[Federal Register Volume 75, Number 188 (Wednesday, September 29, 2010)]
[Rules and Regulations]
[Pages 59935-59963]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-24296]


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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, 301-796-2500.
    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, 301-827-6210.

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

[[Page 59936]]

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:
    <bullet> Findings from clinical studies, epidemiological studies or 
pooled analyses of multiple studies that suggest a significant risk in 
humans exposed to the drug,
    <bullet> Serious suspected adverse reactions that occur at an 
increased rate than listed in the protocol or investigator brochure, 
and
    <bullet> 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:
    <bullet> Replace the defined phrase ``associated with the use of 
the drug''

[[Page 59937]]

with the term ``suspected adverse drug reaction (SADR),''
    <bullet> Require submission of expedited reports of ``information 
sufficient to consider product administration changes,''
    <bullet> Make it clear that safety reports of overall findings or 
data in the aggregate must be submitted in a narrative format,
    <bullet> 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),
    <bullet> 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),
    <bullet> Require a ````minimum data set'' for each report of an 
SADR submitted to FDA, and
    <bullet> 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):
    <bullet> 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):
    <bullet> 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:
    <bullet> Adverse event,
    <bullet> Life-threatening adverse event or life-threatening 
suspected adverse reaction,
    <bullet> Serious adverse event or serious suspected adverse 
reaction,
    <bullet> Suspected adverse reaction, and
    <bullet> 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

[[Page 59938]]

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.
----------------------------------------------------------------------------------------------------------------
312.32(a) Adverse event                   <bullet> Added definition for ``adverse event'' (1)
----------------------------------------------------------------------------------------------------------------
312.32(a) Life-threatening adverse event  <bullet> 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)
----------------------------------------------------------------------------------------------------------------
312.32(a) Serious adverse event or        <bullet> Changed language to accommodate deletion of ``SADR''
 serious suspected adverse reaction        definition and use of alternative terminology (6)
                                          <bullet> Incorporated the definition from former Sec.   312.32(a) of
                                           ``disability'' within the definition of ``serious'' (III.A.2)
                                          <bullet> Revised so that the seriousness determination is based on the
                                           opinion of either the sponsor or investigator (6)
----------------------------------------------------------------------------------------------------------------
312.32(a) Suspected adverse reaction      <bullet> Replaced the term ``SADR'' with the term ``suspected adverse
                                           reaction,'' clarifying the meaning of ``reasonable possibility''
                                           within the definition (1)
----------------------------------------------------------------------------------------------------------------
312.32(a) Unexpected adverse event or     <bullet> 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    <bullet> 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           <bullet> 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    <bullet> Clarified agency's expectation for analysis of previous,
 suspected adverse reactions               similar reports or any other relevant information (16)
                                          <bullet> Withdrew the requirement that the causality assessment be
                                           based on the opinion of the investigator or the sponsor (15)
                                          <bullet> 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      <bullet> 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)
----------------------------------------------------------------------------------------------------------------

[[Page 59939]]

 
312.32(c)(1)(iii) Findings from animal    <bullet> 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        <bullet> 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  <bullet> 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-    <bullet> 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          <bullet> Replaced ``request'' with ``require'' (20)
 frequency
----------------------------------------------------------------------------------------------------------------
312.32(c)(4) Investigations of marketed   <bullet> Clarified requirements for investigations of marketed drugs
 drugs                                     (31)
----------------------------------------------------------------------------------------------------------------
312.32(c)(5) Reporting study endpoints    <bullet> 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                        <bullet> 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            <bullet> Clarified requirements for investigator reports (35 and 36)
----------------------------------------------------------------------------------------------------------------
320.31(d) Applicability of requirements   <bullet> Revised to require that persons conducting bioavailability
 regarding an ``Investigational New Drug   and bioequivalence studies report all serious adverse events (II)
 Application''                            <bullet> 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:
    <bullet> 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.
    <bullet> 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.
    <bullet> 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.

[[Page 59940]]

    <bullet> 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.
    <bullet> 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.
    <bullet> 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:
    <bullet> 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.
    <bullet> 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:
    <bullet> ``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:
    <bullet> 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.
    <bullet> A suspected adverse reaction is a subset of all adverse 
events in which there is a reasonable possibility that the drug caused 
the event.
    <bullet> 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.

[[Page 59941]]

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

[[Page 59942]]

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.

[[Page 59943]]

    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

[[Page 59944]]

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.

[[Page 59945]]

    (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:
    <bullet> 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).
    <bullet> 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).
    <bullet> 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

[[Page 59946]]

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,

[[Page 59947]]

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).

[[Page 59948]]

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

[[Page 59949]]

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.

[[Page 59950]]

    (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

[[Page 59951]]

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

[[Page 59952]]

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 
explained in the preamble to the proposed rule (68 FR 12406 at 12425), 
for this reason, FDA did not explicitly propose to require these 
reports in the proposed rule. However, the agency believes that when 
rates are available, a clinically important increase provides important 
safety information and warrants expedited, rather than annual, 
reporting. Deciding if an increase in the rate of a serious suspected 
adverse reaction over that listed in the protocol or investigator 
brochure is ) ``clinically important'' is a matter of judgment based on 
a variety of factors including the study population, the nature and 
seriousness of the reaction, and the magnitude of the observed increase 
in rate.
    The agency also agrees with the comment that sponsors should 
routinely review incidence rates of all serious and nonserious adverse 
events within their clinical program and expects that this is current 
practice within the industry. If a clinically important increase in a 
serious suspected adverse reaction is identified when compared to the 
rate described in the protocol or investigator brochure, the sponsor 
must report it to FDA expeditiously. Changes in incidence rates for the 
most frequent nonserious adverse events would be reported in the IND 
annual report.
    In response to the comment that requested clarification on the 
utility of these reports in the premarket setting when they have proven 
to be of little value in the postmarketing setting, the agency believes 
that there are differences between the premarket setting (where these 
reports would usually be based on incidence rates from clinical trials) 
and the postmarketing setting (where estimation of incidence rates from 
spontaneous reports is more difficult because, for example, the size of 
the exposed population is unknown). The agency believes that these 
reports contribute information important for understanding and updating 
the safety profile of the investigational drug product.
    (Comment 33) Another comment noted that although FDA's proposed 
rule did not address the U.S. IND annual reporting requirements, it 
recommended that they be modified to be consistent with the ICH and EU 
annual reports in light of the finalization of the EU Clinical Trial 
Directive 2001/20/EC and the publication of their final detailed 
guidance.
    (Response) The agency has been participating in the development of 
the ICH draft guidance, entitled ``E2F Developmental Safety Update 
Report'' (DSUR draft guidance), that describes the format, content, and 
timing for periodic reporting for an investigational drug. As stated in 
the notice announcing the availability of the DSUR draft guidance, the 
DSUR would serve as an internationally harmonized, annual clinical 
trial safety report that could be submitted in the United States in 
place of an annual report for an IND (73 FR 45462, August 5, 2008). 
After the DSUR draft guidance is finalized, the agency will evaluate 
the need to revise our IND annual reporting requirements to take into 
account international standards and recommendations.
    (Comment 34) One comment requested clarification of IND annual 
reporting after an NDA has been approved and clinical studies continue 
under the IND, particularly in light of adoption of the PSUR, which 
includes clinical study data. The comment asked if safety sections in 
the IND annual report would be required after the NDA has been approved 
and the PSUR format is then being followed. The comment also requested 
clarification on whether the data cutoff date would be the IND 
effective date, the NDA approval date, or the international birth date.
    (Response) Clinical development of a drug frequently continues even 
after it has been approved for marketing (e.g., for new indications, 
new dosage strengths, different populations). Therefore, the IND annual 
report continues to be important for evaluating and monitoring the 
safety of the drug. In addition, the DSUR draft guidance discusses the 
relationship between the DSUR and PSUR when clinical studies continue 
after a drug is approved for marketing, and when to initiate a DSUR for 
a marketed product. The guidance recommends that once a drug has 
received marketing approval in any country or region, and clinical 
trials continue or are initiated, both a PSUR and a DSUR should be 
prepared in accordance with directions from local authorities (DSUR 
draft guidance at p. 7). After the DSUR draft guidance is finalized, 
the agency will consider whether to revise our IND annual reporting 
requirements to take into account its current thinking on the issue, 
including adopting an international birthdate. Until that time, the 
data cutoff date for the IND annual report is the IND effective date 
because the annual report must be submitted to FDA within 60 days of 
the anniversary of the date that the IND went into effect (see Sec.  
312.33).

N. Investigator Reports--Proposed Sec.  312.64(b)

    FDA proposed to require that an investigator report to the sponsor 
any serious SADR immediately and any other SADR promptly unless the 
protocol or investigator's brochure specifies a different timetable for 
reporting the SADR.
    (Comment 35) One comment suggested that FDA require investigators 
to report all protocol-defined treatment-emergent adverse events 
(TEAEs) expeditiously regardless of their causal attribution, but 
record their causality assessment when reporting such events. The 
comment defined a TEAE as an event that emerges during treatment having 
been absent pretreatment, or worsens relative to the pretreatment 
state. The comment stated that if the agency's SADR definition is 
implemented as proposed, it is conceivable that investigators will not 
report certain TEAEs if they feel a causal relationship can be ruled 
out. Because there are no standard guidelines for ruling out a possible 
causal relationship, there could be inconsistent causality assessments 
and adverse event reporting across study sites. Another comment stated 
that applying the SADR definition to investigator reporting could 
result in

[[Page 59953]]

underreporting of serious adverse events. The comment maintained that 
the investigator should report all serious adverse events to the 
sponsor, without making a causality assessment. The comment further 
stated that the proposed approach would not be in harmony with ICH 
standards and European regulatory requirements, which require that all 
serious adverse events be immediately reported to the sponsor. One 
comment stated that investigators provide an important and informed 
medical review of causality, especially in the presence of complex 
disease states where many adverse events occur as a result of the 
underlying disease process. The comment suggested that FDA provide 
clear guidance on reportable causality.
    (Response) As noted in Comment 1 of this document, the agency has 
decided not to adopt the proposed SADR definition. FDA believes that 
there is more uncertainty when assessment of causality is based on an 
individual event rather than on aggregate data. The agency also 
believes that the sponsor is better positioned than the individual 
investigator to assess the overall safety of the investigational drug 
because the sponsor has access to serious adverse event reports from 
multiple study sites and is able to aggregate and analyze these 
reports. Therefore, the agency has determined that the sponsors should 
immediately receive reports from investigators of any serious adverse 
events, without regard to causality.
    However, the agency agrees that, because the investigator is 
knowledgeable about the human subject (e.g., medical history, 
concomitant medications), administers the investigational drug, and 
monitors the subject's response to the drug, the investigator's view on 
the causal relationship between an adverse event and the 
investigational drug is important, especially in the presence of 
complex disease states where many adverse events occur as a result of 
the underlying disease process. Because the insight from the 
investigator is important for the sponsor to consider in assessing the 
safety of the drug and determining whether to report expeditiously to 
FDA, the agency has revised the requirement to require that the 
investigator include an assessment of causality in the report to the 
sponsor. Revised Sec.  312.64(b) requires investigators to immediately 
report to the sponsor any serious adverse event, whether or not 
considered drug related, including those listed in the protocol or 
investigator brochure and the report must include an assessment of 
whether there is a reasonable possibility that the drug caused the 
event. Study endpoints that are serious adverse events (e.g., all-cause 
mortality) must be reported in accordance with the protocol unless 
there is evidence suggesting a causal relationship between the drug and 
the event (e.g., death from anaphylaxis). In that case, the 
investigator must immediately report the event to the sponsor.
    (Comment 36) Several comments requested clarification of the terms 
``immediately'' and ``promptly'' in the proposed requirement. The 
comments disagreed with the requirement to report other SADRs (i.e., 
nonserious) promptly to the sponsor, as the term ``promptly'' implies 
``quickly.'' The comments stated that nonserious SADRs are 
traditionally recorded on case report forms during the study, then 
verified and collected by the sponsor during scheduled monitoring 
visits. One comment recommended that the requirement be revised to 
require investigators to record, rather than report, other SADRs 
promptly.
    (Response) The agency expects that, for serious adverse events, the 
investigator would notify the sponsor immediately. The agency 
recognizes that it may take a day to collect adequate information to 
confirm the occurrence of the adverse event but expects that as soon as 
the investigator has confirmed that the event occurred, the 
investigator will report it to the sponsor without delay.
    The agency agrees with the comments that the term ``promptly'' does 
not appropriately describe the best process for documenting and 
notifying the sponsor about nonserious adverse events. Therefore, the 
agency has revised Sec.  312.64(b) to state that the investigator must 
record nonserious adverse events and report them to the sponsor 
according to the timetable for reporting specified in the protocol. The 
sponsor would need to determine the appropriate interval for collecting 
and analyzing nonserious adverse event information based on the drug 
under investigation and other study considerations, and delineate the 
timetable in the protocol.

O. Bioavailability and Bioequivalence Requirements--Proposed Sec.  
320.31(d)

    FDA proposed to require that persons conducting human 
bioavailability or bioequivalence studies that are not subject to an 
IND submit expedited safety reports to FDA in accordance with Sec.  
312.32. In the preamble to the proposed rule (68 FR 12406 at 12415), 
the agency stated that, in general, bioavailability and bioequivalence 
studies that are not being conducted under an IND are safe. However, 
the agency is occasionally made aware of safety-related information 
associated with these types of studies, which could reflect either a 
problem with the drug product being evaluated or with the study design 
being used. Timely review of this safety information is critical to 
ensuring the safety of study subjects. FDA proposed to require that 
these safety reports be transmitted to all participating investigators 
and to the appropriate FDA division in CDER (i.e., safety reports for 
the reference listed drug would be sent to the new drug review division 
that has responsibility for that drug, safety reports for the 
investigational drug product would be sent to the Director, Division of 
Bioequivalence, Office of Generic Drugs) and each report bear prominent 
identification of its contents. For reporting purposes under Sec.  
320.31(d)(3), an unexpected SADR would be any SADR the specificity or 
severity of which is not consistent with the U.S. labeling for the 
reference listed drug.
    In general, the occurrence of a serious adverse event is very 
unusual in a bioavailability or bioequivalence study because the number 
of subjects enrolled in the study is small, the subjects are usually 
healthy volunteers, and drug exposure is typically brief. For these 
reasons, the occurrence of any serious adverse event is of interest. 
The agency reviewed the numbers and types of serious adverse events 
that we have received from these trials (i.e., in study reports 
submitted in abbreviated new drug applications (ANDAs)), and determined 
that they are typically listed in the labeling of the reference listed 
drug and, therefore, would not be subject to reporting under Sec.  
312.32(c)(1)(i) as serious and unexpected suspected adverse reactions 
because they would not meet the regulatory definition of 
``unexpected.'' In addition, because serious adverse events are so 
unusual in these studies, FDA believes that the causality assessment is 
unnecessary under these circumstances and that it is important to 
review all serious ``adverse events.'' Thus, the proposed requirement 
to report serious and unexpected SADRs would not have served its 
intended purpose of alerting the agency to serious adverse events 
occurring in these trials, so the agency has revised the requirement. 
The agency continues to believe that receiving reports from these 
trials is important for human subject protection and, therefore, has 
revised Sec.  320.31(d)(3) to require that any serious adverse event 
must be reported, instead of any serious and unexpected SADR. The 
person

[[Page 59954]]

conducting the study, including any contract research organization, 
must notify FDA and all participating investigators of any serious 
adverse event, as defined in Sec.  312.32(a), from the study as soon as 
possible but in no case later than 15 calendar days after becoming 
aware of its occurrence. Each report must be submitted on FDA Form 
3500A or in an electronic format that FDA can process, review, and 
archive. FDA will periodically issue guidance on how to provide the 
electronic submission (e.g., method of transmission, media, file 
formats, preparation, and organization of files). As proposed, each 
report must bear prominent identification of its contents, i.e., 
``bioavailability/bioequivalence safety report.'' The person conducting 
the study, including any contract research organization, must also 
notify FDA of any fatal or life-threatening adverse event from the 
study as soon as possible but in no case later than 7 calendar days 
after becoming aware of its occurrence. Each notification under Sec.  
320.31(d)(3) must be submitted to the Director, Office of Generic Drugs 
in CDER. Relevant followup information to a bioavailability/
bioequivalence safety report must be submitted as soon as the 
information is available and must be identified as such, i.e., 
``Followup bioavailability/bioequivalence safety report.'' Upon request 
from FDA, the person conducting the study, including any contract 
research organization, must submit to FDA any additional data or 
information that the agency deems necessary, as soon as possible, but 
in no case later than 15 days after receiving the request.
    (Comment 37) Some comments requested clarification about the 
requirement to submit expedited safety reports for qualifying SADRs 
that arise in human bioavailability and bioequivalence studies that do 
not require an IND. The comments requested that the agency clarify 
whether this includes studies conducted outside of the United States 
and how these reports should be submitted in the absence of an IND.
    (Response) Under Sec.  320.31(d)(3), sponsors of human 
bioequivalence or bioavailability studies that are exempt from the IND 
requirements under part 312, but are conducted in the United States, 
must report any serious adverse events from the study to FDA (to the 
Office of Generic Drugs in CDER) and to all participating 
investigators. These requirements do not apply to human bioavailability 
and bioequivalence studies that are exempt from the IND requirements 
under part 312 and are conducted outside of the United States. However, 
as part of the information required to establish that the proposed drug 
product can be expected to have the same therapeutic effect as the 
reference listed product, adverse event reports that occurred in 
foreign clinical studies must be included in the ANDA submission (see 
Sec.  314.94(a)(7)).

P. Reports to Investigators and IRBs

    In proposed Sec.  312.32(c)(1)(i) and (c)(1)(ii), FDA proposed to 
require that sponsors notify FDA and all participating investigators in 
a written IND safety report of any serious and unexpected SADR or 
information sufficient to consider product administration changes. 
Although both of these requirements have been revised (see response to 
Comments 15 to 17 and 23 to 29 of this document), the requirement that 
FDA and all participating investigators receive IND safety reports for 
potential serious risks that emerge during the conduct of a clinical 
investigation has not changed in this final rule (see final Sec.  
312.32(c)(1)).
    In addition, under current Sec.  312.66, the investigator must, 
among other things, assure that he or she will promptly report to the 
IRB all changes in the research activity and all unanticipated problems 
involving risk to human subjects or others, and that he or she will not 
make any changes in the research without IRB approval, except where 
necessary to eliminate apparent immediate hazards to human subjects. 
The agency did not propose any changes to this requirement.
    (Comment 38) Some comments pointed out that the proposed rule did 
not change the frequency or format for providing clinical investigators 
with information on serious, unexpected adverse events associated with 
the use of a drug. One comment agreed that it is imperative that 
investigators responsible for the conduct of studies be informed by the 
sponsor of findings that could adversely affect the safety of study 
participants. However, the comment noted that this process can be 
confusing and overwhelming, particularly for investigators of IND 
studies conducted outside the United States. Several comments proposed 
alternative reporting approaches that would provide investigators with 
reports that are more useful and efficient and less confusing. One 
comment recommended that the requirements for notifying all 
participating investigators be changed to allow a periodic summary and 
analysis of qualifying SADRs rather than individual reports that are 
difficult to track, aggregate, analyze, and interpret at the 
investigational site. Several comments encouraged FDA to further 
harmonize with CIOMS VI and the EU Clinical Trial Directive approach 
for investigator notification because: (1) Periodic (quarterly) 
aggregate line listings of suspected unexpected serious adverse 
reactions (SUSARs) accompanied by a summary of the evolving safety 
profile would provide useful information to investigators and IRBs, 
especially for Phase l-3 studies; (2) presenting all serious, 
unexpected, associated events in line listings regardless of medication 
administered (e.g., active drug, comparator, or placebo) would maintain 
the blind to the investigator; and (3) significant safety issues would 
be communicated as soon as possible to the investigators. These 
comments stated that investigators would recognize that these expedited 
communications represent significant safety information that is to be 
immediately reviewed and provided to their IRBs. The comments noted 
that expedited reporting to FDA and processes for updating the 
investigator brochure would remain unchanged.
    In addition, one comment requested that FDA not require 
investigator notification letters for investigations of marketed 
products, even if conducted under an IND, unless the investigation is 
for a patient population or indication that is different from that 
approved. The comment stated that any significant new safety 
information will be evaluated by the sponsors as part of their signal 
detection process and, if necessary, will be incorporated in the 
product label. The comment recommended that FDA allow periodic line-
listings to be sent to investigators in lieu of individual reports.
    (Response) The agency is aware that for large, multi-center trials, 
investigators have expressed concern about receiving large numbers of 
individual adverse event reports that may not be useful. The agency 
believes that these final requirements will significantly diminish the 
numbers of individual reports that, in isolation, do not provide useful 
information to the investigator. For example, the requirement under 
Sec.  312.32(c)(1)(i), described in the response to Comment 18 of the 
document, makes it clear that specific events (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) are to be reported to FDA and all participating 
investigators only if there is evidence, based on an aggregate 
analysis, to suggest a causal relationship between the drug product and 
the adverse event. The rule also makes it

[[Page 59955]]

clear that study endpoints would ordinarily not be reported as serious, 
unexpected suspected adverse reactions (response to Comment 19 of this 
document). These clarifications are expected to reduce the number of 
reports that do not contribute in a meaningful way to the developing 
profile of the drug.
    FDA does not agree with the comment that suggested that 
investigators not be notified of serious, unexpected suspected adverse 
reactions from investigations of marketed products unless the 
investigation is for a patient population or indication different from 
that approved. Regardless of the patient population or indication, 
information about a serious, unexpected suspected adverse reaction may 
influence the investigator's management of a clinical trial participant 
and, is therefore, critical information for the investigator to 
receive.
    (Comment 39) Some comments stated that although the IRB's charge is 
to have written procedures for reporting ``any unanticipated problems 
involving risks to human subjects or others,'' the proposed rule is 
silent about sending any information to IRBs. These comments 
recommended that the agency provide guidance to sponsors, 
manufacturers, investigators, and IRBs that clearly delineates the 
responsibilities of reporting SADRs to the IRB. One comment requested 
that FDA require that the IRB receive from the sponsor the same 
expedited reports that the sponsor sends to FDA and all participating 
investigators (under proposed Sec.  312.32(c)(1)). Other comments 
pointed out that IRBs are currently overwhelmed with IND safety reports 
and recommended that sponsors provide IRBs with routine timely 
aggregated reports of listings of adverse events instead of individual 
reports. Another comment suggested that investigators be permitted to 
provide these line-listings to their IRBs in lieu of individual 
reports. One comment urged FDA to adopt the CIOMS VI recommendations 
for IRB notification.
    (Response) The agency concurs with the overall sentiments expressed 
by the comments and has provided recommendations for reporting adverse 
event information to IRBs in our ``Guidance for Clinical Investigators, 
Sponsors, and IRBs: Adverse Event Reporting--Improving Human Subject 
Protection.'' We also expect that the more useful individual reports 
submitted by sponsors to FDA and investigators will translate into more 
useful information being provided by investigators to their IRBs. In 
addition, the agency may consider revisions to investigator reporting 
requirements to IRBs in a separate rulemaking initiative.

Q. Miscellaneous Comments

    FDA stated in the preamble to the proposed rule that the term 
``sponsors'' would be used to describe persons subject to the 
premarketing safety reporting regulations (68 FR 12406 at 12412).
    (Comment 40) Two comments asked FDA to clarify how the safety 
reporting requirements apply to investigator-initiated studies, since 
such studies are not mentioned in the agency's definition of 
``sponsors.''
    (Response) The agency considers investigator-initiated studies to 
be synonymous with studies conducted by a sponsor-investigator. A 
sponsor-investigator, as defined in Sec.  312.3, is ``an individual who 
both initiates and conducts an investigation, and under whose immediate 
direction the investigational drug is administered or dispensed. The 
term does not include any person other than an individual. The 
requirements applicable to a sponsor-investigator under this part [312] 
include both those applicable to an investigator and a sponsor.'' 
Therefore, the safety reporting requirements under Sec.  312.32 would 
apply to an investigator-initiated study.
     (Comment 41) One comment suggested that FDA request that the 
National Institutes of Health (NIH) and other Federal agencies that 
have agreed to the Federal Policy for the Protection of Human Subjects 
(Common Rule) also adopt the proposed regulations. The comment stated 
that all participants in the research enterprise must be fully 
committed to the protection of research participants, and fostering 
better and more complete safety reporting will support that commitment.
    (Response) This final rule would apply to FDA-regulated research 
conducted by NIH and other Federal agencies. The agency agrees that 
improved safety reporting should enhance the protection of human 
subjects participating in clinical trials.
    (Comment 42) FDA proposed that the final rule would become 
effective 180 days after its date of publication in the Federal 
Register, except for any final rule regarding the proposal to require 
that postmarketing SADRs in the individual case safety reports be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA), which 
would become effective 1 year after its date of publication in the 
Federal Register.
    Many comments expressed concern that the proposed timeline for 
implementing the new requirements is too aggressive, given its impact 
on systems and processes (e.g., to develop, test, and validate a new 
system). Some comments did not believe 180 days was sufficient 
implementation time unless the final rule was significantly modified. 
One comment requested that FDA allow for a transition period for 
ongoing clinical trials if FDA continues with its interpretation of 
``related,'' as used in the proposed SADR definition. One comment 
agreed with the adoption of MedDRA for premarketing safety reporting 
for clinical trials, but did not believe that the 1-year proposed 
timeline was realistic. Comments requested other implementation 
schedules, ranging from 12 to 18 months for all the requirements.
    (Response) The agency does not agree that an effective date of 180 
days after the date of publication in the Federal Register is too 
aggressive. The agency believes that the revisions to the requirements 
in this final rule will streamline adverse event reporting and are 
crucial to ensuring that timely and accurate safety information about 
clinical trials is received, analyzed, and disseminated. Therefore, as 
proposed, the agency has retained the effective date for the final rule 
to be 180 days after the date of publication in the Federal Register. 
The concerns raised by the comments about the agency's interpretation 
of ``related'' are no longer an issue because the agency did not adopt 
the SADR definition. In addition, the agency did not propose, and is 
not requiring in this final rule, the use of MedDRA for IND safety 
reporting.

R. Initial Analysis of Impacts and Paperwork Burden Estimates

    For the initial analysis of impacts, FDA estimated the costs of 
adding the new premarketing safety reporting requirements (68 FR 12406 
at 12456 and 12457, table 14) (see section VI of this document for 
discussion). For the initial paperwork burden estimates, FDA estimated 
the total annual reporting burden associated with the premarketing 
safety reporting requirements, accounting for not only the additional 
burdens associated with the proposed new requirements, but also for 
burdens already approved by the Office of Management and Budget (OMB) 
for requirements under then-current Sec. Sec.  312.32 and 312.64 (68 FR 
12406 at 12470, table 21) (see section VII of this document for further 
discussion).
    For narrative reports based on information sufficient to consider a 
change in product administration (discussed in section III.G of this 
document), for the initial analysis of

[[Page 59956]]

impacts, FDA estimated that sponsors would spend an additional 4 hours 
per report for up to 600 IND safety reports. For the paperwork burden, 
however, for the same 600 IND safety reports, FDA estimated that 
sponsors would spend a total of 8 hours per report. The 4-hour per 
report estimate in the initial analysis of impacts accounted only for 
the incremental burden of the proposed reports from in vitro studies, 
epidemiological studies, and clinical studies and did not account for 
required reports of ``any finding from tests in laboratory animals that 
suggests a significant risk in human subjects'' under then-current 
Sec.  312.32(c)(1)(i)(B). However, the 8-hour per report paperwork 
burden estimate accounted not only for the burden of complying with the 
new proposed requirements, but also the then-current requirement to 
submit reports from animal tests.
    (Comment 43) Comments from industry stated that FDA underestimated 
the number of IND safety reports and that the proposed SADR definition 
could increase the volume of IND safety reports from 2-fold to 10-fold. 
Furthermore, comments claimed that any additional reports would be 
uninformative. An increase in the number of uninformative safety 
reports would create an additional burden on investigators and IRBs 
without a corresponding benefit. Comments noted that FDA's analysis 
failed to account for the potential impact of these additional reports 
on IRBs and investigators. Moreover, in some cases, additional 
uninformative reports could force sponsors to unnecessarily break the 
blind of a clinical trial, potentially reducing the power of double-
blind clinical trials to detect safety issues and imposing additional 
burdens to industry.
    (Response) As discussed in response to Comment 1 of this document, 
the agency has decided not to adopt the proposed SADR definition, and 
instead adopted definitions for the terms ``adverse event'' and 
``suspected adverse reaction.'' In addition, FDA clarified the 
circumstances under which IND safety reports need to be submitted. With 
these changes, we expect fewer reports. Therefore, the comments stating 
that FDA underestimated the number of IND safety reports have been 
addressed.
    (Comment 44) Some industry comments stated that FDA underestimated 
the number of hours required to prepare a narrative report based on 
information sufficient to consider changes in product administration or 
risk profile. These comments stated that preparing a narrative report 
requires more than 8 hours.
    (Response) Although comments stated that preparing a narrative 
report requires more than 8 hours, none of these comments provided 
estimates for a specific number of hours. Without other information, we 
are unable to respond directly to these comments. Nevertheless, we 
recognize that there may be some situations and types of findings that 
would require sponsors to spend more time preparing a narrative report. 
Therefore, to capture the uncertainty of this estimate, FDA has decided 
to use a range of hours (from 4 to 12 hours) to estimate the 
incremental burden of this requirement instead of the 4-hour estimate 
used in our initial analysis of impacts (section VI of this document) 
or the total 8-hour estimate used in the initial paperwork burden 
analysis (section VII of this document).

IV. Legal Authority

    The premarket approval provisions of the act authorize FDA to 
require that drug labeling provide the practitioner with adequate 
information to permit safe and effective use of the drug product. 
Section 505 of the Federal Food, Drug, and Cosmetic Act (the act) (21 
U.S.C. 355) requires us to weigh evidence of effectiveness and safety 
to determine whether the evidence supports drug approval, whether data 
are adequate to permit a clinical investigation to proceed under the 
IND regulations, and/or whether a product is appropriately labeled. 
Section 351(a)(2)(C)(i)(1)) of the Public Health Service Act (the PHS 
Act) (42 U.S.C. 262(a)(2)(C)(i)(I)) authorizes the agency to approve a 
biologics license application (BLA) only if the applicant demonstrates 
that the product is safe, pure, and potent. Section 351(a)(2)(A) of the 
PHS Act authorizes the agency to establish, by regulation, requirements 
for the approval, suspension, and revocation of biologics licenses. 
Section 701(a) of the act (21 U.S.C. 371(a)) authorizes FDA to issue 
regulations for the efficient enforcement of the act. These statutory 
provisions authorize us to issue regulations requiring sponsors to 
submit safety information to the agency to support an IND, NDA, ANDA, 
or BLA.

V. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VI. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this final rule is not a significant regulatory action under the 
Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the new reporting requirements are likely to 
impose a minimal burden on small entities (less than 0.2 percent of the 
average value of shipments of entities with less than 10 employees), 
the agency believes that the final rule will probably not have a 
significant economic impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $135 million, using the most current (2009) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    In accordance with Executive Order 12866, FDA has previously 
analyzed the potential economic effects of the proposed rule. Although 
FDA determined that the proposed rule was an economically significant 
rule as described in the Executive order, the final rule covers a 
smaller subset of the proposed regulatory actions and is only related 
to premarket safety reporting and safety reporting for certain 
bioavailability and bioequivalence studies. Consequently, the annual 
estimated costs of this final rule are projected to equal less than 
$0.7 million. We are unable to quantify the benefits of the final rule, 
but expect that

[[Page 59957]]

the potential benefits of harmonized and improved safety reporting will 
justify the minimal costs of this rule.

A. Need for the Regulation

    Ambiguous regulatory requirements may cause sponsors to 
unnecessarily submit certain IND safety reports to FDA and 
investigators. As described in section I of this document, lack of 
clarity about definitions and regulatory reporting requirements may 
create uncertainty about when to submit an IND safety report and may 
lead to over- or underreporting to FDA and investigators. Uncertainty 
about safety reporting requirements can result in reports being 
submitted for adverse events when there is little evidence of a causal 
relationship between the drug and the adverse event. Such reports can 
produce so-called ``noise'' in the system and hinder the development of 
the premarket safety profile of an investigational drug. Conversely, 
exempting certain bioavailability and bioequivalence studies from 
safety reporting requirements may lead to underreporting of some 
serious adverse events.
    The rule will finalize definitions and IND safety reporting 
standards that are as consistent as possible with ICH documents, 
require expedited reporting of study findings suggesting a significant 
risk to humans, and establish reporting requirements for certain 
bioavailability and bioequivalence studies. Moreover, the final rule 
clarifies when certain safety information, such as study endpoints, 
should be reported, potentially reducing the number of uninformative 
reports sent to FDA, participating investigators, and IRBs.

B. Costs of the Regulation (to Prepare and Submit Safety Reports)

1. Number of Reports
    For the initial analysis of impacts, we estimated that sponsors 
would submit up to 200 reports per year to comply with the new 
requirement for safety reporting of bioavailability and bioequivalence 
studies under proposed Sec.  320.31(d). No comments were received on 
this estimate. Consequently, in the final analysis of impacts, we 
retain our original estimate of 200 reports per year.
    In the initial analysis of impacts, we estimated that sponsors 
would submit up to 600 written IND safety reports annually based on 
information sufficient to consider a change in product administration 
(proposed Sec.  312.32(c)(1)(ii))\3\. Consistent with ICH 
recommendations for IND safety reporting, the proposed rule would have 
clarified that sponsors should submit written IND safety reports when 
they receive information suggesting significant human risk sufficient 
to consider changes in the conduct of a clinical trial or product 
administration. Information suggesting a significant human risk could 
come from animal studies, in vitro studies, epidemiological studies, or 
clinical studies. We received no comments on this estimate.
---------------------------------------------------------------------------

    \3\ The proposed premarketing reporting requirement revised the 
existing requirements and expanded the types of findings that 
sponsors should report as expedited narrative IND safety reports. As 
discussed in sections III.R and VII of this document, the estimated 
average incremental burden of the regulatory action in the initial 
analysis of impacts (i.e., 4 hours) accounted for then-current 
compliance (i.e., reports based on findings from animal tests) under 
then-current Sec.  312.32(c)(1)(i)(B)).
---------------------------------------------------------------------------

    In contrast to the ICH recommendation that sponsors rapidly report 
an increase in the rate of occurrence of an expected, serious SADR, the 
preamble of the proposed rule noted that sponsors should submit this 
type of information in IND annual reports under Sec.  312.33(b)(1) (68 
FR at 12406 at 12425). Because no changes to the IND annual reports 
were proposed, FDA did not estimate the incremental impact of these 
reports. For the final rule, however, increases in the occurrence rates 
of serious suspected adverse reactions over that listed in the protocol 
or investigator brochure must be reported as expedited IND safety 
reports. We have insufficient information to determine the potential 
impact of reporting increases in occurrence rates of serious suspected 
adverse reactions over that listed in the protocol or investigator 
brochure as expedited reports as opposed to including this information 
in annual reports. As part of good clinical practice, sponsors 
routinely review and analyze the incidence rates of serious and 
nonserious adverse events of their investigational drugs. Therefore, we 
expect that the incremental burden of this requirement will be minimal 
and estimate that sponsors will submit up to 10 additional reports per 
year.
    Furthermore, the final rule clarifies the definition of a suspected 
adverse reaction for reporting purposes (Sec.  312.32(a)) and adds a 
requirement that sponsors only submit reports of study endpoints in 
unusual circumstances not described in the protocol (Sec.  
312.32(c)(5)). We anticipate that by clarifying what is a suspected 
adverse reaction for reporting purposes and the circumstances under 
which study endpoints should be submitted as expedited reports, the 
number of uninformative expedited reports will be reduced, thus 
reducing the burden on sponsors, investigators, IRBs, and FDA. However, 
we have no information to estimate the magnitude of this reduced 
burden.
    Last, the final rule clarifies safety reporting requirements for 
investigators to report to sponsors (Sec.  312.64(b)). Instead of 
requiring that investigators promptly report any adverse event 
reasonably caused or probably caused by the drug, the final rule 
requires that investigators immediately report any serious adverse 
event to the sponsor and include an assessment of whether there is a 
reasonable possibility that the drug caused the event. Because it is 
common practice for sponsors to outline similar reporting 
responsibilities in their clinical trial protocols, we assume that this 
final requirement will impose no additional burden.
2. Costs to Prepare and Submit Safety Reports
    As shown in table 3 of this document, we estimate that it takes an 
average of 14 hours to prepare a safety report for a bioavailability 
and bioequivalence study. Based on 2007 hourly median wages for the 
pharmaceutical manufacturing industry, each of these reports will cost 
sponsors about $950.
    As discussed in Comment 44 of this document, the additional time 
needed to prepare a report of findings suggesting a significant risk in 
humans may vary. We estimate that sponsors could spend from 4 to 12 
hours additional time to prepare a narrative IND safety report. The 
average incremental cost of a narrative IND safety report ranges from 
$250 to $750 (table 3 of this document).

[[Page 59958]]



                  Table 3.--Estimated Incremental Burden and Unit Costs for IND Safety Reports
----------------------------------------------------------------------------------------------------------------
                                            Burden (hours) and Type of Expertise
                                                          Required
                                         ------------------------------------------ Total Burden    Total Cost
             Type of Report                             Epidemiology                   (hours)        ($)\4\
                                          Clerical\1\   and Clinical    Regulatory
                                                         Medicine\2\    Affairs\3\
----------------------------------------------------------------------------------------------------------------
Bioavailability and Bioequivalence                  2               1           11            14             950
 Safety Reports
----------------------------------------------------------------------------------------------------------------
IND Safety Reports--lower estimate\5\               1               1            2             4             250
----------------------------------------------------------------------------------------------------------------
IND Safety Reports--upper estimate\5\               3               3            6            12             750
----------------------------------------------------------------------------------------------------------------
Numbers are rounded.
Source: U.S. Department of Labor, Bureau of Labor Statistics, May 2007 (Ref. 4).
\1\ Based on median hourly wages for Office and Administrative Support Occupations (43-0000) and 40 percent
  benefits ($24.43 = $17.44 x 1.4).
\2\ Based on median hourly wages for Medical and Health Services Managers (11-9111) and 40 percent benefits
  ($75.03 = $53.59 x 1.4).
\3\ Based on median hourly wages for Management Occupations (11-0000) and 40 percent benefits ($74.96 = $53.54 x
  1.4).
\4\ Unit costs are rounded.
\5\ Includes reports based on findings suggesting a significant risk in humans from epidemiological studies,
  pooled analysis of multiple studies, other clinical studies, or in vitro testing. Reports from animal testing
  are not included (see footnote 3 of this document).

    Table 4 of this document summarizes the estimated total costs of 
the final rule. Annually, sponsors will submit up to 200 safety reports 
for bioavailability and bioequivalence studies and up to 610 IND safety 
reports. We estimate that the total costs of the final rule will equal 
less than $0.7 million annually.

                                Table 4.--Estimated Total Costs of the Final Rule
----------------------------------------------------------------------------------------------------------------
            Type of Report                  Unit Costs ($)       Annual No. of Reports    Total Annual Costs ($)
----------------------------------------------------------------------------------------------------------------
Bioavailability and Bioequivalence                         950                      200                  190,000
 Safety Reports\1\
----------------------------------------------------------------------------------------------------------------
IND Safety Reports\2\                               250 to 750                      610       150,000 to 460,000
----------------------------------------------------------------------------------------------------------------
Total Costs                            .......................  .......................       340,000 to 650,000
----------------------------------------------------------------------------------------------------------------
Numbers are rounded; total costs are rounded to the nearest ten thousand dollar increment.
\1\ We received no comments that provided sufficient information to revise our initial estimate. Because these
  events occur sporadically and the number of reports will vary from year to year, these numbers represent
  reasonable estimates of the annual average number of reports.
\2\ The annual number of IND safety reports includes the proposed 600 reports of information suggesting a
  significant human risk (from epidemiological studies, pooled analysis of multiple studies, other clinical
  studies, or in vitro testing, but not from animal testing (see footnote 3 of this document)) and an additional
  10 reports of increases in the occurrence rates of serious suspected adverse reactions over that listed in the
  protocol or investigator brochure.

C. Benefits of the Regulation

    Benefits for the initial analysis of impacts were based on 
potential improvements in public health from better postmarket safety 
reporting and surveillance. The definitions and other requirements of 
the final rule provide a standardized framework against which adverse 
events and adverse reactions can be evaluated, reducing ambiguity and 
uncertainty about when and how to submit IND safety reports.
    The final rule adds a requirement to submit safety reports for 
certain bioavailability and bioequivalence studies that have been 
exempt from safety reporting. These studies have been exempted from 
safety reporting requirements because serious adverse events in these 
types of studies are rare. As described elsewhere in this document, 
most serious adverse events would be listed in the labeling of the 
reference listed drug and thus would not meet the threshold for 
expedited IND safety reporting. However, reporting such unusual events 
would alert FDA to serious adverse events occurring in these trials. 
For this reason, it is prudent that FDA review such safety information. 
However, we lack sufficient information to estimate the magnitude of 
these potential benefits.
    The revised IND safety reporting requirements will clarify when a 
sponsor should send a narrative IND safety report to FDA and 
participating investigators. Regardless of who conducts a study or 
whether a study is conducted under an IND, any finding that suggests a 
significant risk to humans must be reported as an expedited report. A 
risk is considered significant if it will ordinarily result in a 
safety-related change in the protocol, informed consent, investigator 
brochure, or conduct of the clinical investigation. Findings of a 
significant risk to humans can come from many sources, including 
epidemiological studies, pooled analysis of multiple studies, clinical 
studies, animal testing, or in vitro testing. Expedited reports of 
important safety information will enable FDA to more quickly review and 
monitor the safety profile of investigational drugs. However, because 
we lack estimates of the impact of expedited reporting on drug safety, 
we are not able to estimate the potential benefits of this reporting 
requirement.
    The final rule includes a new requirement to report clinically 
important increases in the occurrence rates of serious suspected 
adverse reactions over that listed in the protocol or investigator 
brochure as expedited IND safety reports. Because these reports are 
usually based on incidence rates from clinical trials (i.e., known 
exposure rates), such reports can alert FDA to previously undetected 
human safety risks. Although these reports can occur sporadically, such 
reports can provide important information that

[[Page 59959]]

could affect drug safety profiles. However, we lack sufficient 
information to estimate the magnitude of these potential benefits.
    Uncertainty about reporting requirements can lead sponsors to 
overreport or underreport safety events. Overreporting can introduce 
so-called ``noise'' that can delay the detection of possible safety 
problems. Underreporting potential safety problems can also delay 
identification of an important new risk. We expect that the final rule 
will remove some of the uncertainty that may lead sponsors to over- and 
underreport adverse events. In addition, we expect that FDA will 
receive expedited reports of safety information that suggest a 
significant risk in humans. Such reports can promote timely review of 
important drug safety information. Although we are unable to make a 
quantitative estimate of the benefits of the final rule, we believe 
that the potential benefits realized through more informative, 
accurate, and timely safety reports will justify the minimal costs of 
the final rule.

D. Final Regulatory Flexibility Analysis

    This final rule will harmonize certain FDA safety reporting 
requirements with international initiatives and improve the quality of 
safety reporting for IND products and certain marketed products. 
According to the Table of Small Business Size Standards, the U.S. Small 
Business Administration (SBA) considers pharmaceutical preparation 
manufacturing entities (NAICS 325412) with 750 or fewer employees and 
biological product manufacturing entities (NAICS 325414) with 500 or 
fewer employees to be small. Statistics on the classification of firms 
by employment size from the U.S. Bureau of the Census show that in 
2005, at least 85 percent of pharmaceutical manufacturing and 
biological product manufacturing entities had fewer than 500 employees 
and would have been considered small by SBA.
    Entities have sufficient expertise to comply with the new safety 
reporting requirements. As shown in table 5 of this document, the unit 
costs of a safety report total less than 0.2 percent of the average 
value of shipments for the smallest entities. As further explained 
previously, the agency does not believe that this final rule will have 
a significant economic impact on a substantial number of small 
entities, but the impact is uncertain. Although some final requirements 
extend to investigators, we anticipate no additional burden on 
investigators who would meet the SBA definition of small entity.

     Table 5.--Unit Costs of Safety Reports as a Percentage of the Average Value of Shipments for Very Small
                                                 Establishments
----------------------------------------------------------------------------------------------------------------
                                           Pharmaceutical Preparation         Biological Product Manufacturing
-------------------------------------    Manufacturing (NAICS 325412)\1\              (NAICS 325414)\2\
                                     ---------------------------------------------------------------------------
          No. of employees                    <5                <10                 <5                <10
----------------------------------------------------------------------------------------------------------------
Total value of shipments ($1,000)               187,933            561,636             32,011            115,307
----------------------------------------------------------------------------------------------------------------
No. of establishments                               228                339                 67                109
----------------------------------------------------------------------------------------------------------------
Average value of shipments ($)                  824,268          1,656,743            477,776          1,057,862
----------------------------------------------------------------------------------------------------------------
Unit costs of an IND safety report         0.0% to 0.1%       0.0% to 0.0%       0.1% to 0.2%       0.0% to 0.1%
 as a percentage of the average
 value of shipments\3\
----------------------------------------------------------------------------------------------------------------
Unit costs of a bioavailability or                 0.1%               0.1%               0.2%               0.1%
 bioequivalence report as a
 percentage of the average value of
 shipments\4\
----------------------------------------------------------------------------------------------------------------
Numbers are rounded.
\1\ Source: U.S. Department of Commerce, Bureau of the Census, 2002 (Ref. 5).
\2\ Source: U.S. Department of Commerce, Bureau of the Census, 2002 (Ref. 6).
\3\ Based on a unit cost ranging from $250 to $750.
\4\ Based on a unit cost = $950.

VII. Paperwork Reduction Act of 1995

    This final rule contains information collection requirements that 
are subject to review by OMB under the Paperwork Reduction Act of 1995 
(44 U.S.C. 3501-3520) (the PRA). The title, description, and respondent 
description of the information collection provisions are shown in the 
following paragraphs with an estimate of the annual reporting burden. 
Our estimate includes the time for reviewing instructions, searching 
existing data sources, gathering and maintaining the data needed, and 
completing and reviewing each collection of information, not accounted 
for under then-current Sec.  312.32 or Sec.  312.64, already approved 
by OMB (OMB control number 0910-0014).
    Title: Investigational New Drug Safety Reporting Requirements for 
Human Drug and Biological Products and Safety Reporting Requirements 
for Bioavailability and Bioequivalence Studies in Humans
    Description: The final rule clarifies the agency's expectations for 
timely review, evaluation, and submission of relevant and useful safety 
information and implements internationally harmonized definitions and 
reporting standards for IND safety reports. The final rule also 
subjects bioavailability and bioequivalence studies to safety reporting 
requirements. The final rule is intended to improve the utility of IND 
safety reports, expedite FDA's review of critical safety information, 
better protect human subjects enrolled in clinical trials, and 
harmonize safety reporting requirements internationally.

The Final Rule and Estimates of Reporting Burden

    The rule finalizes revisions to the IND safety reporting 
requirements found in part 312 and the safety reporting requirements 
for bioavailability and bioequivalence studies found in part 320. For 
the initial PRA analysis for the proposed rule, FDA estimated for the 
annual reporting burdens for collections of information for the entire 
proposal (i.e., pre- and postmarketing safety reporting requirements). 
For this PRA analysis, FDA has estimated only for the annual reporting 
burdens for collections of information included in this final rule 
(i.e., requirements found in

[[Page 59960]]

Sec. Sec.  312.32, 312.64, and 320.31). In addition, in the initial PRA 
analysis for the proposed rule, FDA estimated for the total reporting 
burden associated with the proposed reporting requirements in 
Sec. Sec.  312.32, 312.64, and 320.31 (as opposed to only the increased 
burdens associated with the proposed rule). Because OMB has approved 
paperwork burdens for many of the reporting requirements found in 
Sec. Sec.  312.32 and 312.64, for purposes of this final rule and this 
PRA analysis, FDA is providing estimates for only the additional 
burdens not already approved by OMB for Sec. Sec.  312.32, 312.64, and 
320.31 (OMB control number 0910-0014). The following provisions of the 
final rule contain collections of information and the following burden 
estimates are based on those discussed in the Analysis of Impacts 
(section VI.B of this document).
    Section 312.32(c)(1)(i) specifies the requirements for reporting to 
FDA in an IND safety report potential serious risks from clinical 
trials within 15 calendar days for reports of serious and unexpected 
suspected adverse reactions and provides examples of what evidence 
supports a suggestion that there is a causal relationship between the 
drug and the adverse event. For purposes of this final rule, there is 
no new information collection because the reporting burden is unchanged 
from former Sec.  312.32 and the information collection is already 
approved by OMB (OMB control number 0910-0014).
    Section 312.32(c)(1)(ii) requires reporting to FDA in an IND safety 
report potential serious risks from clinical trials within 15 calendar 
days for findings from epidemiological studies, pooled analyses of 
multiple studies, or other clinical studies that suggest a significant 
risk in humans exposed to the drug. This reporting requirement was not 
included in former Sec.  312.32. Section 312.32(c)(1)(iii) specifies 
the requirements for reporting to FDA in an IND safety report potential 
serious risks from clinical trials within 15 calendar days for findings 
from animal or in vitro testing that suggest a significant risk to 
humans. While reports from in vitro testing that suggest a significant 
risk to humans were not required to be reported under former Sec.  
312.32, reports from any finding from tests in laboratory animals were 
required to be reported (former Sec.  312.32(c)(1)(i)(B)). For purposes 
of this final rule, for the provisions that are unchanged from former 
Sec.  312.32, the information collection is already approved by OMB 
(OMB control number 0910-0014). For the additional reporting 
requirements (i.e., the proposed narrative reports excluding animal 
testing) in the initial PRA analysis, FDA estimated that sponsors would 
spend a total of 8 hours per report to prepare and submit these 
narrative reports. In response to comments, FDA has revised the 
estimate from an incremental 4 hours to a range from 4 hours to 12 
hours per report. Given this range, the upper estimate of additional 
paperwork burden associated with this requirement for each applicant 
could be an additional 12 hours to prepare each narrative report. 
Therefore, for an additional 600 reports, FDA estimates the total 
annual reporting burden of this final rule could be as high as 7,200 
hours.
    Section 312.32(c)(1)(iv) requires reporting to FDA in an IND safety 
report within 15 calendar days any clinically important increase in the 
rate of occurrence of serious suspected adverse reactions over that 
listed in the protocol or investigator brochure (Sec.  
312.32(c)(1)(iv)). These reports were not required to be submitted 
within 15 days under former Sec.  312.32. FDA estimates that the 
minimal incremental burden for this requirement to be approximately 10 
reports per year. Using the same upper estimate for the burden as 
discussed previously (i.e., 12 hours to prepare each report), FDA 
estimates the additional burden associated with this requirement could 
be as high as 120 hours. We request industry to comment on whether the 
requirement will impose an increased burden and if so, provide an 
estimate of the reporting burden.
    Section 312.32(c)(2) requires reporting within 7 days any 
unexpected fatal or life-threatening suspected adverse reaction. For 
purposes of this final rule, there is no new information collection 
because the reporting burden is unchanged from former Sec.  312.32 and 
the information collection is already approved by OMB (OMB control 
number 0910-0014).
    Section 312.32(c)(4) requires a sponsor of a clinical study of a 
drug marketed or approved in the United States that is conducted under 
an IND to submit safety reports for suspected adverse reactions that 
are observed in the clinical study. For purposes of this final rule, 
there is no new information collection because the reporting burden is 
unchanged from former Sec.  312.32 and the information collection is 
already approved by OMB (OMB control number 0910-0014).
    Section 312.32(c)(5) clarifies the circumstances under which study 
endpoints should be submitted to FDA. FDA believes that these 
clarifications to former Sec.  312.32 are likely to result in a 
reduction in the number of expedited reports that currently are 
accounted for by OMB. However, FDA has insufficient information to 
provide an estimate and was unable to ascertain from industry an 
estimate for such a reduction. Therefore, FDA requests that industry 
comment on the impact of this provision on reporting burdens. Any 
reduction in reports will be reflected the next time the information 
collection for Sec.  312.32 (OMB control number 0910-0014) is extended.
    Section 312.32(d)(1)-(3) requires followup reporting requirements. 
For purposes of this final rule, there is no new information collection 
because the reporting burden is unchanged from former Sec.  312.32 and 
the information collection is already approved by OMB (OMB control 
number 0910-0014).
    Section 312.64(b) requires investigators to report immediately to 
the sponsor any serious adverse event and include an assessment of 
whether there is a reasonable possibility that the drug caused the 
event. FDA revised former Sec.  312.64(b) for clarity and to reflect 
current practices for investigator reporting to sponsors. For purposes 
of this final rule, there is no new information collection because we 
believe that the reporting burden is unchanged from former Sec.  312.64 
and the information collection is already approved by OMB (OMB control 
number 0910-0014).
    Finally, Sec.  320.31(d)(3) subjects bioavailability and 
bioequivalence studies to safety reporting requirements. This reporting 
requirement was not included in former Sec.  320.31. Therefore, all of 
these reports would be new. For purposes of the initial PRA analysis 
and this PRA analysis, FDA estimated up to 200 new safety reports 
required under Sec.  320.31(d) from bioavailability and bioequivalence 
studies. For these 200 reports, FDA estimates that it could take 
applicants an additional 14 hours to prepare and submit each report. 
The burden for bioavailability and bioequivalence safety reporting 
requirements would total 2,800 hours per year as a result of this final 
rule.
    Description of Respondents: Business or other for-profit 
organizations.
    Table 6 of this document presents the estimated annualized 
reporting burden of the final rule, providing estimates for those 
safety reports not already approved under OMB control number 0910-0014.

[[Page 59961]]



                                            Table 6.--Estimated Annual Reporting Burden of the Final Rule\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                          No. of          No. of Responses       Total Annual          Hours per
                  21 CFR Section                        Respondents        per Respondent          Responses           Response           Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
320.31(d) Bioavailability and Bioequivalence                        10                    20                 200                  14               2,800
 Safety Reports
--------------------------------------------------------------------------------------------------------------------------------------------------------
312.32(c)(1)(ii) and (c)(1)(iii) IND Safety                        100                     6                 600                  12               7,200
 Reports\2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
312.32(c)(1)(iv) IND Safety Reports\3\                              10                     1                  10                  12                 120
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection. The estimates are for the additional burdens beyond
  those already approved for then-current Sec.  Sec.   312.32 and 312.64.
\2\ Includes reports based on findings suggesting a significant risk in humans from epidemiological studies, pooled analysis of multiple studies, other
  clinical studies, or in vitro testing. Reports from animal testing are not included (see footnote 3 of this document).
\3\ Includes reports of clinically important increases in the rate of occurrence of serious suspected adverse reactions over that listed in the protocol
  or investigator brochure.

    The information collection provisions of this final rule have been 
submitted to OMB for review. Prior to the effective date of this final 
rule, FDA will publish a notice in the Federal Register announcing 
OMB's decision to approve, modify, or disapprove the information 
collection provisions in this final rule. An agency may not conduct or 
sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number.

VIII. Executive Order 13132: Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the final rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

IX. References

    The following references have been placed on display in the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852, and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday. 
(FDA has verified the Web site addresses, but FDA is not responsible 
for any subsequent changes to the Web sites after this document 
publishes in the Federal Register.)

    1. Enterprise Directorate-General, European Commission, 
``Detailed Guidance on the Collection, Verification and Presentation 
of Adverse Reaction Reports Arising From Clinical Trials on 
Medicinal Products for Human Use,'' revision 2, Brussels, ENTR/CT 3, 
April 2006 (http://ec.europa.eu/enterprise/index_en.htm).
    2. Council for International Organizations of Medical Sciences, 
``Guidelines for Preparing Core Clinical-Safety Information on 
Drugs. Second Edition, Including New Proposals for Investigator's 
Brochures,'' Report of CIOMS Working Groups III and V, Geneva, 1999.
    3. Council for International Organizations of Medical Sciences, 
``Management of Safety Information From Clinical Trials,'' Report of 
CIOMS Working Group VI, Geneva, 2005.
    4. U.S. Department of Labor, Bureau of Labor Statistics, 
National Industry-Specific Occupational Employment and Wage 
Estimates. NAICS 325400 - Pharmaceutical and Medicine Manufacturing, 
May 2007, extracted September 3, 2008, http://www.bls.gov/oes/current/naics4_325400.htm.
    5. U.S. Department of Commerce, Bureau of the Census, Economic 
Census, Manufacturing Industry Series, Pharmaceutical Preparation 
Manufacturing, Table 4, EC02-311-325412 (RV), 2002.
    6. U.S. Department of Commerce, Bureau of the Census, Economic 
Census, Manufacturing Industry Series, Biological Product 
Manufacturing, Table 4, EC02-311-325414 (RV), 2002.

List of Subjects

21 CFR Part 312

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

21 CFR Part 320

    Drugs, Reporting and recordkeeping requirements.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act, the Public 
Health Service Act, and under authority delegated to the Commissioner 
of Food and Drugs, 21 CFR parts 312 and 320 are amended as follows:

PART 312-- INVESTIGATIONAL NEW DRUG APPLICATION

0
1. The authority citation for 21 CFR part 312 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360bbb, 371; 
42 U.S.C. 262.

0
2. Section 312.32 is revised to read as follows:


Sec.  312.32   IND safety reporting.

    (a) Definitions. The following definitions of terms apply to this 
section:
    Adverse event means any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related.
    Life-threatening adverse event or life-threatening suspected 
adverse reaction. An adverse event or suspected adverse reaction is 
considered ``life-threatening'' if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject 
at immediate risk of death. It does not include an adverse event or 
suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death.
    Serious adverse event or serious suspected adverse reaction. An 
adverse event or suspected adverse reaction is considered ``serious'' 
if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes: Death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, 
a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require

[[Page 59962]]

medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.
    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.
    Unexpected adverse event or unexpected suspected adverse reaction. 
An adverse event or suspected adverse reaction is considered 
``unexpected'' if it is not listed in the investigator brochure or is 
not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as 
amended. For example, under this definition, hepatic necrosis would be 
unexpected (by virtue of greater severity) if the investigator brochure 
referred only to elevated hepatic enzymes or hepatitis. Similarly, 
cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the investigator brochure listed 
only cerebral vascular accidents. ``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.
    (b) Review of safety information. The sponsor must 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, reports in the scientific 
literature, and unpublished scientific papers, as well as reports from 
foreign regulatory authorities and reports of foreign commercial 
marketing experience for drugs that are not marketed in the United 
States.
    (c)(1) IND safety reports. The sponsor must 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 paragraph (c)(1)(i), (c)(1)(ii), 
(c)(1)(iii), or (c)(1)(iv) of this section. 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.
    (i) Serious and unexpected suspected adverse reaction. The sponsor 
must report any suspected adverse reaction that is both serious and 
unexpected. The sponsor must report an adverse event as a suspected 
adverse reaction only if there is evidence to suggest a causal 
relationship between the drug and the adverse event, such as:
    (A) 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);
    (B) 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);
    (C) 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.
    (ii) Findings from other studies. The sponsor must report any 
findings from epidemiological studies, pooled analysis of multiple 
studies, or clinical studies (other than those reported under paragraph 
(c)(1)(i) of this section), 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. 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.
    (iii) Findings from animal or in vitro testing. The sponsor must 
report any findings from 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, 
or carcinogenicity, or reports of significant organ toxicity at or near 
the expected human exposure. 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.
    (iv) Increased rate of occurrence of serious suspected adverse 
reactions. The sponsor must report any clinically important increase in 
the rate of a serious suspected adverse reaction over that listed in 
the protocol or investigator brochure.
    (v) Submission of IND safety reports. The sponsor must submit each 
IND safety report in a narrative format or on FDA Form 3500A or in an 
electronic format that FDA can process, review, and archive. FDA will 
periodically issue guidance on how to provide the electronic submission 
(e.g., method of transmission, media, file formats, preparation and 
organization of files). The sponsor may submit foreign suspected 
adverse reactions on a Council for International Organizations of 
Medical Sciences (CIOMS) I Form instead of a FDA Form 3500A. Reports of 
overall findings or pooled analyses from published and unpublished in 
vitro, animal, epidemiological, or clinical studies must be submitted 
in a narrative format. Each notification to FDA must bear prominent 
identification of its contents, i.e., ``IND Safety Report,'' and must 
be transmitted to the review division in the Center for Drug Evaluation 
and Research or in the Center for Biologics Evaluation and Research 
that has responsibility for review of the IND. Upon request from FDA, 
the sponsor must submit to FDA any additional data or information that 
the agency deems necessary, as soon as possible, but in no case later 
than 15 calendar days after receiving the request.
    (2) Unexpected fatal or life-threatening suspected adverse reaction 
reports. The sponsor must also notify FDA of any unexpected fatal or 
life-threatening suspected adverse reaction as soon as possible but in 
no case later than 7 calendar days after the sponsor's initial receipt 
of the information.
    (3) Reporting format or frequency. FDA may require a sponsor to 
submit IND safety reports in a format or at a

[[Page 59963]]

frequency different than that required under this paragraph. The 
sponsor may also propose and adopt a different reporting format or 
frequency if the change is agreed to in advance by the director of the 
FDA review division that has responsibility for review of the IND.
    (4) Investigations of marketed drugs. 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 of 
this chapter).
    (5) Reporting study endpoints. 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 paragraph (c) 
of this section. 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).
    (d) Followup. (1) The sponsor must promptly investigate all safety 
information it receives.
    (2) Relevant followup information to an IND safety report must be 
submitted as soon as the information is available and must be 
identified as such, i.e., ``Followup IND Safety Report.''
    (3) If the results of a sponsor's investigation show that an 
adverse event not initially determined to be reportable under paragraph 
(c) of this section is so reportable, the sponsor must report such 
suspected adverse reaction in an IND safety report as soon as possible, 
but in no case later than 15 calendar days after the determination is 
made.
    (e) Disclaimer. A safety report or other information submitted by a 
sponsor under this part (and any release by FDA of that report or 
information) does not necessarily reflect a conclusion by the sponsor 
or FDA that the report or information constitutes an admission that the 
drug caused or contributed to an adverse event. A sponsor need not 
admit, and may deny, that the report or information submitted by the 
sponsor constitutes an admission that the drug caused or contributed to 
an adverse event.

0
3. Section 312.64 is amended by revising paragraph (b) to read as 
follows:


Sec.  312.64   Investigator reports.

* * * * *
    (b) Safety reports. An investigator must immediately report to the 
sponsor any serious adverse event, whether or not considered drug 
related, including those listed in the protocol or investigator 
brochure and must include an assessment of whether there is a 
reasonable possibility that the drug caused the event. Study endpoints 
that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the drug and the event (e.g., 
death from anaphylaxis). In that case, the investigator must 
immediately report the event to the sponsor. The investigator must 
record nonserious adverse events and report them to the sponsor 
according to the timetable for reporting specified in the protocol.
* * * * *

PART 320--BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS

0
4. The authority citation for 21 CFR part 320 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 351, 352, 355, 371.

0
5. Section 320.31 is amended in paragraphs (d)(1) and (d)(2) by 
removing the word ``shall'' and by adding in its place the word 
``must,'' and by removing ``and'' at the end of paragraph (d)(1) and 
replacing ``this chapter.'' at the end of paragraph (d)(2) with ``this 
chapter; and'', and by adding paragraph (d)(3) to read as follows:


Sec.  320.31   Applicability of requirements regarding an 
``Investigational New Drug Application.''

* * * * *
    (d) * * *
    (3) The person conducting the study, including any contract 
research organization, must notify FDA and all participating 
investigators of any serious adverse event, as defined in Sec.  
312.32(a), observed during the conduct of the study as soon as possible 
but in no case later than 15 calendar days after becoming aware of its 
occurrence. Each report must be submitted on FDA Form 3500A or in an 
electronic format that FDA can process, review, and archive. FDA will 
periodically issue guidance on how to provide the electronic submission 
(e.g., method of transmission, media, file formats, preparation and 
organization of files). Each report must bear prominent identification 
of its contents, i.e., ``bioavailability/bioequivalence safety 
report.'' The person conducting the study, including any contract 
research organization, must also notify FDA of any fatal or life-
threatening adverse event from the study as soon as possible but in no 
case later than 7 calendar days after becoming aware of its occurrence. 
Each notification under this paragraph must be submitted to the 
Director, Office of Generic Drugs in the Center for Drug Evaluation and 
Research at FDA. Relevant followup information to a bioavailability/
bioequivalence safety report must be submitted as soon as the 
information is available and must be identified as such, i.e., 
``Followup bioavailability/bioequivalence safety report.'' Upon request 
from FDA, the person conducting the study, including any contract 
research organization, must submit to FDA any additional data or 
information that the agency deems necessary, as soon as possible, but 
in no case later than 15 calendar days after receiving the request.

    Dated: September 23, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-24296 Filed 9-28-10; 8:45 am]
BILLING CODE 4160-01-S