
[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]


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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.

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    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 The input from the meeting will be used to develop a draft guidance 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 http://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 http://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 
http://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 http://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 http://www.regulations.gov.
    Transcripts: Please be advised that as soon as a transcript is 
available, it will be accessible at http://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 http://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 
http://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).

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    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


