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

Federal Register: Volume 76, Number 246 (Thursday, December 22, 2011)
                  Pages 79689-79691

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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 either electronic or written comments on the collection 
of information by February 21, 2012.

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: Ila S. Mizrachi, Office of Information 
Management, Food and Drug Administration, 1350 Piccard Dr., PI50-400B, 
Rockville, MD 20850, (301) 796-7726, Ila.Mizrachi@fda.hhs.gov.

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 one or more ongoing clinical trials. The DMC advises the sponsor 
regarding the continuing safety of current trial subjects and those yet 
to be recruited to the trial, as well as the continuing validity and 
scientific merit of the trial.
    The guidance document referenced in this 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 based on meeting minutes to 
the sponsor, (3) sponsor reports to 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 certain serious and unexpected 
adverse events in drugs and biologics trials (Sec.  312.32 (21 CFR 
312.32)) and unanticipated adverse device effects in the case of device 
trials (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 DMCs should 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. SOPs for DMCs

    In the guidance, FDA recommends that sponsors establish procedures 
to do the following things:
     Assess potential conflicts of interest of proposed DMC 
members;
     Ensure that those with serious conflicts of interest are 
not included in the DMC;
     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;

[[Page 79690]]

     Identify and disclose any concurrent service of any DMC 
member on other DMCs of the same, related, or competing products;
     Ensure separation, and designate a different statistician 
to advise on the management of the trial, if the primary trial 
statistician takes on the responsibility for interim analysis and 
reporting to the DMC; and
     Minimize the risks of bias that are associated with an 
arrangement under which the primary trial 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)).
    a. Description of Respondents: The submission and data collection 
recommendations described in this document affect sponsors of clinical 
trials and DMCs.
    b. 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.
    c. 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 Drugs 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. 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 of 
the meeting records should be maintained per clinical trial.
    The ``Average Burden per Response'' and ``Average Burden per 
Recordkeeping'' are based on FDA's experience with comparable 
recordkeeping and reporting provisions applicable to FDA regulated 
industry. The ``Average Burden per Response'' includes the time the 
respondent would spend reviewing, gathering, and preparing the 
information to be submitted to the DMC, FDA, or the sponsor. The 
``Average Burden per Recordkeeping'' includes the time to record, 
gather, and maintain the information.
    The information collection provisions in the guidance for 
Sec. Sec.  312.30, 312.32, 312.38, 312.55, and 312.56 have been 
approved under OMB control number 0910-0014; Sec.  314.50 has been 
approved under OMB control number 0910-0001; and Sec. Sec.  812.35 and 
812.150 have been approved under OMB control number 0910-0078.
    FDA estimates the burden of this collection of information as 
follows:

                                 Table 1--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                        Average
  Section of guidance/reporting      Number of     responses per   Total annual     burden per      Total hours
            activity                respondents     respondent       responses       response
----------------------------------------------------------------------------------------------------------------
4.4.1.2. Sponsor notification to               1               1               1            0.25            0.25
 the DMC regarding waivers......                                                       (15 min.)
4.4.3.2. DMC reports of meeting              370               2             740               1          740
 minutes to the sponsor.........
5. Sponsor reporting to FDA on                37               1              37            0.50           18.5
 DMC recommendations related to                                                        (30 min.)
 safety.........................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............          758.75
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


                               Table 2--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                        Average
      Section of guidance/           Number of      records per    Total annual     burden per      Total hours
     recordkeeping activity        recordkeepers   recordkeeper       records      recordkeeping
----------------------------------------------------------------------------------------------------------------
4.1. and 6.4 SOPs for DMCs......              37               1              37               8             296
4.4.3.2. DMC meeting records....             370               1             370               2             740
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............           1,036
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.



[[Page 79691]]

    Dated: December 16, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-32776 Filed 12-21-11; 8:45 am]
BILLING CODE 4160-01-P