous knowledge about the drug
or drug class. In some cases, the threshold for including an adverse
event may be lower if it could result in a significant adverse outcome
for trial participants.
    The investigator brochure describes adverse events that may be
predicted to occur based on the pharmacological properties of the drug.
For reporting purposes, if an adverse event occurs that has not
previously been observed with the drug under investigation, the event
is considered ``unexpected.'' To make clear that such predicted adverse
events are considered ``unexpected,'' the final rule revises the
proposed definition of ``unexpected'' to state explicitly that the term
also refers to adverse events or suspected adverse reactions that are
mentioned in the investigator brochure as occurring with a class of
drugs or as anticipated from the pharmacological properties of the
drug, but are not specifically mentioned as occurring with the
particular drug under investigation.

    The agency expects the sponsor to update the investigator brochure
on an ongoing basis with new important safety information. However, the
agency agrees with the comment that, until the investigator brochure
and other applicable reference safety information are updated to
include a new serious, suspected adverse reaction, subsequent reports
of similar serious, suspected adverse reactions must be submitted
expeditiously in IND safety reports.
    Finally, sponsors submit and the agency accepts a variety of
formats for the investigator brochure. For this reason, we are not
formally adopting use of the DCSI document in this final rule. However,
we agree that a sponsor could incorporate a document such as the DCSI
into the investigator brochure for use as the reference for
``expectedness'' for reporting purposes if the DCSI contains the
required safety information about the investigational drug.

B. Review of Safety Information--Proposed Sec.  312.32(b)

    IND safety reporting regulations in former Sec.  312.32(b) required
that sponsors promptly review all information relevant to the safety of
the drug obtained or otherwise received by the sponsor from any source,
foreign or domestic. Examples of potential sources of information in
the former regulation included information derived from any clinical or
epidemiological investigations, animal investigations, commercial
marketing experience, reports in the scientific literature, as well as
unpublished scientific papers, and reports from foreign regulatory
authorities that had not been previously reported to FDA by the
sponsor. Proposed Sec.  312.32(b) would have amended this requirement
to include in vitro studies as another example of a potential source of
information and to clarify that ``reports from commercial marketing
experience'' is intended to apply only to reports from foreign
commercial marketing experience for drugs that are not marketed in the
United States. As proposed, reports from IND studies of drugs that are
marketed in the United States would be required to be reported as
described under Sec.  312.32(c)(4), if applicable.
    (Comment 9) One comment stated that reportable information can come
from a wider variety of media or sources than those listed in the
proposed rule. The comment maintained that investigators or sponsors
participating in public or private meetings or conferences can learn of
reportable events from colleagues or other professionals. The comment
recommended that the list of potential sources of reportable
information include such alternative sources.
    (Response) The sponsor is required to ``promptly review all
information relevant to the safety of the drug obtained or otherwise
received by the sponsor from foreign or domestic sources, including
information derived from any clinical or epidemiological
investigations, animal or in vitro studies * * *'' (emphasis added).
The sources listed in the requirement are not all inclusive, but
represent examples of the variety of sources that may yield safety
information. Therefore, the agency agrees that reportable information
can come from sources other than those listed in Sec.  312.32(b) and
that one such source could be from public or private meetings. However,
the agency does not believe that it is necessary to amend the
requirement to provide additional examples.
    (Comment 10) One comment agreed with the clarification that
reporting from commercial marketing experience applies only to foreign
commercial marketing experience for drugs that are not marketed in the
United States. The comment requested that FDA further make it clear
that expedited reporting under Sec.  312.32 is not required for reports
from foreign commercial marketing experience for a different
formulation of the same active moiety as a drug product that is
lawfully marketed in the United States and that those reports should be
submitted to the most appropriate new drug application (NDA) for the
active moiety.
    (Response) As described further in Comment 31 of this document, IND
safety reports are required under Sec.  312.32(c)(4) for suspected
adverse reactions observed in clinical studies that are being conducted
under an IND for a drug marketed or approved in the United States. In
general, an expedited report from domestic or foreign commercial
marketing experience for a drug lawfully marketed in the United States
would not be submitted to the IND, but instead, must be submitted in
accordance with the relevant postmarketing reporting requirements
(e.g., Sec. Sec.  310.305, 314.80, and 600.80). Similarly, a report of
a suspected adverse reaction from foreign marketing experience for a
different formulation of the drug product (same active moiety) that is
lawfully marketed in the United States must be submitted in accordance
with the relevant postmarketing reporting requirements.
    (Comment 11) One comment agreed with the proposal to add in vitro
studies to the list of information that should be reviewed by the
sponsor in its ongoing assessment of the safety of an investigational
drug. Some comments stated that it would be helpful if FDA could
provide examples, in addition to carcinogenicity, mutagenicity and
teratogenicity, of when safety data from in vitro studies would yield
relevant, important information that should be reviewed for IND
reporting purposes.
    (Response) Data from in vitro microsusceptibility, drug
interaction, or genotoxicity studies are examples of other data from in
vitro studies that may yield important safety information.
    (Comment 12) One comment expressed concern that once a sponsor
provides FDA with the animal and in vitro studies, emails, and reports
from foreign regulatory authorities and any other information it
reviewed in determining whether to report safety information, FDA may
have to make the information publicly available under the Freedom of
Information Act (FOIA). The comment stated that, before implementing
the requirement, FDA should explain why these additional data are
needed and how they will be handled for FOIA purposes. The comment
requested that the requirement be withdrawn.
    (Response) The agency uses the safety information submitted by the
sponsor, from any source, to continually monitor and evaluate the
safety of the drug. Data and information in an IND are disclosed
consistent with applicable statutes and regulations. The requirements
under Sec.  312.130 describe the availability for public disclosure of
data and information in an IND. The minor clarifications made to these
requirements do not change these protections against public disclosure.
Therefore, the agency declines to withdraw the requirement as requested
by the comment.

C. IND Safety Reports (Requirement for Minimum Data Set)--Proposed
Sec.  312.32(c)

    FDA proposed to amend Sec.  312.32(c) to require that sponsors must
not submit an individual case safety report for an SADR if the report
does not contain a minimum data set, but instead must maintain records
of any information received or otherwise obtained for the SADR along
with a record of its efforts to obtain a minimum data set. In the
preamble to the proposed rule, the agency stated that sponsors should
include in any written IND safety reports subsequently filed with FDA a
chronological history of their efforts to acquire the minimum data set
if there is a delay in obtaining the information, but that it was not
necessary to include the chronological history in IND safety reports
sent to investigators (68 FR

12406 at 12424). In addition, FDA proposed in Sec.  312.32(c)(1)(i)
that a sponsor must submit an IND safety report within 15 calendar days
after receipt by the sponsor of the minimum data set for the SADR.
    As noted in Comment 5 of this document, the agency has reconsidered
the proposed requirement under Sec.  312.32(c) that would have required
sponsors to only submit an individual case safety report for an SADR if
the report contained a minimum data set. Most IND safety reports are
derived from observations from clinical trials. In the setting of a
clinical trial, information is collected in a controlled environment
where the four elements in the definition of minimum data set, as well
as other information needed to evaluate the suspected adverse reaction
(e.g., information that would be contained in a narrative report or on
FDA Form 3500A), are generally readily available. Accordingly, the
agency has revised Sec.  312.32(c)(1) to eliminate the minimum data set
language and to require instead that the sponsor submit an IND safety
report after it determines that the information qualifies for reporting
under Sec.  312.32(c)(1)(i), (c)(1)(ii), (c)(1)(iii), or (c)(1)(iv).
    (Comment 13) One comment stated that waiting for collection of all
the elements of the minimum data set, especially for determination of
causality, could result in a significant delay in reporting to FDA. The
comment requested clarification on when the reporting timeclock would
start. Another comment requested clarification on whether the date of
receipt of the minimum data set for the SADR represents day zero or day
one.
    (Response) The reporting timeclock starts (i.e., day zero) as soon
as the sponsor determines that the information qualifies for reporting
under Sec.  312.32(c)(1)(i), (c)(1)(ii), (c)(1)(iii), or (c)(1)(iv).
For a serious and unexpected suspected adverse reaction from a clinical
trial, this would be the day the sponsor receives information from the
clinical investigator. If any information necessary to evaluate and
report the suspected adverse reaction is missing or unknown, the
sponsor should actively seek such information.
    (Comment 14) Several comments stated that including in an IND
safety report a chronological history of their efforts to acquire the
minimum data set is inconsistent with standards for non-U.S. regulators
and the ICH E2A guidance, adds no value, may lead to potential legal
risk in the event of litigation, may impede electronic transmission of
individual case safety reports, and will become an administrative
burden. Some comments suggested that records of efforts to obtain the
minimum data set should be maintained within the case record in the
sponsor's files, available upon request or during agency inspections.
One comment suggested FDA require manufacturers to have procedures in
place to acquire a minimum data set. One comment stated that the agency
needs to define the minimum requirements for conducting due diligence
to avoid variation from sponsor to sponsor. Another comment recommended
reinforcing the need for sponsors to conduct followup activities and
for FDA to audit industry for compliance. One comment requested
clarification on the sponsor's timeframe for maintaining records of its
efforts to obtain the minimum data set. One comment pointed out that
although FDA stated in the preamble that the chronological history
included in the IND safety report would not need to be sent to
investigators, this statement creates conflict because sponsors must
tell investigators the same information that is reported to FDA.
    (Response) The agency agrees with comments that including a
chronological history in an IND safety report of efforts to acquire
information is not necessary and could be an administrative burden
without added value. Accordingly, the proposed requirement for a
chronological history has been deleted from Sec.  312.32(c). Under
Sec.  312.32(d)(1), sponsors are required to promptly investigate all
safety information received, so it is inherent in that requirement that
sponsors promptly and diligently attempt to obtain the information
necessary for evaluating a suspected adverse reaction. If critical
information is missing or unknown, the sponsor should actively seek the
information. The regulations do not include specific procedures for
conducting or documenting due diligence activities because the agency
recognizes that there is more than one approach that would be
appropriate, depending on the situation.
    Similarly, because the minimum data set requirement is no longer
included, the agency is not adopting the proposed requirement in Sec.
312.32(c) to maintain records of any information received or otherwise
obtained for the SADR when the sponsor does not have a reportable
minimum data set. The agency notes that sponsors are required under
Sec.  312.57(c) to retain records and reports required under part 312
(including safety information received by the sponsor) for 2 years
after a marketing application is approved for the drug or, if an
application is not approved for the drug, until 2 years after shipment
and delivery of the drug for an investigational use is discontinued and
FDA has been so notified. The agency may audit these records as part of
its inspection process.

D. Serious and Unexpected SADR--Proposed Sec.  312.32(c)(1)(i)

    In proposed Sec.  312.32(c)(1)(i), FDA proposed that the sponsor
must notify FDA and all participating investigators in a written IND
safety report of any SADR that, based on the opinion of the
investigator or sponsor, is both serious and unexpected, as soon as
possible, but in no case later than 15 calendar days after receipt by
the sponsor of the minimum data set for the serious, unexpected SADR.
In addition, FDA proposed that the sponsor must identify all safety
reports previously filed with the IND concerning a similar SADR, and
must analyze the significance of the SADR in light of the previous,
similar reports.
    (Comment 15) One comment agreed with the proposal that the
assessment of whether the event is serious or unexpected be based on
the opinion of the ``investigator or sponsor,'' while other comments
expressed concern. Several comments indicated that investigators should
not be required to assess ``expectedness.'' One comment stated that
``expectednessx'' is a regulatory definition that would be difficult
for an investigator to apply in a consistent manner. Another comment
suggested replacing the proposed language with ``any SADR that is
serious based on the opinion of the investigator or sponsor and
unexpected.''
    (Response) The agency agrees that, in contrast to the assessments
of whether an adverse event or suspected adverse reaction is
``serious'' and ``life-threatening,'' which require medical judgment by
the investigator or sponsor, the assessment of whether an adverse event
or suspected adverse reaction is ``unexpected'' in this context refers
to a regulatory definition (i.e., not listed in the investigator
brochure) that is more appropriately applied by the sponsor. The
sponsor is usually in a better position to assess the adverse event
information and determine whether the adverse event is ``unexpected''
for reporting purposes because the sponsor has access to more
information (e.g., from all the investigative sites in a multi-center
study). Therefore, the agency has revised this proposed requirement by
deleting the phrase ``based on the opinion of the investigator or
sponsor,'' which leaves this determination to the sponsor.

    (Comment 16) Several comments asked for clarification on various
aspects of the requirement to identify all safety reports previously
filed with the IND concerning a similar SADR and to analyze the
significance of the SADR in the context of the previous, similar
reports. One comment requested clarification on the meaning of
``previously filed with the IND'' and whether this should include an
analysis of previous similar reports across multiple open INDs or only
a single IND. The comment noted that there could be company-sponsored
IND studies and investigator-sponsored IND studies ongoing
simultaneously, with safety data stored in different places. One
comment requested clarification on what constitutes a ``similar'' SADR
and on the meaning of ``analyze the significance.'' This comment noted
that companies should already have processes and procedures in place to
periodically review and analyze safety data to detect ``signals,'' and
asked whether FDA expects an ``analysis'' for postmarketing study
reports filed to the IND or all reports for the product, including
postmarketing spontaneous reports. The comment suggested that FDA
remove this requirement for both IND and postmarketing studies, since
for IND studies, companies should already be performing these analyses
and updating their investigator brochures with significant new safety
information, and for postmarketing studies, analyses of all adverse
events are being performed in the periodic safety update report (PSUR).
    (Response) The agency expects the analysis of the significance of
the suspected adverse reaction in the context of similar reports to
include all INDs held by the sponsor and any other relevant information
of which the sponsor is aware. To make this clear, the agency revised
the provision in final Sec.  312.32(c)(1) to require that in each IND
safety report, the sponsor must identify all IND safety reports
previously submitted to FDA concerning a similar suspected adverse
reaction, and must analyze the significance of the suspected adverse
reaction in light of previous, similar reports or any other relevant
information.
    The agency declines to withdraw the requirement as suggested by the
comment because we consider this information to be critical for the
ongoing evaluation of the investigational drug's safety. Because this
is not a new requirement (see former Sec.  312.32(c)(1)(ii)), the
agency agrees that companies should have processes in place to
periodically review and analyze their safety data and update their
investigator brochures with significant new safety information. This
analysis should include an evaluation of the suspected adverse reaction
in the context of other related reports or adverse events, including
those that may have occurred in postmarketing studies.
    (Comment 17) One comment asked whether the IND safety report should
be sent only to investigators participating in company-sponsored
studies or to studies conducted under all open INDs for the product.
One comment requested that FDA clarify its expectations for cross-
reporting to investigators participating in different trials under the
same IND or different INDs with the same active moiety. One comment
asked if followup IND safety reports containing only minor refinements
are to be sent to FDA and all investigators who received the initial
safety report or only to FDA.
    (Response) The sponsor must report to any participating
investigators under all open INDs, including those held by the sponsor
and those to which the sponsor provides the investigational drug
(investigator-sponsored). To make this clear, the agency revised the
provision in Sec.  312.32(c)(1) to require that a sponsor notify FDA
and all participating investigators (i.e., all investigators to whom
the sponsor is providing drug under its INDs or under any
investigator's IND) in an IND safety report of potential serious risks,
from clinical trials or any other source, as soon as possible, but in
no case later than 15 calendar days after the sponsor determines that
the information qualifies for reporting under Sec.  312.32(c)(1)(i),
(c)(1)(ii), (c)(1)(iii), or (c)(1)(iv).
    Followup reports should be sent to investigators to inform and
update them about an important suspected adverse reaction if it
significantly affects the care of the subjects or conduct of the study.
Minor refinements that do not significantly affect care of subjects or
conduct of the study need to be sent to FDA but need not be sent to
investigators. Such information may be communicated to investigators in
a routine update of the investigator brochure.
    (Comment 18) As stated in Comment 1 of this document, there were
many comments opposed to FDA's proposed SADR definition, some of which
recommended against adopting the proposed SADR definition, and instead,
urged FDA to clarify the types of evidence that suggest there is a
reasonable possibility that a drug product caused the adverse event.
    (Response) Before submitting an IND safety report under Sec.
312.32(c)(1)(i), the sponsor must determine that the event: (1) Is
serious, (2) is unexpected, and (3) meets the definition of ``suspected
adverse reaction'' in Sec.  312.32(a) (i.e., that there is a
``reasonable possibility'' that the drug caused the event). These
criteria have not changed from former Sec.  312.32(c)(1)(i)(A). Making
this determination will always require judgment based on the best
available information.
    Currently, sponsors often report in an expedited manner serious
adverse events that may be due to the underlying disease or that occur
commonly in the study population, even when there is little reason to
believe that the drug caused the event. Such reports are generally
uninformative and, therefore, do not meaningfully contribute to the
developing safety profile of the drug. The agency believes that
clarifying what evidence suggests a causal relationship will increase
the likelihood that information reported to FDA will meaningfully
contribute to the developing safety profile of the product and improve
the overall quality of safety reporting.
    Therefore, to assist sponsors with determining whether an adverse
event meets the definition of suspected adverse reaction, the agency
revised the proposed requirement under Sec.  312.32(c)(1)(i) to make it
clear that sponsors are to report to FDA and all participating
investigators only if there is evidence to suggest a causal
relationship between the drug and the adverse event. Final Sec.
312.32(c)(1)(i) also provides the following examples:
     A single occurrence of an event that is uncommon and known
to be strongly associated with drug exposure (e.g., angioedema, hepatic
injury, Stevens-Johnson Syndrome).
     One or more occurrences of an event that is not commonly
associated with drug exposure, but is otherwise uncommon in the
population exposed to the drug (e.g., tendon rupture).
     An aggregate analysis of specific events observed in a
clinical trial (such as known consequences of the underlying disease or
condition under investigation or other events that commonly occur in
the study population independent of drug therapy) that indicates those
events occur more frequently in the drug treatment group than in a
concurrent or historical control group.

E. Alternative Reporting Arrangements

    In the preamble to the proposed rule, FDA acknowledged that the
proposed

definition of SADR (which defined ``reasonable possibility'' to mean
that the causal relationship between a product and a response to the
product cannot be ruled out) may result in submission of numerous
safety reports to the agency for which the reported SADR is not
informative as a single report because it is very likely to have been a
consequence of the patient's disease. FDA invited comment on use of
alternative reporting methods that would minimize overreporting of
uninformative events and assure submission of meaningful reports of
unexpected events. For example, one such alternative would be to
include in study protocols or other documentation a list of known
consequences of the disease that would not be submitted to FDA in an
expedited manner as individual case safety reports (e.g., events that
are endpoints of the study) (68 FR 12406 at 12418).
    (Comment 19) Some comments agreed with the agency's suggestion that
protocols could be written to exclude specific disease-related events
from expedited reporting if these events are study endpoints. Other
comments expressed concern that alternative reporting methods would not
have the intended effect of reducing overreporting and could exacerbate
problems with the proposed SADR definition of reasonable possibility in
which the causal relationship ``cannot be ruled out.'' They argued that
effectively eliminating clinical judgment in reporting coupled with an
ad hoc exemption mechanism would lead to different standards across
clinical programs, between different sponsors of studies, and across
FDA review divisions. These comments further pointed out that
negotiating and managing exemptions to expedited reporting would place
a significant burden on FDA and companies and would necessitate the
creation of an FDA structure and process to ensure consistency across
products. While many of these comments recommended against finalizing
the proposed definition, others suggested alternatives (e.g., waiver
provisions) to alleviate overreporting caused by the proposed
definition. One comment recommended that approaches to minimize
overreporting only be considered for late stage development (i.e.,
Phase 3 and 4 studies). One comment recommended that FDA mandate
expanded reporting for clinical trials only for those companies that
have had documented poor performance in the past or for clinical trials
once a study or design has been identified as posing a potential or
unforeseen risk to participants.
    (Response) As previously described in the response to Comment 1 of
this document, the agency is not adopting the proposed SADR definition
and, instead, is adopting a definition of ``suspected adverse
reaction'' that relies on clinical judgment to determine if there is a
reasonable possibility that the drug caused the event. While FDA
believes this definition addresses many of the concerns about
overreporting, the agency agrees with the comments that stated that
protocols could be written to exclude from expedited reporting specific
disease-related events that are study endpoints. The agency does not
believe that it is appropriate to report study endpoints as IND safety
reports for trials that are designed to evaluate the effect of the drug
on disease-related mortality or morbidity. Therefore, the agency added
the requirement at Sec.  312.32(c)(5) that study endpoints (e.g.,
mortality or major morbidity) must be reported to FDA by the sponsor as
described in the protocol and ordinarily would not be reported under
Sec.  312.32(c). However, if a serious and unexpected adverse event
occurs for which there is evidence suggesting a causal relationship
between the drug and the event (e.g., death from anaphylaxis), the
event must be reported under Sec.  312.32(c)(1)(i) as a serious and
unexpected suspected adverse reaction even if it is a component of the
study endpoint (e.g., all-cause mortality). FDA does not believe that
this requirement will pose an additional burden on sponsors or the
agency because sponsors of large outcome trials are accustomed to
describing in the protocol how mortality or major morbidity endpoints
will be measured and analyzed, and FDA review divisions are accustomed
to reviewing such protocols.
    The agency does not agree that the safety reporting requirements
should be revised, as suggested by the comment, to address specific
study or design risks or company compliance. The agency is authorized
to require additional reporting or inspection, or to take action, on a
case-by-case basis if, for example, such problems expose human subjects
to unreasonable and significant risk of illness or injury, or if the
sponsor does not comply with the requirements under Sec.  312.32 (see
e.g., Sec.  312.42 clinical holds and requests for modifications, Sec.
312.44 termination).
    (Comment 20) Several comments supported the use of alternative
reporting arrangements for serious adverse events that are not the
study endpoints (e.g., known consequences of the underlying disease or
condition). These comments recommended that these events not be
reported to FDA in an expedited manner as individual case safety
reports, but be identified in the study protocol with clear
instructions for handling, be monitored by the sponsor, and be reported
to the agency if, in aggregate, it appears that the product may be
causing an increase in these adverse events. One comment endorsed this
type of arrangement because it offers the potential for improvements in
protocol design by providing expanded opportunity for sponsors to
discuss the ``ground rules'' for SADR reporting for specific studies
with the agency during the protocol design phase. Two comments
recommended that FDA make clear to investigators, sponsors,
manufacturers, and IRBs that such arrangements are acceptable. One
comment stated that allowing this type of alternative reporting
arrangement will provide a loophole for industry to underreport adverse
events.
    (Response) Under former Sec.  312.32(c)(3), sponsors were permitted
to propose alternative reporting formats or frequencies for submitting
IND safety reports; this requirement has not changed in this final
rule. The agency agrees with the comments recommending that at the time
of protocol development the sponsor identify the serious adverse events
(i.e., known consequences of the disease or those otherwise common in
the study population) that it plans not to report individually in an
expedited manner but that it will monitor during the course of the
trial. FDA encourages use of this process. Should an aggregate analysis
indicate that those events occur more frequently in the drug treatment
group, the sponsor must then report that information in an IND safety
report under Sec.  312.32(c)(1)(i). However, the agency recognizes that
it is not possible, nor desirable, to list in the protocol every
adverse event that may be anticipated to occur in the study population;
the protocol should therefore limit such a list to those events that
are common, even in the absence of drug exposure. For example, in a
long-term osteoporosis trial in an elderly population, it would be
reasonable to list myocardial infarction, but unreasonable to list
acute narrow angle glaucoma--an event that can occur in this elderly
population, but is relatively rare. In addition, the agency believes
that there may be other situations for which alternative reporting
arrangements are appropriate based on the clinical circumstances. For
example,

the agency may require a sponsor to continue to report expeditiously a
medically significant suspected adverse reaction that is listed in the
investigator brochure as observed with the drug (i.e., expected) so
that its rate can be carefully monitored. The agency may also require
an alternative reporting format or frequency for clinical trials once a
study or design has been identified as posing a potential or unforeseen
risk to participants. In other instances, a sponsor may request that a
certain adverse event be submitted in a different format or at a
different frequency than required. Section 312.32(c)(3) permits such
arrangements. The agency does not agree that allowing alternative
reporting formats or frequencies creates loopholes for sponsors to
underreport, but believes that such arrangements will lead to greater
vigilance since particular adverse events of interest have been
identified in advance. The agency is clarifying the language in former
Sec.  312.32(c)(3) that stated ``FDA may request a sponsor to submit
IND safety reports in a format or at a frequency different than that
required under this paragraph'' by replacing the word ``request'' with
``require'' to better reflect the existing process.

F. Unblinding

    In the preamble to the proposed rule, FDA noted that reports from
blinded clinical studies should have the blind broken to identify the
drug product, but that alternative arrangements could be made with FDA
for exceptions to breaking the blind for a clinical study in which
mortality or serious morbidities are the clinical endpoint of the
study. FDA invited comment on whether the blind should also be broken
for other serious SADRs that are not the clinical endpoint of the
study, but occur at a rate high enough that the overall study blind
would be threatened if each such case were individually unblinded (68
FR 12406 at 12420).
    (Comment 21) Several comments expressed concern that breaking the
blind to identify the suspect drug could potentially bias both the
sponsor and investigator, and suggested alternatives to unblinding so
that sponsors and investigators could remain blinded. In addition,
several comments responded to FDA's request for comment on whether the
blind should be broken for serious SADRs that are not the clinical
endpoint of the study. One comment stated that for other serious SADRs
(e.g., expected), if a safety signal is observed, sponsors are
obligated to unblind studies for individual subject cases, but other
comments stated that medical management of the subject who experiences
the serious SADR does not always require unblinding. One comment stated
that the sponsor and FDA should define in advance the nature of such
serious SADRs that would not be subject to routine expedited reporting
and unblinding. One comment stated that for studies in which
alternative arrangements have been made to maintain the blind, FDA
should receive interim analyses, disaggregated by group, which might
suggest increased overall dangers to those getting the drug.
    (Response) The agency believes that the concerns expressed about
breaking the blind have been addressed by clarifying the reporting
requirements for serious and unexpected suspected adverse reactions
(Sec.  312.32(c)(1)(i)) and for study endpoints (Sec.  312.32(c)(5)),
and the provision permitting alternative reporting arrangements (Sec.
312.32(c)(3)). In particular, because there should generally be no need
to report study endpoints in an IND safety report, unblinding due to
such endpoints should typically not occur. In other cases, however,
where the serious, unexpected, suspected adverse reaction must be
reported expeditiously, the agency expects the blind to be broken.
Knowledge of the treatment received may be essential for the medical
management of the subject and may provide critical safety information
about the drug that could have implications for the ongoing conduct of
the trial (e.g., monitoring, informed consent). The agency does not
believe that unblinding single or small numbers of informative cases
will compromise the integrity of the study. However, if patient safety
can be assured without breaking the blind, the agency encourages the
sponsor to discuss alternative reporting arrangements with the
appropriate FDA review division. Any anticipated alternative
arrangements to maintain the blind would need to be described in the
protocol, including identification of the serious adverse events that
will not be reported on an individual basis and the plan for monitoring
and reporting results to FDA.
    (Comment 22) Several comments made recommendations on the need for,
and role of independent data safety monitoring boards (DSMBs), called
Data Monitoring Committees (DMCs) in FDA's guidance for industry
entitled ``Guidance for Clinical Trial Sponsors: Establishment and
Operation of Clinical Trial Data Monitoring Committees'' (71 FR 15421,
March 28, 2006) (DMC guidance). One comment stated that an obligation
to have an independent DSMB would prevent routine unblinding. Other
comments recommended the use of DSMBs that have processes for vetting
and reporting adverse reactions to the agency, including monitoring for
increases in disease-related complications. One comment recommended
that the agency concurrently amend the IRB regulations and guidelines
to incorporate a mandate of more frequent review of overall safety
data, including a requirement for an independent safety monitoring
committee, under predefined circumstances. Another comment urged the
agency to require a DSMB for all Phase 3 studies and to also require
that sponsors provide DSMB reports to IRBs. One comment said that
clarity on the role of the DSMB for Phase 3 and 4 studies when
reviewing SADRs could help reduce redundancy of SADR reporting
evaluations by IRBs, and allow IRBs to more efficiently focus their
attention on local SADRs.
    (Response) The agency agrees that DMCs can be useful for monitoring
adverse events and preventing routine unblinding in certain trials. A
DMC is not required and is not necessary for most studies, particularly
those evaluating symptomatic treatments. DMCs are generally associated
with a large, randomized multisite trial that is designed to evaluate
treatments intended to improve survival or reduce the risk of major
morbidity. In that case, the independent DMC would be expected to
monitor serious events that are study endpoints and also may assess the
rate of other known consequences of the underlying disease or other
events that are common in the study population. FDA's DMC guidance also
notes another potential use for a DMC. Some sponsors have used a DMC to
monitor the overall event rates as the safety database accumulates in
ongoing studies (DMC guidance at p. 23). A DMC could periodically
analyze and evaluate the aggregated, unblinded events in the entire IND
safety database to determine if the drug is the suspected cause. During
these analyses, investigators and study participants would remain
blinded. FDA's DMC guidance also provides more information on
determining the need for and the role of a DMC. In addition, the
agency's guidance for industry entitled ``Guidance for Clinical
Investigators, Sponsors, and IRBs: Adverse Event Reporting--Improving
Human Subject Protection'' provides recommendations on efficient
approaches to meeting the requirements for reporting unanticipated
problems to IRBs (74 FR 2599, January 15, 2009).

G. Information Sufficient to Consider Product Administration Changes--
Proposed Sec.  312.32(c)(1)(ii)

    In addition to requiring sponsors to provide written IND safety
reports to FDA and investigators for any serious and unexpected adverse
experience, former Sec.  312.32(c)(1)(i) required a written IND safety
report for ``[a]ny finding from tests in laboratory animals that
suggests a significant risk for human subjects including reports of
mutagenicity, teratogenicity, or carcinogenicity.'' FDA proposed to
revise this requirement to require sponsors to submit a written IND
safety report if the sponsor receives information sufficient to
consider product administration changes. The proposed rule described
information sufficient to consider product administration changes as
``information that, based on appropriate medical judgment, might
materially influence the benefit-risk assessment of an investigational
drug or that would be sufficient to consider changes in either product
administration or in the overall conduct of a clinical investigation''
(68 FR 12406 at 12476). Examples of the types of information that might
give rise to such a report were described as ``any significant
unanticipated safety finding or data in the aggregate from an in vitro,
animal, epidemiological, or clinical study, whether or not conducted
under an IND, that suggests a significant human risk, such as reports
of mutagenicity, teratogenicity, or carcinogenicity or reports of a
lack of efficacy with a drug product used in treating a life-
threatening or serious disease'' (68 FR 12406 at 12476).
    (Comment 23) Several comments maintained that the threshold for
submission of this category of IND safety report--information
sufficient to consider product administration changes--needs
clarification. Some comments stated the ``information sufficient to
consider product administration changes'' is too vague a criterion on
which to base a reporting requirement and that ``product
administration'' may have different interpretations in the context of
safety. Some comments pointed out that there is ongoing
``consideration'' of the implications, for product administration, of
information that emerges during the conduct of a trial and often, upon
consideration, it will be concluded that no changes are needed. Some
comments recommended that there be an IND safety report only in the
event of a product administration change or other change in the conduct
of the investigation. One comment recommended that FDA consider the
implications (e.g., potential confusion) of informing investigators
about information sufficient to consider product administration changes
before a decision has been made about whether to make a change. That
comment recommended that only FDA receive the information sufficient to
consider product administration changes and that the investigator be
notified only in the event of an actual product administration change.
Some comments pointed out that the proposed language does not
differentiate among the range of possible product administration
changes and thus would seem to require an expedited report for minor
changes that do not warrant expedited reporting. The comments suggested
that there be expedited reporting only in the event of significant
product administration changes. One comment stated that information
sufficient to consider product administration changes is a reasonable
category for an IND safety report. The comment asked that FDA clarify
that significant risk to humans is intended to include instances of
significant impairment or dysfunction.
    (Response) The agency concurs that, as proposed, the requirement
may be confusing. In response to comments, the agency has revised the
proposed requirement for reporting data or findings from clinical or
epidemiological studies to address the concerns about vagueness of
terms and criteria that could lead to differences in interpretation.
The revised requirement eliminates the association with ``product
administration changes'' and makes clear the types of findings that
would trigger the requirement to report under this provision. In
addition, the revised requirement also makes clear that the findings
from clinical studies that are subject to this requirement are other
than those reported under Sec.  312.32(c)(1)(i) (e.g., findings from a
drug interaction study). The agency has revised Sec.  312.32(c)(1)(ii)
to require the sponsor to report any findings from epidemiological
studies, pooled analysis of multiple studies, or clinical studies
(other than those reported under Sec.  312.32(c)(1)(i)),whether or not
conducted under an IND and whether or not conducted by the sponsor,
that suggest a significant risk in humans exposed to the drug. The
provision goes on to state that, ordinarily, such a finding would
result in a safety-related change in the protocol, informed consent,
investigator brochure (excluding routine updates of these documents),
or other aspects of the overall conduct of the clinical investigation.
    These changes to the proposed requirement also address the comments
concerned about potentially prematurely notifying all investigators
prior to conclusively determining whether a finding might change the
product administration or conduct of the investigation because the
sponsor would report to FDA and notify all participating investigators,
as required by Sec.  312.32(c)(1), after that determination has been
made by the sponsor.
    In addition, FDA agrees with the comment that ``significant risk in
humans'' would include instances of significant impairment or
dysfunction.
    (Comment 24) One comment asked that FDA clarify what is meant by
``might materially influence the benefit-risk assessment'' (68 FR 12406
at 12476). The comment pointed out that a literal interpretation would
require an IND safety report for a finding that is favorable to the
benefit-risk assessment as well as a finding that is unfavorable to the
benefit-risk assessment, but would have no effect on the clinical use
of the drug. Another comment maintained that the term benefit-risk has
no clear meaning in the premarket context because efficacy has not been
proven, i.e., there is no established benefit for the product being
studied.
    (Response) The agency agrees that the proposed requirement may be
confusing. Therefore, the agency has not included the phrase ``might
materially influence the benefit-risk assessment'' in Sec.
312.32(c)(1)(ii).
    (Comment 25) Some comments questioned FDA's intent and otherwise
expressed concern about requiring IND safety reports of lack of
efficacy for a drug intended to treat a life-threatening or serious
disease. One comment pointed out that ``lack of efficacy'' is rarely
used in the clinical trial setting to refer to cases of disease
progression or nonresponders. The comment maintained that because of
the difficulty in judging lack of efficacy, such reports should be
limited to cases in which the investigator has specifically determined
that there was lack of efficacy. One comment maintained that the term
is incongruous in the clinical trial setting because efficacy of the
drug has not been demonstrated. One comment pointed out that the term
``lack of efficacy'' is not used consistently throughout the proposed
rule (i.e., premarket compared to postmarket setting).
    (Response) The agency agrees with the comment stating that the term
``lack of efficacy'' is incongruous in the

clinical trial setting because the effectiveness of the drug has
generally not been established. Therefore, the final rule does not
include this proposed provision.
    (Comment 26) One comment stated that in vitro and animal findings
should not be lumped together with clinical findings for purposes of
the information sufficient to consider product administration changes
IND safety reports because in vitro and animal findings typically are
assessed differently than clinical findings. The comment also argued
that there is significant variation in the interpretation of the
current reporting requirements for nonclinical findings and recommended
establishing distinct, well-defined criteria for reporting of
nonclinical findings. The comment recommended a separate safety report
for animal and in vitro findings with the following criteria: (1) A
drug-related finding, (2) an unanticipated finding, and (3) a finding
that suggests a serious risk to humans. The comment further maintained
that the company's core safety information about the drug should be the
basis for determining whether the finding is unanticipated and the term
``serious'' should be defined, in this context, as suggesting a
significant human risk, including, but not limited to, reports of
carcinogenicity, mutagenicity, or teratogenicity.
    (Response) The agency agrees that the way in which in vitro and
animal findings are assessed differs from clinical findings. To make
this distinction clear, the agency has revised the proposed requirement
to separate reports of findings from nonclinical and clinical studies.
Under Sec.  312.32(c)(1)(iii), the sponsor must report any findings
from any animal or in vitro testing, whether or not conducted by the
sponsor, that suggest a significant risk in humans exposed to the drug,
such as reports of mutagenicity, teratogenicity, carcinogenicity, or
reports of significant organ toxicity at or near the expected human
exposure. The provision states that, ordinarily, any such findings
would result in a safety-related change in the protocol, informed
consent, investigator brochure (excluding routine updates of these
documents), or other aspects of the overall conduct of the clinical
investigation.
    The revised requirement also eliminates the terms ``unanticipated''
and ``serious.'' The agency agrees with the comment that an
unanticipated, drug-related finding that suggests a significant risk to
humans would meet the requirement for reporting.
    (Comment 27) Two comments asked FDA to clarify the scope of what is
meant by ``an animal finding suggestive of significant human safety
risk.'' One comment asked whether there are any animal findings other
than carcinogenicity, mutagenicity, or teratogenicity that would be
considered a significant human safety risk and whether a finding needs
to originate from a reproducible validated controlled model. One
comment stated that the final rule should state explicitly that only
those findings of carcinogenicity, mutagenicity, or teratogenicity that
the sponsor considers suggestive of significant risk to humans should
be reported. The comment pointed out that some carcinogenicity,
mutagenicity, and teratogenicity findings are known to be species-
specific or for other reasons known not to suggest significant
potential human risk and thus should not be subject to expedited
reporting. Another comment suggested a distinction be made between a
nonclinical finding that requires ``changes in either product
administration or in the overall conduct of a clinical investigation''
as opposed to a nonclinical finding that requires information only
(e.g., action is limited to a nonurgent update of the investigator
brochure and informed consent).
    (Response) The requirement has been revised to make it clear that,
ordinarily, a finding would be considered suggestive of a significant
risk in humans if it results in a safety-related change in the
protocol, informed consent, investigator brochure, or other aspects of
the overall conduct of the clinical investigation. Nonurgent, routine
updates to the investigator brochure and informed consent would not
meet the criteria for reporting under this provision and should not be
reported in an expedited IND safety report.
    The sponsor must determine whether a finding suggests a significant
risk in humans in order for the finding to be reportable. Animal
findings such as carcinogenicity, mutagenicity or teratogenicity are
meant to be examples of the types of findings that could suggest a
significant human risk, but there are others that could meet the
criteria for reporting. For clarity, the agency added another example
in Sec.  312.32(c)(1)(iii) (i.e., reports of significant organ toxicity
at or near the expected human exposure). Findings from animal studies
do not necessarily need to be replicated to meet the criteria for
expedited reporting to FDA. For example, the agency would not expect a
long-term carcinogenicity study to be replicated if findings from the
original study suggested a significant risk to humans. The validity of
the model would be a factor taken into account in evaluating the
strength of the evidence of significant risk.
    (Comment 28) Many comments expressed concern about in vitro testing
alone as a basis for an IND safety report. One comment pointed out that
certain types of in vitro findings that are known to be associated with
an increased risk of carcinogenicity or mutagenicity are always
reported, but other findings are not obviously worthy of reporting.
Some comments argued that expanding the scope of expedited reporting to
include in vitro testing is not warranted or useful. Some comments
maintained that in vitro testing is often exploratory and not validated
and thus lends itself to unanticipated findings, but the clinical
implications of in vitro testing are often not understood until later
when the data can be assessed in light of animal or clinical findings.
Given this delay in the interpretability of in vitro findings, the
comments asked FDA to clarify when an in vitro finding becomes
reportable for purposes of an IND safety report. Some comments argued
that the increased reporting burden for in vitro findings would result
in large numbers of uninformative reports that would burden FDA and
dilute the impact of truly informative safety reports. Some comments
also maintained that expanded reporting requirements may deter sponsors
from conducting the kinds of in vitro testing that could reduce the
number of animal studies needed.
    (Response) In response to comments and as stated in Comments 26 and
27, the agency has revised the proposed requirement Sec.
312.32(c)(1)(iii) to make it clear that an in vitro or animal finding
is reportable for the purposes of an IND safety report if it suggests a
significant risk in humans exposed to the drug. The sponsor would not
report an in vitro finding in an expedited report unless it determined
that the finding suggests a significant risk in humans.
    (Comment 29) Some comments asked FDA to clarify the timeframe for
reporting under this requirement, including when in vitro and animal
studies become reportable sources of safety information by explaining
how ``the determination by the sponsor that the information qualifies
for reporting under this paragraph'' applies to nonclinical findings.
One comment suggested that the reporting clock for in vitro and animal
findings start on the date the final study report is completed. One
comment asked that FDA clarify that the day that the 15-day period
begins is day zero and not day one.

    (Response) The agency believes that the revisions to this
requirement have sufficiently detailed how information qualifies for
reporting by providing examples of the outcome of such a finding (i.e.,
the finding would ordinarily result in a safety-related change in the
protocol, informed consent, investigator brochure, or in other aspects
of the overall conduct of the clinical investigation). The 15-day
reporting clock begins (i.e., day zero) on the day that the sponsor
determines that a finding suggests a significant risk in humans. In
general, it is not necessary for a final study report to be completed
before a sponsor is able to make this determination.

H. Submission of Written Reports--Proposed Sec.  312.32(c)(1)(iii)

    Under proposed Sec.  312.32(c)(1)(iii), FDA proposed that each
written report may be submitted on an FDA Form 3500A or in a narrative
format. Foreign SADRs may be submitted on an FDA Form 3500A or on a
CIOMS I form. FDA also proposed that reports of overall findings or
data in the aggregate from published and unpublished in vitro, animal,
epidemiological, or clinical studies must be submitted in a narrative
format. In addition, FDA proposed to require that each written notice
bear prominent identification of its contents and be transmitted to the
FDA review division that has responsibility for the review of the IND.
FDA also proposed to require that if the agency determines that
additional data are needed, FDA may require further data to be
submitted.
    The agency has also revised the requirement (final Sec.
312.32(c)(1)(v)) to allow for electronic submission of these reports
because the agency anticipates that these reports will be submitted by
means other than paper in the future. In addition, the agency has
revised the requirement to make clear that the period of time for
submitting additional data requested by the agency is 15 calendar days,
the same as required under Sec.  312.32(d) for submitting followup
information. The time for submission of this additional information was
not specified in the proposed rule.
    (Comment 30) Two comments asked if the agency would accept the
CIOMS I form for reporting domestic SADRs. One comment strongly
recommended that the CIOMS I form be acceptable for reporting domestic
SADRs because it would decrease workload burden, enhance timeliness
compliance with reporting timeframes, and integrate globally accepted
formats.
    (Response) FDA will continue, as proposed, the current practice of
permitting submission of IND safety reports on FDA Form 3500A or in a
narrative format for reports of domestic suspected adverse reactions
and on FDA Form 3500A, in a narrative format or on a CIOMS I form for
reports of foreign suspected adverse reactions. FDA declines to permit
submission of domestic suspected adverse reactions on the CIOMS I form
because the CIOMS I form has fewer data elements than FDA Form 3500A
(see 60 FR 11284 at 11287, March 1, 1995; 62 FR 52237 at 52246, October
7, 1997) and FDA believes the additional data elements are useful for
evaluating the report. FDA is continuing to accept the CIOMS I form for
foreign reports because we believe that harmonization facilitates
compliance with the reporting requirements, thereby expediting FDA's
receipt of foreign suspected adverse reaction reports. In the future,
the agency anticipates that electronic reporting of suspected adverse
reactions will replace the use of paper forms.

I. Telephone and Facsimile Transmission Safety Reports--Proposed Sec.
312.32(c)(2)

    FDA proposed to require that the sponsor notify FDA by telephone or
by facsimile transmission of any unexpected fatal or life-threatening
SADR based on the opinion of the investigator or sponsor as soon as
possible but in no case later than 7 calendar days after receipt by the
sponsor of the minimum data set.
    Because the agency anticipates that these reports will be submitted
by means other than telephone or facsimile in the future (e.g.,
electronically), the agency has revised the requirement to eliminate
the specificity that these reports be submitted only by telephone or
facsimile. The agency also changed the paragraph heading to
``Unexpected fatal or life-threatening suspected adverse reaction
reports.'' For consistency with the agency's decision that assessment
of whether the event is serious and unexpected should be based on the
opinion of the sponsor (not the investigator), the agency eliminated
the phrase ``based on the opinion of the investigator or sponsor'' (see
comment 15 of this document and Sec.  312.32(c)(1)(i)). For consistency
with the agency's decision to eliminate the definition of ``minimum
data set,'' the agency replaced the phrase ``after receipt by the
sponsor of the minimum data set'' in the proposed codified with ``after
the sponsor's initial receipt of the information'' (see section III.C
of this document).

J. Investigations of Marketed Drugs--Proposed Sec.  312.32(c)(4)

    FDA proposed that ``a sponsor of a clinical study under an IND for
a drug marketed in the United States is only required to submit IND
safety reports to FDA (review division that has responsibility for the
IND) for SADRs from the clinical study itself, whether from domestic or
foreign study sites of the IND.'' As proposed, the sponsor would also
be required to submit to FDA safety information from these clinical
studies as prescribed by the postmarketing safety reporting
requirements under Sec. Sec.  310.305, 314.80, and 600.80.
    (Comment 31) One comment supported the clarification of this
requirement. Other comments requested further clarification. One
comment asked what should be submitted to the IND from foreign studies
not conducted under an IND (e.g., Phase 1-3 studies, Phase 4
postmarketing studies), both before and after a U.S. NDA is approved.
One comment recommended that FDA finalize a provision to require that
serious, unexpected SADRs that occur in studies not being conducted
under an IND be submitted as expedited reports to an IND, if one
exists. This comment also requested that FDA clarify whether serious,
unexpected SADRs observed in IND-exempt studies of marketed drugs are
required to be submitted to both an IND if one exists and the NDA. The
comment recommended submitting these cases only to the NDA. One comment
stated that although the requirement references the postmarketing
safety reporting requirements, the postmarketing requirements do not
mention foreign studies. This comment requested that FDA clarify the
postmarketing requirements. Another comment stated that for products
marketed and being studied globally, it is confusing to decide on the
appropriate route of reporting given the different licensed status of
products in different countries and different indications being
investigated. This comment recommended that FDA provide a centralized
reporting location so that FDA could route and file the report to the
appropriate application.
    (Response) The only reports that must be submitted to an IND for a
drug marketed or approved in the United States are those arising from a
study conducted under the IND (at domestic or foreign sites). All other
reports (e.g., marketing experience, studies not under an IND), must be
reported in accordance with the relevant postmarketing safety reporting
requirements. In response to

the comments, the agency clarified Sec.  312.32(c)(4) to state that a
sponsor of a clinical study of a drug marketed or approved in the
United States that is conducted under an IND is required to submit IND
safety reports for suspected adverse reactions that are observed in the
clinical study at domestic or foreign study sites. The sponsor must
also submit safety information from the clinical study as prescribed by
the postmarketing safety reporting requirements (e.g., Sec. Sec.
310.305, 314.80, and 600.80).
    Table 2 of this document summarizes the reporting requirements for
the various scenarios identified in the comments about submitting
safety reports from a clinical study.

                        Table 2.--Safety Reporting Requirements From Clinical Studies\1\
----------------------------------------------------------------------------------------------------------------
     Drug marketed or                                                                          Must report per
approved\2\ in the United     Under U.S. IND?         Trial site        Must report to IND?     postmarketing
         States?                                                                                requirements?
----------------------------------------------------------------------------------------------------------------
                     Yes                   Yes       U.S. or Foreign                   Yes                   Yes
----------------------------------------------------------------------------------------------------------------
                     Yes                    No       U.S. or Foreign                    No                   Yes
----------------------------------------------------------------------------------------------------------------
                      No                   Yes        U.S.or Foreign                   Yes   ...................
----------------------------------------------------------------------------------------------------------------
                      No                    No               Foreign   ....................  ...................
----------------------------------------------------------------------------------------------------------------
\1\ Areas in the table are left blank when an IND or marketing application would not exist.
\2\ If a drug is approved in the United States, but is not currently being marketed in the United States, the
  postmarketing requirements would still apply.

    The agency does not agree with the comment that stated that the
postmarketing requirements do not mention foreign studies. The
postmarketing reporting requirements do apply to postmarketing studies
conducted at foreign sites if the drug is marketed in the United
States. For example, Sec. Sec.  314.80(b) and 600.80(b) require
applicants to review all adverse drug experience information from any
source, ``foreign or domestic,'' and Sec. Sec.  314.80(e) and 600.80(b)
require expedited reporting from a postmarketing study, whether or not
conducted under an IND, if there is a reasonable possibility that the
drug caused the adverse experience.
    In addition, the agency revised the proposed language listing the
postmarketing safety reporting requirements by including the
parenthetical ``(e.g., Sec. Sec.  310.305, 314.80, and 600.80),''
thereby clarifying that the listed postmarketing regulations are
examples and other postmarketing safety reporting requirements may
apply (e.g., reports related to certain over-the-counter (OTC) products
under the Dietary Supplement and Nonprescription Drug Consumer
Protection Act (Public Law 109-462); records regarding blood or blood
products under Sec.  606.170).
    With respect to submitting reports to FDA to one central location,
currently, postmarketing safety reports are entered into the Adverse
Event Reporting System (AERS) database, whereas IND safety reports are
sent directly to the review division that has responsibility for the
review of the IND. Current capabilities do not permit direct electronic
submission through a Web-based system. However, FDA is committed to
adapting its business practices to evolving technology, including using
the significant advancements in Web-based, electronic systems. We
anticipate that, in future rulemakings, Web-based filing of most
submissions will eventually be required. We anticipate that when such a
change to an electronic submission system is implemented, future
guidance will address any technical questions related to such
submissions. Until such time that FDA develops a system to route and
manage IND safety reports within the AERS database, or another
database, the sponsor must submit them in the manner described in the
regulations and to the appropriate FDA location identified in the
regulations.

K. Followup--Proposed Sec.  312.32(d)

    Section 312.32(d) provides the requirements for investigating and
submitting followup information to an IND safety report, making minor
revisions in Sec.  312.32(d)(2) to clarify how relevant followup
information submitted under this paragraph must be identified (i.e.,
``Followup IND Safety Report''). The agency proposed revising the
terminology in Sec.  312.32(d)(3) to be consistent with the proposed
use of the term SADR. The terminology in Sec.  312.32(d)(3) is
consistent with terms used in the final rule. Former Sec.  312.32(d)(4)
required that results of a sponsor's investigation of other safety
information must be submitted, as appropriate, in an information
amendment or annual report. The agency has eliminated this requirement
because it is redundant--Sec. Sec.  312.31 and 312.33 contain the
submission requirements for information amendments and annual reports.

L. Disclaimer--Proposed Sec.  312.32(e)

    The agency proposed revising the terminology in Sec.  312.32(e) to
be consistent with the proposed use of the term SADR. The terminology
in Sec.  312.32(e) is consistent with terms used in the final rule.

M. Annual Reports

    Although the agency did not propose any changes to the IND annual
reporting requirements, FDA stated in the preamble to the proposed rule
that it would not require reports of an increase in the rate of
occurrence of expected, serious SADRs to be submitted to the agency in
an expedited manner. The agency stated that instead, sponsors should
report this information to FDA in their IND annual reports under Sec.
312.33(b)(1) (68 FR at 12406 at 12425).
    (Comment 32) One comment disagreed with FDA's proposal to deviate
from the ICH E2A guidance, which recommends rapid communication to
regulatory authorities for an increase in the rate of occurrence of an
``expected,'' serious ADR that is judged to be clinically important (60
FR 11284 at 11286), because expedited reporting of this information may
alert FDA to situations of more widespread and serious risks than were
previously known or of use in populations that had not been previously
identified as at risk. One comment agreed with the agency's departure
from the ICH E2A guidance recommendation for expedited reporting of
increased frequency of serious, expected SADRs. However, it questioned
the utility of including this information in the IND annual report, as
proposed by FDA. The comment stated that including this information may
be difficult, given the timing of various

clinical trials relative to the IND annual reporting cycle. The comment
suggested that rather than requiring increased frequency analysis of
serious SADRs in IND annual reports, sponsors should routinely review
incidence rates of all serious and nonserious adverse events within
their clinical program, and report any significant changes in the IND
annual report, when detected. Another comment recommended that the
agency provide guidance on what would be deemed a ``clinically
important'' increased rate of reports. The comment asked that FDA
explain what the value added of such reporting is, given the agency's
statements that such reports have limited reliability and have proven
to be of little value in identifying increased incidences of serious,
labeled events in the postmarketing setting (see 62 FR 34166, June 25,
1997).
    (Response) To be consistent with the recommendations in the ICH E2A
guidance and in response to comments about reporting serious
)``expected'' SADRs, the agency is adding a requirement under Sec.
312.32(c)(1)(iv) that the sponsor expeditiously report any clinically
important increase in the rate of a serious suspected adverse reaction
over that listed in the protocol or investigator brochure. The agency
acknowledges that baseline incidence rates from clinical trial data as
a basis for comparison may not be available in all cases, and as