Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans, 59935-59963 [2010-24296]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 75, Number 188 (Wednesday, September 29, 2010)]
[Rules and Regulations]
[Pages 59935-59963]
From the Federal Register Online via the Government Printing 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.
---------------------------------------------------------------------------

    FDA received numerous comments in response to the proposed rule, 
many of which stated that the proposal would not meet its stated goals 
and requested that the agency reevaluate specific aspects of the 
proposal. FDA agreed with some of these comments and has reevaluated 
and revised aspects of the proposal. To make the rulemaking process 
more manageable, FDA has decided to issue revisions to the premarketing 
and postmarketing safety reporting regulations in two separate 
rulemakings. By separating these rules, the agency has been able to 
reevaluate and refine each requirement in the premarketing and 
postmarketing settings to better ensure that the rules will achieve 
their goals.
    This rule finalizes revisions to the IND safety reporting 
regulations found in part 312 and the safety reporting requirements for 
bioavailability and bioequivalence studies found in part 320. The 
agency is working on revisions to the postmarketing safety reporting 
regulations found in parts 310, 314, 600, 601, and 606 separately, and 
will address these sections in a future rule. Therefore, revisions to 
and comments about postmarketing safety reporting requirements found in 
parts 310, 314, 600, 601, and 606 are not addressed in this rulemaking. 
This document discusses information relevant to and comments about the 
proposed revisions found in parts 312 and 320.

A. Rationale for Rulemaking

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

B. The Proposed Rule

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

[[Page 59937]]

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

II. Overview of the Final Rule

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

A. Definitions

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

B. Review of Safety Information

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

C. Reporting Requirements

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

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

[[Page 59939]]

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

III. Comments on the Proposed Rule

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

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

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

[[Page 59940]]

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

[[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 https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. The Center for Biologics Evaluation and 
Research (CBER)-related information is posted at https://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 t