Meta-Analyses of Randomized Controlled Clinical Trials (RCTs) for the Evaluation of Risk To Support Regulatory Decisions; Notice of Public Meeting; Request for Comments, 63479-63481 [2013-24939]
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Federal Register / Vol. 78, No. 206 / Thursday, October 24, 2013 / Notices
meetings and will make every effort to
accommodate persons with physical
disabilities or special needs. If you
require special accommodations due to
a disability, please contact Glendolynn
S. Johnson at least 7 days in advance of
the meeting.
FDA is committed to the orderly
conduct of its advisory committee
meetings. Please visit our Web site at
https://www.fda.gov/Advisory
Committees/AboutAdvisoryCommittees/
ucm111462.htm for procedures on
public conduct during advisory
committee meetings.
Notice of this meeting is given under
the Federal Advisory Committee Act (5
U.S.C. app. 2).
Dated: October 18, 2013.
Jill Hartzler Warner,
Acting Associate Commissioner for Special
Medical Programs.
[FR Doc. 2013–24912 Filed 10–23–13; 8:45 am]
BILLING CODE 4160–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2013–N–1276]
Meta-Analyses of Randomized
Controlled Clinical Trials (RCTs) for
the Evaluation of Risk To Support
Regulatory Decisions; Notice of Public
Meeting; Request for Comments
AGENCY:
Food and Drug Administration,
HHS.
Notice of public meeting;
request for comments.
mstockstill on DSK4VPTVN1PROD with NOTICES
ACTION:
The Food and Drug Administration
(FDA or the Agency) is announcing a
public meeting to obtain input on
scientific approaches for the conduct
and assessment of meta-analyses of
randomized controlled clinical trials
(RCTs) to evaluate safety risks
associated with the use of human drugs
or biological products within the
framework of regulatory
decisionmaking. The term meta-analysis
refers to the combining of evidence from
independent studies using appropriate
statistical methods. The purpose of the
public workshop is to initiate
constructive discussion and information
sharing among regulators, researchers,
health care providers, representatives
from the pharmaceutical industry and
health care organizations, and others
from the general public, about the use
of meta-analyses of randomized trials as
a tool for safety assessment in the
regulation of pharmaceutical products.
The format of the meeting consists of a
series of presentations describing and
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17:25 Oct 23, 2013
Jkt 232001
illustrating the methodological issues
that arise in the use of meta-analyses to
evaluate safety risks, followed by a
discussion of those issues from invited
panelists and audience members. This
meeting satisfies an FDA commitment
that is part of the fifth authorization of
the Prescription Drug User Fee Act
(PDUFA V). The input from the meeting
will be used to develop a draft guidance
that describes best practices for the
conduct of meta-analyses and FDA’s
intended approach for the use of metaanalyses in regulatory decision-making.
FDA is also publishing a white paper to
facilitate discussion at the public
meeting, which is available online at
https://www.fda.gov/ForIndustry/
UserFees/PrescriptionDrugUserFee/
ucm360080.htm. The public is invited
to comment on this paper through
Docket Number FDA–2013–N–1276 and
at the public meeting.
Date and Time: The meeting will be
held on November 25, 2013, from 8:30
a.m. to 4:30 p.m.
Location: The public meeting will be
held at FDA’s White Oak Campus,
10903 New Hampshire Ave., Bldg. 31,
rm. 1503, Silver Spring, MD 20993.
Entrance for public meeting attendees is
through Building 1, where routine
security check procedures will be
performed. For parking and security
information, please refer to https://
www.fda.gov/AboutFDA/Workingat
FDA/BuildingsandFacilities/WhiteOak
CampusInformation/ucm241740.htm.
Contact: Indira Hills, Food and Drug
Administration, Center for Drug
Evaluation and Research, 10903 New
Hampshire Ave., Bldg. 21, Rm. 4508,
Silver Spring, MD 20993, 301–796–
9686, FAX: 301–796–9907, email:
indira.hills@fda.hhs.gov.
Registration and Requests for Oral
Presentation: The FDA Conference
Center at the White Oak location is a
Federal facility with security procedures
and limited seating. Individuals who
wish to attend the public meeting must
register on or before November 18, 2013,
by visiting https://
www.surveymonkey.com/s/QRKMGNY
and contacting Indira Hills (see Contact
Person). Early registration is
recommended. Registration is free and
will be on a first-come, first-served
basis. However, FDA may limit the
number of participants from each
organization based on space limitations.
Onsite registration on the day of the
meeting will be based on space
availability.
Time will be reserved during the
meeting for planned presentations from
the audience. If you would like to
present at the meeting, please indicate
this in your meeting registration. Time
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63479
for audience presentations is limited
and will be assigned on a first-come,
first-served basis. Note also that time
will be designated throughout the day
for general comments and questions
from the audience following the panel
discussions.
In this Federal Register notice, FDA
has included specific issues that will be
addressed by the panel. If you wish to
address one or more of these issues in
your presentation, please indicate this at
the time you register so that FDA can
consider that in organizing the
presentations. FDA will do its best to
accommodate requests to speak, and
will determine the amount of time
allotted to each presenter and the
approximate time that each oral
presentation is scheduled to begin. An
agenda will be available approximately
2 weeks before the meeting at https://
www.fda.gov/ForIndustry/UserFees/
PrescriptionDrugUserFee/
ucm360080.htm.
If you need special accommodations
because of disability, please contact
Indira Hills (see Contact Person) at least
7 days before the meeting.
Streaming Webcast of the Public
Meeting: A live webcast of this meeting
will be viewable at https://
collaboration.fda.gov/
metaanalysis1113/ on the day of the
meeting. A video record of the meeting
will be available at the same web
address for 1 year.
Comments: Regardless of attendance
at the public meeting, interested persons
may submit either electronic comments
regarding this document to https://
www.regulations.gov or written
comments to the Division of Dockets
Management (HFA–305), Food and Drug
Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD. It is only necessary
to send one set of comments. Identify
comments with the docket number
found in brackets in the heading of this
document. To ensure consideration,
submit comments by December 16,
2013. Received comments may be seen
in the Division of Dockets Management
between 9 a.m. and 4 p.m., Monday
through Friday, and will be posted to
the docket at https://
www.regulations.gov.
Transcripts: Please be advised that as
soon as a transcript is available, it will
be accessible at https://
www.regulations.gov. It may be viewed
at the Division of Dockets Management
(see Comments). A transcript will also
be available in either hard copy or on
CD–ROM, after submission of a
Freedom of Information request. Written
requests are to be sent to the Division
of Freedom of Information (ELEM–
1029), Food and Drug Administration,
E:\FR\FM\24OCN1.SGM
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63480
Federal Register / Vol. 78, No. 206 / Thursday, October 24, 2013 / Notices
12420 Parklawn Dr, Element Bldg.,
Rockville, MD 20857.
SUPPLEMENTARY INFORMATION:
mstockstill on DSK4VPTVN1PROD with NOTICES
I. Background
On July 9, 2012, the President signed
into law the Food and Drug
Administration Safety and Innovation
Act (FDASIA) (Pub. L. 112–144). Title I
of FDASIA reauthorizes PDUFA and
provides FDA with the user fee
resources necessary to maintain an
efficient review process for human drug
and biological products. The
reauthorization of PDUFA includes
performance goals and procedures for
the Agency that represent FDA’s
commitments during fiscal years 2013–
2017. These commitments are fully
described in the document entitled
‘‘PDUFA Reauthorization Performance
Goals and Procedures Fiscal Years 2013
through 2017’’ (‘‘PDUFA Goals Letter’’),
available on FDA’s Web site at https://
www.fda.gov/downloads/ForIndustry/
UserFees/PrescriptionDrugUserFee/
UCM270412.pdf. Section IX of the
PDUFA Goals Letter, titled ‘‘Enhancing
Regulatory Science and Expediting Drug
Development,’’ includes an
enhancement to advance the science of
meta-analysis methodologies. As part of
this enhancement, FDA committed to
hold a public meeting to engage
stakeholders in a discussion of current
and emerging scientific approaches and
methods for the conduct of metaanalyses and to facilitate stakeholder
input regarding the use of meta-analyses
in FDA’s regulatory review process. The
public meeting announced by this
notice will fulfill this commitment.
II. Purpose and Scope of the Meeting
The objectives of the meeting are to:
1. Initiate constructive discussion and
information-sharing about best practices
in meta-analyses of clinical trial data
that can be used to evaluate potential
drug risks while limiting spurious
findings,
2. Share current experience regarding
the criteria considered by FDA to be
important in making regulatory
decisions when evaluating the strength
and quality of evidence provided by a
meta-analysis, and
3. Obtain input on specific issues
identified by FDA on procedures,
methods, and potential sources of bias
in the design, conduct and use of metaanalysis.
Although many external stakeholders
conduct meta-analyses, FDA’s use of
meta-analyses and other safety
evaluation tools has the potential to
result in consequential regulatory
actions, including market withdrawal or
concluding that a safety concern is not
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17:25 Oct 23, 2013
Jkt 232001
supported by data. As a result, FDA
must adopt a rigorous approach to these
analyses and be transparent regarding
its evidentiary standards and how it
weighs the evidence of a meta-analysis
in arriving at a decision or regulatory
action. The public meeting will focus on
meta-analyses conducted for purposes
of safety evaluation using data from
RCTs.
FDA acknowledges that meta-analyses
conducted to evaluate a product’s
effectiveness, either overall or within
specific subgroups, are occasionally of
interest to the Agency, but the primary
use of meta-analyses in the regulatory
setting is for the assessment of product
risk. Furthermore, although metaanalyses of non-randomized studies
may be informative for the assessment
of certain safety endpoints, the issues
related to such a meta-analysis are not
the focus of the meeting.
FDA expects that this meeting will
build upon prior stakeholder feedback
on the design, conduct, and assessment
of meta-analyses obtained at the ‘‘DIA/
FDA Best Practices for Regulatory
Information Synthesis of Randomized
Controlled Trials for Product Safety
Evaluation’’ workshop held on March
10 and 11, 2011, in Bethesda, MD.
The public input from the meeting
will be used to develop a draft guidance
describing best practices for the conduct
and use of meta-analyses of randomized
controlled trials for the evaluation of
risks associated with the use of human
drugs or biological products within the
framework of regulatory
decisionmaking. The future guidance
will be intended for FDA reviewers, the
pharmaceutical industry, and for thirdparty entities that prepare or evaluate
meta-analyses to assess the safety of
regulated products, as there is currently
no FDA guidance in this area.
Specifically, this guidance will describe
FDA’s view of various aspects of the
criteria considered important when
evaluating the strength and quality of
evidence provided by a meta-analysis.
To facilitate discussions at the public
meeting, FDA is publishing a white
paper on considerations in the conduct
and use of meta-analyses of RCTs that
are intended to support regulatory
decisionmaking about a product’s
safety. This document is available on
FDA’s Web site at https://www.fda.gov/
ForIndustry/UserFees/
PrescriptionDrugUserFee/
ucm360080.htm.
III. Scope of Public Input Requested
FDA seeks input on a range of topics
related to the design and conduct of
meta-analyses and the interpretation of
meta-analysis results when evaluating
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risk in the regulation of pharmaceutical
products. These include the following:
1. Potential sources of bias that may
arise in designing a meta-analysis,
including:
a. Advance or prior knowledge of
individual study results and their
influence on study selection.
b. Lack of or inadequate prespecification of the meta-analysis
hypothesis.
c. Inclusion of the hypothesisgenerating study in the meta-analysis
designed to confirm the hypothesis.
d. Other sources of bias that may exist
but cannot be identified.
2. Potential for spurious findings
because of the examination of multiple
hypotheses, endpoints, and subgroups,
and use of data driven analyses, in a
meta-analysis.
3. Methodological issues in the
conduct of the meta-analysis, including
the following:
a. The use of fixed versus random
effects models in evaluating a metaanalytic hypothesis, especially with
regard to individual and overall study
power, study heterogeneity, and
generalizability.
b. The relative value of the use of
frequentist versus Bayesian methods for
meta-analyses.
c. The choice of statistical levels of
uncertainty of the results, including the
significance level for the primary and
secondary hypotheses.
d. The most appropriate methods to
incorporate studies with few events and
those with no events.
4. Issues related to the individual
studies constituting a meta-analysis,
including:
a. Measures of individual study
quality, including availability of
protocols and amendments.
b. Outcome and exposure
ascertainment in each study.
c. The use of patient-level versus
study-level data.
5. Issues related to the overall quality
of the meta-analysis, including the
following:
a. Whether there is adequate
documentation of the pre-specification
and proper conduct of a meta-analysis,
and more generally, how researchers
should document their methods,
including the important issues of prespecification, in support of their proper
conduct of a meta-analysis.
b. Use and pre-specification of the
types of sensitivity analyses to evaluate
the impact of various sources of bias
(see section III.1) on the meta-analysis
findings.
c. Evaluating the results of a metaanalysis when one or a few large studies
dominate the findings (often recognized
before the analysis).
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Federal Register / Vol. 78, No. 206 / Thursday, October 24, 2013 / Notices
d. The overall framework to evaluate
the quality of the meta-analysis;
whether there is a basis for establishing
a hierarchy of evidence for judging the
quality of the meta-analysis.
Dated: October 21, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013–24939 Filed 10–23–13; 8:45 am]
BILLING CODE 4160–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2013–N–0001]
Peripheral and Central Nervous
System Drugs Advisory Committee;
Notice of Meeting
AGENCY:
Food and Drug Administration,
HHS.
mstockstill on DSK4VPTVN1PROD with NOTICES
ACTION:
Notice.
This notice announces a forthcoming
meeting of a public advisory committee
of the Food and Drug Administration
(FDA). The meeting will be open to the
public.
Name of Committee: Peripheral and
Central Nervous System Drugs Advisory
Committee.
General Function of the Committee:
To provide advice and
recommendations to the Agency on
FDA’s regulatory issues.
Date and Time: The meeting will be
held on November 13, 2013, from 8 a.m.
to 5 p.m.
Location: Sheraton Silver Spring
Hotel, Cypress Ballroom, 8777 Georgia
Ave., Silver Spring, MD 20910. The
hotel’s telephone number is 301–589–
0800.
Contact Person for More Information:
Glendolynn S. Johnson, Center for Drug
Evaluation and Research, Food and
Drug Administration, 10903 New
Hampshire Ave., Bldg. 31, Rm. 2417,
Silver Spring, MD 20993–0002, 301–
796–9001, FAX: 301–847–8533, email:
PCNS@fda.hhs.gov, or FDA Advisory
Committee Information Line, 1–800–
741–8138 (301–443–0572 in the
Washington, DC area). A notice in the
Federal Register about last minute
modifications that impact a previously
announced advisory committee meeting
cannot always be published quickly
enough to provide timely notice.
Therefore, you should always check the
Agency’s Web site at https://
www.fda.gov/AdvisoryCommittees/
default.htm and scroll down to the
appropriate advisory committee meeting
link, or call the advisory committee
VerDate Mar<15>2010
17:25 Oct 23, 2013
Jkt 232001
information line to learn about possible
modifications before coming to the
meeting.
Agenda: The committee will discuss
supplemental biologics license
application (sBLA) 103948–5139,
alemtuzumab injection, proposed trade
name LEMTRADA, submitted by
Genzyme Corporation, a Sanofi
Company. The proposed indication is
for the treatment of patients with
relapsing forms of multiple sclerosis to
slow or reverse the accumulation of
physical disability and reduce the
frequency of clinical exacerbations.
FDA intends to make background
material available to the public no later
than 2 business days before the meeting.
If FDA is unable to post the background
material on its Web site prior to the
meeting, the background material will
be made publicly available at the
location of the advisory committee
meeting, and the background material
will be posted on FDA’s Web site after
the meeting. Background material is
available at https://www.fda.gov/
AdvisoryCommittees/Calendar/
default.htm. Scroll down to the
appropriate advisory committee meeting
link.
Procedure: Interested persons may
present data, information, or views,
orally or in writing, on issues pending
before the committee. Written
submissions may be made to the contact
person on or before November 6, 2013.
Oral presentations from the public will
be scheduled between approximately 1
p.m. and 2 p.m. Those individuals
interested in making formal oral
presentations should notify the contact
person and submit a brief statement of
the general nature of the evidence or
arguments they wish to present, the
names and addresses of proposed
participants, and an indication of the
approximate time requested to make
their presentation on or before October
30, 2013. Time allotted for each
presentation may be limited. If the
number of registrants requesting to
speak is greater than can be reasonably
accommodated during the scheduled
open public hearing session, FDA may
conduct a lottery to determine the
speakers for the scheduled open public
hearing session. The contact person will
notify interested persons regarding their
request to speak by October 31, 2013.
Persons attending FDA’s advisory
committee meetings are advised that the
Agency is not responsible for providing
access to electrical outlets.
FDA welcomes the attendance of the
public at its advisory committee
meetings and will make every effort to
accommodate persons with physical
disabilities or special needs. If you
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63481
require special accommodations due to
a disability, please contact Glendolynn
S. Johnson at least 7 days in advance of
the meeting.
FDA is committed to the orderly
conduct of its advisory committee
meetings. Please visit our Web site at
https://www.fda.gov/
AdvisoryCommittees/
AboutAdvisoryCommittees/
ucm111462.htm for procedures on
public conduct during advisory
committee meetings.
Notice of this meeting is given under
the Federal Advisory Committee Act (5
U.S.C. app. 2).
Dated: October 18, 2013.
Jill Hartzler Warner,
Acting Associate Commissioner for Special
Medical Programs.
[FR Doc. 2013–24908 Filed 10–23–13; 8:45 am]
BILLING CODE 4160–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2013–N–1277]
Therapeutic Area Standards Initiative
Project Plan; Availability
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
The Food and Drug
Administration (FDA) is announcing the
availability of the Therapeutic Area
Standards Initiative Project Plan. This
therapeutic area (TA) Project Plan will
be the primary document for guiding all
major aspects of FDA’s multi-year
initiative to develop and implement TA
standards to support the regulatory
review process for drugs and biologics.
The TA Project Plan will be updated
annually and made available for public
comment.
DATES: Although you can comment on
this TA Project Plan at any time, to
ensure that the Agency considers your
comment on this TA Project Plan before
it begins work on the next version of the
TA Project Plan, submit either
electronic or written comments on the
TA Project Plan by December 23, 2013.
ADDRESSES: Submit written requests for
single copies of the TA Project Plan to
the Division of Drug Information, Center
for Drug Evaluation and Research, Food
and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 2201,
Silver Spring, MD 20993–0002 or Office
of Communication, Outreach and
Development (HFM–40). Send one selfaddressed adhesive label to assist that
SUMMARY:
E:\FR\FM\24OCN1.SGM
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]]>Agencies
[Federal Register Volume 78, Number 206 (Thursday, October 24, 2013)]
[Notices]
[Pages 63479-63481]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-24939]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2013-N-1276]
Meta-Analyses of Randomized Controlled Clinical Trials (RCTs) for
the Evaluation of Risk To Support Regulatory Decisions; Notice of
Public Meeting; Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of public meeting; request for comments.
-----------------------------------------------------------------------
The Food and Drug Administration (FDA or the Agency) is announcing
a public meeting to obtain input on scientific approaches for the
conduct and assessment of meta-analyses of randomized controlled
clinical trials (RCTs) to evaluate safety risks associated with the use
of human drugs or biological products within the framework of
regulatory decisionmaking. The term meta-analysis refers to the
combining of evidence from independent studies using appropriate
statistical methods. The purpose of the public workshop is to initiate
constructive discussion and information sharing among regulators,
researchers, health care providers, representatives from the
pharmaceutical industry and health care organizations, and others from
the general public, about the use of meta-analyses of randomized trials
as a tool for safety assessment in the regulation of pharmaceutical
products. The format of the meeting consists of a series of
presentations describing and illustrating the methodological issues
that arise in the use of meta-analyses to evaluate safety risks,
followed by a discussion of those issues from invited panelists and
audience members. This meeting satisfies an FDA commitment that is part
of the fifth authorization of the Prescription Drug User Fee Act (PDUFA
V). The input from the meeting will be used to develop a draft guidance
that describes best practices for the conduct of meta-analyses and
FDA's intended approach for the use of meta-analyses in regulatory
decision-making. FDA is also publishing a white paper to facilitate
discussion at the public meeting, which is available online at https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm360080.htm.
The public is invited to comment on this paper through Docket Number
FDA-2013-N-1276 and at the public meeting.
Date and Time: The meeting will be held on November 25, 2013, from
8:30 a.m. to 4:30 p.m.
Location: The public meeting will be held at FDA's White Oak
Campus, 10903 New Hampshire Ave., Bldg. 31, rm. 1503, Silver Spring, MD
20993. Entrance for public meeting attendees is through Building 1,
where routine security check procedures will be performed. For parking
and security information, please refer to https://www.fda.gov/AboutFDA/WorkingatFDA/BuildingsandFacilities/WhiteOakCampusInformation/ucm241740.htm.
Contact: Indira Hills, Food and Drug Administration, Center for
Drug Evaluation and Research, 10903 New Hampshire Ave., Bldg. 21, Rm.
4508, Silver Spring, MD 20993, 301-796-9686, FAX: 301-796-9907, email:
indira.hills@fda.hhs.gov.
Registration and Requests for Oral Presentation: The FDA Conference
Center at the White Oak location is a Federal facility with security
procedures and limited seating. Individuals who wish to attend the
public meeting must register on or before November 18, 2013, by
visiting https://www.surveymonkey.com/s/QRKMGNY and contacting Indira
Hills (see Contact Person). Early registration is recommended.
Registration is free and will be on a first-come, first-served basis.
However, FDA may limit the number of participants from each
organization based on space limitations. Onsite registration on the day
of the meeting will be based on space availability.
Time will be reserved during the meeting for planned presentations
from the audience. If you would like to present at the meeting, please
indicate this in your meeting registration. Time for audience
presentations is limited and will be assigned on a first-come, first-
served basis. Note also that time will be designated throughout the day
for general comments and questions from the audience following the
panel discussions.
In this Federal Register notice, FDA has included specific issues
that will be addressed by the panel. If you wish to address one or more
of these issues in your presentation, please indicate this at the time
you register so that FDA can consider that in organizing the
presentations. FDA will do its best to accommodate requests to speak,
and will determine the amount of time allotted to each presenter and
the approximate time that each oral presentation is scheduled to begin.
An agenda will be available approximately 2 weeks before the meeting at
https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm360080.htm.
If you need special accommodations because of disability, please
contact Indira Hills (see Contact Person) at least 7 days before the
meeting.
Streaming Webcast of the Public Meeting: A live webcast of this
meeting will be viewable at https://collaboration.fda.gov/metaanalysis1113/ on the day of the meeting. A video record of the
meeting will be available at the same web address for 1 year.
Comments: Regardless of attendance at the public meeting,
interested persons may submit either electronic comments regarding this
document to https://www.regulations.gov or written comments to the
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD. It is only necessary to
send one set of comments. Identify comments with the docket number
found in brackets in the heading of this document. To ensure
consideration, submit comments by December 16, 2013. Received comments
may be seen in the Division of Dockets Management between 9 a.m. and 4
p.m., Monday through Friday, and will be posted to the docket at https://www.regulations.gov.
Transcripts: Please be advised that as soon as a transcript is
available, it will be accessible at https://www.regulations.gov. It may
be viewed at the Division of Dockets Management (see Comments). A
transcript will also be available in either hard copy or on CD-ROM,
after submission of a Freedom of Information request. Written requests
are to be sent to the Division of Freedom of Information (ELEM-1029),
Food and Drug Administration,
[[Page 63480]]
12420 Parklawn Dr, Element Bldg., Rockville, MD 20857.
SUPPLEMENTARY INFORMATION:
I. Background
On July 9, 2012, the President signed into law the Food and Drug
Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-144).
Title I of FDASIA reauthorizes PDUFA and provides FDA with the user fee
resources necessary to maintain an efficient review process for human
drug and biological products. The reauthorization of PDUFA includes
performance goals and procedures for the Agency that represent FDA's
commitments during fiscal years 2013-2017. These commitments are fully
described in the document entitled ``PDUFA Reauthorization Performance
Goals and Procedures Fiscal Years 2013 through 2017'' (``PDUFA Goals
Letter''), available on FDA's Web site at https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM270412.pdf. Section IX
of the PDUFA Goals Letter, titled ``Enhancing Regulatory Science and
Expediting Drug Development,'' includes an enhancement to advance the
science of meta-analysis methodologies. As part of this enhancement,
FDA committed to hold a public meeting to engage stakeholders in a
discussion of current and emerging scientific approaches and methods
for the conduct of meta-analyses and to facilitate stakeholder input
regarding the use of meta-analyses in FDA's regulatory review process.
The public meeting announced by this notice will fulfill this
commitment.
II. Purpose and Scope of the Meeting
The objectives of the meeting are to:
1. Initiate constructive discussion and information-sharing about
best practices in meta-analyses of clinical trial data that can be used
to evaluate potential drug risks while limiting spurious findings,
2. Share current experience regarding the criteria considered by
FDA to be important in making regulatory decisions when evaluating the
strength and quality of evidence provided by a meta-analysis, and
3. Obtain input on specific issues identified by FDA on procedures,
methods, and potential sources of bias in the design, conduct and use
of meta-analysis.
Although many external stakeholders conduct meta-analyses, FDA's
use of meta-analyses and other safety evaluation tools has the
potential to result in consequential regulatory actions, including
market withdrawal or concluding that a safety concern is not supported
by data. As a result, FDA must adopt a rigorous approach to these
analyses and be transparent regarding its evidentiary standards and how
it weighs the evidence of a meta-analysis in arriving at a decision or
regulatory action. The public meeting will focus on meta-analyses
conducted for purposes of safety evaluation using data from RCTs.
FDA acknowledges that meta-analyses conducted to evaluate a
product's effectiveness, either overall or within specific subgroups,
are occasionally of interest to the Agency, but the primary use of
meta-analyses in the regulatory setting is for the assessment of
product risk. Furthermore, although meta-analyses of non-randomized
studies may be informative for the assessment of certain safety
endpoints, the issues related to such a meta-analysis are not the focus
of the meeting.
FDA expects that this meeting will build upon prior stakeholder
feedback on the design, conduct, and assessment of meta-analyses
obtained at the ``DIA/FDA Best Practices for Regulatory Information
Synthesis of Randomized Controlled Trials for Product Safety
Evaluation'' workshop held on March 10 and 11, 2011, in Bethesda, MD.
The public input from the meeting will be used to develop a draft
guidance describing best practices for the conduct and use of meta-
analyses of randomized controlled trials for the evaluation of risks
associated with the use of human drugs or biological products within
the framework of regulatory decisionmaking. The future guidance will be
intended for FDA reviewers, the pharmaceutical industry, and for third-
party entities that prepare or evaluate meta-analyses to assess the
safety of regulated products, as there is currently no FDA guidance in
this area. Specifically, this guidance will describe FDA's view of
various aspects of the criteria considered important when evaluating
the strength and quality of evidence provided by a meta-analysis.
To facilitate discussions at the public meeting, FDA is publishing
a white paper on considerations in the conduct and use of meta-analyses
of RCTs that are intended to support regulatory decisionmaking about a
product's safety. This document is available on FDA's Web site at
https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm360080.htm.
III. Scope of Public Input Requested
FDA seeks input on a range of topics related to the design and
conduct of meta-analyses and the interpretation of meta-analysis
results when evaluating risk in the regulation of pharmaceutical
products. These include the following:
1. Potential sources of bias that may arise in designing a meta-
analysis, including:
a. Advance or prior knowledge of individual study results and their
influence on study selection.
b. Lack of or inadequate pre-specification of the meta-analysis
hypothesis.
c. Inclusion of the hypothesis-generating study in the meta-
analysis designed to confirm the hypothesis.
d. Other sources of bias that may exist but cannot be identified.
2. Potential for spurious findings because of the examination of
multiple hypotheses, endpoints, and subgroups, and use of data driven
analyses, in a meta-analysis.
3. Methodological issues in the conduct of the meta-analysis,
including the following:
a. The use of fixed versus random effects models in evaluating a
meta-analytic hypothesis, especially with regard to individual and
overall study power, study heterogeneity, and generalizability.
b. The relative value of the use of frequentist versus Bayesian
methods for meta-analyses.
c. The choice of statistical levels of uncertainty of the results,
including the significance level for the primary and secondary
hypotheses.
d. The most appropriate methods to incorporate studies with few
events and those with no events.
4. Issues related to the individual studies constituting a meta-
analysis, including:
a. Measures of individual study quality, including availability of
protocols and amendments.
b. Outcome and exposure ascertainment in each study.
c. The use of patient-level versus study-level data.
5. Issues related to the overall quality of the meta-analysis,
including the following:
a. Whether there is adequate documentation of the pre-specification
and proper conduct of a meta-analysis, and more generally, how
researchers should document their methods, including the important
issues of pre-specification, in support of their proper conduct of a
meta-analysis.
b. Use and pre-specification of the types of sensitivity analyses
to evaluate the impact of various sources of bias (see section III.1)
on the meta-analysis findings.
c. Evaluating the results of a meta-analysis when one or a few
large studies dominate the findings (often recognized before the
analysis).
[[Page 63481]]
d. The overall framework to evaluate the quality of the meta-
analysis; whether there is a basis for establishing a hierarchy of
evidence for judging the quality of the meta-analysis.
Dated: October 21, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-24939 Filed 10-23-13; 8:45 am]
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