[Federal Register Volume 73, Number 196 (Wednesday, October 8, 2008)]
[Notices]
[Pages 58970-58972]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-23833]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2008-N-0521]


Agency Information Collection Activities; Proposed Collection; 
Comment Request; Guidance for Clinical Trial Sponsors: Establishment 
and Operation of Clinical Trial Data Monitoring Committees

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing an 
opportunity for public comment on the proposed collection of certain 
information by the agency. Under the Paperwork Reduction Act of 1995 
(the PRA), Federal agencies are required to publish notice in the 
Federal Register concerning each proposed collection of information, 
including each proposed extension of an existing collection of 
information, and to allow 60 days for public comment in response to the 
notice. This notice solicits comments on the collection of information 
concerning the establishment and operation of clinical trial data 
monitoring committees.

DATES: Submit written or electronic comments on the collection of 
information by December 8, 2008.

ADDRESSES: Submit electronic comments on the collection of information 
to http://www.regulations.gov. Submit written comments on the 
collection of information to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. All comments should be identified with the docket 
number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: Jonna Capezzuto, Office of Information 
Management (HFA-710), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-796-3794.

SUPPLEMENTARY INFORMATION: Under 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, including 
each proposed extension of an existing 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 these topics: (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.

Guidance for Clinical Trial Sponsors: Establishment and Operation of 
Clinical Trial Data Monitoring Committees--(OMB Control Number 0910-
0581)--Extension

    Sponsors are required to monitor studies evaluating new drugs, 
biologics, and devices (21 CFR 312.50 and 312.56 for drugs and 
biologics, and 21 CFR 812.40 and 812.46 for devices). Various 
individuals and groups play different roles in clinical trial 
monitoring. One such group is a Data Monitoring Committee (DMC), 
appointed by a sponsor to evaluate the accumulating outcome data in 
some trials. A clinical trial DMC is a group of individuals with 
pertinent expertise that reviews on a regular basis accumulating data 
from an

[[Page 58971]]

ongoing clinical trial. The DMC advises the sponsor regarding the 
continuing safety of current participants and those yet to be 
recruited, as well as the continuing validity and scientific merit of 
the trial.
    FDA's guidance document is intended to assist sponsors of clinical 
trials in determining when a DMC is needed for monitoring a study, and 
how such committees should operate. The guidance addresses the roles, 
responsibilities, and operating procedures of DMCs, describes certain 
reporting and recordkeeping responsibilities, including the following: 
(1) Sponsor notification to the DMC regarding waivers, (2) DMC reports 
of meeting minutes to the sponsor, (3) sponsor reports to the FDA on 
DMC recommendations related to safety, (4) standard operating 
procedures (SOPs) for DMCs, and (5) DMC meeting records.
1. Sponsor Notification to the DMC Regarding Waivers
    The sponsor must report to FDA serious unexpected adverse events in 
drugs and biologics trials (Sec.  312.32 (21 CFR 312.32)) and 
unanticipated adverse events in the case of device trials under (Sec.  
812.150(b)(1) (21 CFR 812.150(b)(1))). The agency recommends in the 
guidance that sponsors notify DMCs about any waivers granted by FDA for 
expedited reporting of certain serious events.
2. DMC Reports of Meeting Minutes to the Sponsor
    The agency recommends in the guidance that the DMC issue a written 
report to the sponsor based on the DMC 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.
3. Sponsor Reporting to FDA on DMC Recommendations Related to Safety
    The requirement of the sponsor to report DMC recommendations 
related to serious adverse events in an expedited manner in clinical 
trials of new drugs (Sec.  312.32(c)) would not apply when the DMC 
recommendation is related to an excess of events not classifiable as 
serious. Nevertheless, the agency recommends in the guidance that 
sponsors inform FDA about all recommendations related to the safety of 
the investigational product whether or not the adverse event in 
question meets the definition of ``serious.''
4. Standard Operating Procedures for DMCs
    In the guidance, we recommend that sponsors establish procedures to 
do the following things:
    <bullet> Assess potential conflicts of interest of proposed DMC 
members;
    <bullet> Ensure that those with serious conflicts of interest are 
not included in the DMC;
    <bullet> Provide disclosure to all DMC members of any potential 
conflicts that are not thought to impede objectivity and, thus, would 
not preclude service on the DMC;
    <bullet> Identify and disclose any concurrent service of any DMC 
member on other DMCs of the same, related or competing products;
    <bullet> Ensure separation, and designate a different statistician 
to advise on the management of the trial, if the primary study 
statistician takes on the responsibility for interim analysis and 
reporting to the DMC; and
    <bullet> Minimize the risks of bias that arise when the primary 
study statistician takes on the responsibility for interim analysis and 
reporting to the DMC, if it appears infeasible or highly impractical 
for any other statistician to take over responsibilities related to 
trial management.
5. DMC Meeting Records
    The agency recommends in the 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) (21 CFR 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 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 guidance.

Reporting and Recordkeeping Burdens

    Based on information from FDA review divisions, FDA estimates there 
are approximately 740 clinical trials with DMCs regulated by the Center 
for Biologics Evaluation and Research, the Center for Drug Evaluation 
and Research, and the Center for Devices and Radiological Health. 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, resulting in an estimated 37 sponsors that are 
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 is 
necessary to revise or update them for use for other clinical studies. 
FDA receives very few requests for waivers regarding expedited 
reporting of certain serious events; therefore, FDA has estimated one 
respondent per year to account for the rare instance a request may be 
made. FDA estimates that the DMCs would hold two meetings per year per 
clinical trial resulting in the issuance of two DMC reports of 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 
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 meeting minutes 
to the sponsor. One set of both meeting records should be maintained 
per clinical trial.
    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. The ``Hours per Record'' include the time to record, gather, 
and maintain the information.
    The information collection provisions in the guidance for 
Sec. Sec.  312.30 (21 CFR 312.30), 312.32, 312.38 (21 CFR 312.38), 
312.55 (21 CFR 312.55), and 312.56 have been approved under OMB Control 
No. 0910-0014; Sec.  314.50 has been approved under OMB Control No. 
0910-0001; and Sec. Sec.  812.35 (21 CFR 812.35) and 812.150 have been 
approved under OMB Control No. 0910-0078.
    FDA estimates the burden of this collection of information as 
follows:

[[Page 58972]]



                                                     Table 1.--Estimated Annual Reporting Burden\1\
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                                                              No. of       Annual Frequency per     Total Annual        Hours Per
        Section of Guidance/Reporting Activity             Respondents            Response           Responses           Response         Total Hours
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4.4.1.2. Sponsor notification to the DMC regarding                      1                     1                  1                .25                .25
 waivers
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4.4.3.2. DMC reports of meeting minutes to the sponsor                370                     2                740                  1                740
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5. Sponsor reporting to FDA on DMC recommendations                     37                     1                 37                 .5               18.5
 related to safety
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Total                                                                                                                                             758.75
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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\
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                                                              No. of         Annual Frequency       Total Annual
                Recordkeeping Activity                    Recordkeepers      per Recordkeeping        Records       Hours Per  Record     Total Hours
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4.1. and 6.4 SOPs for DMCs                                             37                     1                 37                  8                296
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4.4.3.2. DMC meeting records                                          370                     1                370                  2                740
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Total                                                                                                                                              1,036
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    Please note that on January 15, 2008, the FDA Division of Dockets 
Management Web site transitioned to the Federal Dockets Management 
System (FDMS). FDMS is a Government-wide, electronic docket management 
system. Electronic comments or submissions will be accepted by FDA only 
through FDMS at http://www.regulations.gov.

    Dated: September 29, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-23833 Filed 10-7-08; 8:45 am]
BILLING CODE 4160-01-S