[Federal Register Volume 66, Number 224 (Tuesday, November 20, 2001)]
[Notices]
[Pages 58151-58153]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-28962]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 01D-0489]


Draft ``Guidance for Clinical Trial Sponsors on the Establishment 
and Operation of Clinical Trial Data Monitoring Committees;'' 
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a draft document entitled ``Guidance for Clinical Trial 
Sponsors on the Establishment and Operation of Clinical Trial Data 
Monitoring Committees'' dated November 2001. The draft guidance 
document, when finalized, will assist sponsors of clinical trials in 
determining when a data monitoring committee (DMC) is needed for 
optimal study monitoring and how such committees should operate.

DATES: Submit written or electronic comments on the draft guidance to 
ensure their adequate consideration in preparation of the final 
document by February 19, 2002. General comments on agency guidance 
documents are welcome at any time. Submit written or electronic 
comments on the collections of information by January 22, 2002.

ADDRESSES: Submit written requests for single copies of the draft 
guidance to the Office of Communication, Training, and Manufacturers 
Assistance (HFM-40), Center for Biologics Evaluation and Research 
(CBER), Food and Drug Administration, 1401 Rockville Pike, Rockville, 
MD 20852-1448; the Drug Information Branch (HFD-210), Center for Drug 
Evaluation and Research (CDER), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857; or the Division of Small 
Manufacturers, International, and Consumer Assistance (HFZ-220), Center 
for Devices and Radiological Health (CDRH), Food and Drug 
Administration, 1350 Piccard Dr., Rockville, MD 20850. Send one self-
addressed adhesive label to assist the office in processing your 
requests. The document may also be obtained by mail by calling the CBER 
Voice Information System at 1-800-835-4709 or 301-827-1800, or by fax 
by calling the FAX Information System at 1-888-CBER-FAX or 301-827-
3844; or the CDRH Facts-On-Demand system at 1-800-899-0381 or 301-827-
0111. See the SUPPLEMENTARY INFORMATION section for electronic access 
to the draft guidance document.
    Submit written comments on the document to the Dockets Management 
Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 
1061, Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT:
    Stephen M. Ripley, Center for Biologics Evaluation and Research 
(HFM-17), Food and Drug Administration, 1401 Rockville Pike, Rockville, 
MD 20852-1448, 301-827-6210;
    Robert Temple, Center for Drug Evaluation and Research (HFD-40), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
301-594-6758; or
    Joanne Less, Center for Devices and Radiological Health (HFZ-403), 
Food and Drug Administration, 9200 Corporate Blvd., Rockville, MD 
20850, 301-594-1190.

SUPPLEMENTARY INFORMATION:

[[Page 58152]]

I. Background

    FDA is announcing the availability of a draft document entitled 
``Guidance for Clinical Trial Sponsors on the Establishment and 
Operation of Clinical Trial Data Monitoring Committees'' dated November 
2001. The draft guidance document, when finalized, will assist sponsors 
of clinical trials in determining when a DMC is needed for optimal 
study monitoring, and how such committees should operate. The draft 
guidance addresses the roles, responsibilities, and operating 
procedures of DMCs.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). This draft guidance 
document represents the agency's current thinking on this topic. It 
does not create or confer any rights for or on any person and does not 
operate to bind FDA or the public. An alternative approach may be used 
if such approach satisfies the requirement of the applicable statutes 
and regulations.

II. The Paperwork Reduction Act of 1995

    Under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 
3501-3520), Federal agencies must obtain approval from the Office of 
Management and Budget (OMB) for each collection of information they 
conduct or sponsor. ``Collection of Information'' is defined in 44 
U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes agency requests or 
requirements that members of the public submit reports, keep records, 
or provide information to a third party. Section 3506(c)(2)(A) of the 
PRA (44 U.S.C. 3506(c)(2)(A)) requires Federal agencies to provide a 
60-day notice in the Federal Register concerning each proposed 
collection of information before submitting the collection to OMB for 
approval. To comply with this requirement, FDA is publishing notice of 
the proposed collection of information set forth in this document.
    With respect to the following collection of information, FDA 
invites comments on: (1) Whether the proposed collection of information 
is necessary for the proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    Title: Draft Guidance for Clinical Trial Sponsors on the 
Establishment and Operation of Clinical Trial Data Monitoring 
Committees
    Description: FDA is issuing a draft guidance document that will 
assist sponsors of clinical trials in determining when a DMC is needed 
for optimal study monitoring, and how such committees should operate. 
The draft guidance addresses the roles, responsibilities, and operating 
procedures of DMCs, and describes certain reporting and recordkeeping 
responsibilities including the following: (1) Standard operating 
procedures (SOPs); (2) interim reports by a sponsor to a DMC, 
statistical approach to FDA, DMC report of meeting minutes to the 
sponsor; and (3) meeting records. The information collection provisions 
for Sec. 314.50(d)(5)(ii) (21 CFR 314.50(d)(5)(ii)) have been approved 
under OMB Control No. 0910-0001.

A. Standard Operating Procedures

    Under the draft guidance, the agency recommends that all DMCs have 
well-defined SOPs. Subjects to be addressed in SOPs should include, but 
may not be limited to, the following:
      Schedule and format for meetings,
      Format for presentation of data,
      Identification of individuals who will have access to 
interim data to ensure confidentiality,
      Identification of individuals who may attend all or part 
of the DMC meetings,
      Method and timing of providing DMC members with interim 
study reports,
      Specification of the statistical approach that will be 
used to evaluate treatment effects and approach to considering early 
termination of the study for benefit or harm,
      Assessment of potential conflicts of interest of proposed 
DMC members,
      Interaction between FDA and DMC members for certain 
products, and
      Rapid unblinding of treatment codes to DMC members when 
needed.
    The agency also recommends that the sponsor submit a description of 
the SOPs to FDA.

B. Interim Reports by a Sponsor to a DMC

    The agency recommends in the draft guidance that the sponsor or 
sponsor's contractor submit an interim report, including information to 
be presented by the statistician at the DMC meeting, to the DMC. The 
interim report provides the DMC with essential information regarding 
the trial upon which they may base their recommendations.

C. Statistical Approach

    The agency recommends in the draft guidance that the final 
statistical approach be submitted to FDA before initiation of interim 
monitoring. FDA reviews this information and may provide comments to 
the sponsor.

D. DMC Report of Meeting Minutes to Sponsor

    The agency recommends in the draft guidance that the DMC issue a 
written report to the sponsor based on the meeting minutes. Reports to 
the sponsor should include only those data generally available to the 
sponsor. The sponsor may convey the relevant information in this report 
to other interested parties such as study investigators. Meeting 
minutes or other information that include discussion of confidential 
data would not be provided to the sponsor.

E. Meeting Records

    The agency recommends in the draft guidance that the DMC or the 
group preparing the interim reports to the DMC maintain all meeting 
records. This information should be submitted to FDA with the clinical 
study report (Sec. 314.50(d)(5)(ii)).
    Description of Respondents: The submission and data collection 
recommendations described in this document affect sponsors of clinical 
trials and DMCs.
    Burden Estimate: Table 1 of this document provides the burden 
estimate of the annual reporting burden for the information to be 
submitted in accordance with the draft guidance. Table 2 of this 
document provides the burden estimate of the annual recordkeeping 
burden for the information to be maintained in accordance with the 
draft guidance.

Reporting and Recordkeeping Burdens

    Based on information from FDA review divisions, FDA estimates there 
are currently 740 clinical trials with DMCs regulated by CBER, CDER, 
and CDRH. FDA estimates that the average length of a clinical trial is 
2 years, resulting in an annual estimate of 370 clinical trials. 
Because FDA has no information on which to project a change in the use 
of DMCs, FDA estimates that the number of clinical trials with DMCs 
will not change significantly in the next few years. For purposes of 
this information collection, FDA estimates that each sponsor is 
responsible for approximately 10 trials,

[[Page 58153]]

resulting in an estimated 37 sponsors affected by the guidance 
annually.
    Based on information provided to FDA by sponsors that have 
typically used DMCs for the kinds of studies for which this guidance 
recommends them, FDA estimates that the majority of sponsors have 
already prepared SOPs for DMCs, and only a minimum amount of time would 
be necessary to revise or update them for use for other clinical 
studies. Based on FDA's experience with clinical trials using DMCs, FDA 
estimates that the sponsor on average would issue two interim reports 
per clinical trial to the DMC. FDA estimates that the DMCs would hold 
two meetings per year per clinical trial resulting in the issuance of 
two DMC reports of the meeting minutes to the sponsor. One set of both 
of the meeting records should be maintained per clinical trial. Based 
on FDA's experience with the submission of investigational new drug 
applications (INDs), FDA estimates that one statistical approach per 
clinical trial would be submitted to FDA.
    The hours per response and hours per record are based on FDA's 
experience with comparable recordkeeping and reporting provisions 
applicable to FDA regulated industry. The hours per response include 
the time the respondent would spend reviewing, gathering, and preparing 
the information to be submitted to the DMC, FDA, or the sponsor. 
Because clinical trials vary greatly in complexity, FDA estimates that 
the time needed to prepare and submit an interim report by a sponsor or 
sponsor's contractor to the DMC would generally range from 40 to 200 
hours with an average of 120 hours for each report. The hours per 
record include the time to record, gather, and maintain the 
information.
    The total estimated burden for both the reporting and recordkeeping 
burdens under the draft guidance are 93,684 hours.
    FDA invites comments on this analysis of information collection 
burdens. FDA estimates the burden of this information collection as 
follows:

                                 Table 1.--Estimated Annual Reporting Burden\1\
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  Reporting                        No. of Responses      Total Annual
  Activity    No. of Respondents    per Respondent         Responses      Hours per Response      Total Hours
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SOPs                 37                   1                  37                   4                 148
Interim             370                   2                 740                 120              88,800
 reports by
 the sponsor
 to a DMC
Statistical         370                   1                 370                   8               2,960
 approach to
 FDA
DMC report          370                   2                 740                   1                 740
 of meeting
 minutes to
 the sponsor
Total                                                                                            92,648
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


                               Table 2.--Estimated Annual Recordkeeping Burden\1\
----------------------------------------------------------------------------------------------------------------
   21 CFR           No. of         Annual Frequency      Total Annual          Hours per
   Section       Recordkeepers     per Recordkeeping        Records          Recordkeeper         Total Hours
----------------------------------------------------------------------------------------------------------------
SOPs                 37                   1                  37                   8                 296
Meeting             370                   1                 370                   2                 740
 records
Total                                                                                             1,036
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

III. Comments

    This draft document is being distributed for comment purposes only 
and is not intended for implementation at this time. Interested persons 
may submit to the Dockets Management Branch (address above) written or 
electronic comments regarding this draft guidance document and on the 
collection of information. Submit written or electronic comments to 
ensure adequate consideration in preparation of the final document by 
February 19, 2002. Two copies of any comments are to be submitted, 
except that individuals may submit one copy. Comments should be 
identified with the docket number found in the brackets in the heading 
of this document. A copy of the document and received comments are 
available for public examination in the Dockets Management Branch 
between 9 a.m. and 4 p.m., Monday through Friday.

IV. Electronic Access

    Persons with access to the Internet may obtain the document at 
http://www.fda.gov/cber/guidelines.htm, http://www.fda.gov/cder/guidance/index.htm, http://www.fda.gov/cdrh, or http://www.fda.gov/ohrms/dockets/default.htm.

    Dated: November 14, 2001.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 01-28962 Filed 11-19-01; 8:45 am]
BILLING CODE 4160-01-S