[Federal Register Volume 89, Number 30 (Tuesday, February 13, 2024)]
[Notices]
[Pages 10084-10087]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-02849]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2001-D-0219]


Use of Data Monitoring Committees in Clinical Trials; Draft 
Guidance for Industry; Availability; Agency Information Collection 
Activities; Proposed Collection; Comment Request

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is 
announcing the availability of a draft guidance for industry entitled 
``Use of Data Monitoring Committees in Clinical Trials.'' This guidance 
is intended to assist sponsors of clinical trials in determining when a 
data monitoring committee (DMC) (also known as a data and safety 
monitoring board (DSMB), a data and safety monitoring committee (DSMC), 
or an independent data monitoring committee (IDMC)) would be useful for 
trial monitoring and what procedures and practices should be considered 
to guide their operation. When finalized, this guidance will supersede 
the final guidance for clinical trial sponsors entitled ``Establishment 
and Operation of Clinical Trial Data Monitoring Committees,'' issued in 
March 2006. This draft guidance is not final nor is it in effect at 
this time.

DATES: Submit either electronic or written comments on the draft 
guidance by April 15, 2024 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 
version of the guidance. Submit electronic or written comments on the 
proposed collection of information in the draft guidance by April 15, 
2024.

ADDRESSES: You may submit comments on any guidance at any time as 
follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2001-D-0219 for ``Use of Data Monitoring Committees in Clinical 
Trials.'' Received comments will be placed in the docket and, except 
for those submitted as ``Confidential Submissions,'' publicly viewable 
at https://www.regulations.gov or at the Dockets Management Staff 
between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential

[[Page 10085]]

information that you do not wish to be made publicly available, submit 
your comments only as a written/paper submission. You should submit two 
copies total. One copy will include the information you claim to be 
confidential with a heading or cover note that states ``THIS DOCUMENT 
CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will review this copy, 
including the claimed confidential information, in its consideration of 
comments. The second copy, which will have the claimed confidential 
information redacted/blacked out, will be available for public viewing 
and posted on https://www.regulations.gov. Submit both copies to the 
Dockets Management Staff. If you do not wish your name and contact 
information to be made publicly available, you can provide this 
information on the cover sheet and not in the body of your comments and 
you must identify this information as ``confidential.'' Any information 
marked as ``confidential'' will not be disclosed except in accordance 
with 21 CFR 10.20 and other applicable disclosure law. For more 
information about FDA's posting of comments to public dockets, see 80 
FR 56469, September 18, 2015, or access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of this draft guidance to 
the Division of Drug Information, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10001 New Hampshire Ave., 
Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002, or to the 
Office of Communication, Outreach and Development, Center for Biologics 
Evaluation and Research (CBER), Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002, or to 
the Office of Policy, Guidance and Policy Development, Center for 
Devices and Radiological Health, Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 66, Rm. 5431, Silver Spring, MD 20993-0002. 
Send one self-addressed adhesive label to assist that office in 
processing your requests. See the SUPPLEMENTARY INFORMATION section for 
information on electronic access to the draft guidance document.

FOR FURTHER INFORMATION CONTACT: 
    With regard to the draft guidance: Dat Doan, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 3334 Silver Spring, MD 20993, 240-402-
8926; or James Myers, Center for Biologics Evaluation and Research, 
Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 
7256, Silver Spring, MD 20993-0002, 240-402-7911; or Ouided Rouabhi, 
Center for Devices and Radiological Health, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 66, Rm. G221, Silver 
Spring, MD 20993-0002, 301-796-6359.
    With regard to the proposed collection of information: Rachel 
Showalter, Office of Operations, Food and Drug Administration, Three 
White Flint North, 10A-12M, 11601 Landsdown St., North Bethesda, MD 
20852, 240-994-7399, [email protected].

SUPPLEMENTARY INFORMATION: 

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``Use of Data Monitoring Committees in Clinical Trials.'' This 
guidance pertains primarily to the sponsor's responsibility for 
clinical trial management and decision making, but may also be relevant 
to any individual or group to whom the sponsor has delegated applicable 
trial management responsibilities. This guidance provides 
recommendations to help sponsors of clinical trials determine: (1) when 
a DMC (also known as a DSMB, a DSMC, or an IDMC) would be useful for 
trial monitoring and (2) what procedures and practices should be 
considered to guide their operation. Under FDA regulations, sponsors 
are not required to use DMCs in clinical trials except under 21 CFR 
50.24(a)(7)(iv), where an institutional review board can approve a 
clinical trial without requiring informed consent from all research 
subjects, provided certain requirements are met, including the 
establishment of an independent DMC.
    Although the use of DMCs initially was more common in disease areas 
associated with significant morbidity or mortality, since 2006, there 
has been an increase in the use of DMCs in many disease areas not 
involving serious morbidity or mortality. For example, DMCs can provide 
the specialized expertise to evaluate emerging efficacy and safety data 
for trials in rare diseases (e.g., certain genetic disorders), for 
trials in vulnerable populations (e.g., neonates), and for oncologic 
therapies with highly specific targets and potential serious risks 
(e.g., biological products for genetic targets, immunotherapies). DMCs 
are also being used in early phase trials in serious diseases or 
conditions. With this growth of DMC use, a variety of approaches to DMC 
operations has been developed.
    This draft guidance revises the guidance for clinical trial 
sponsors entitled ``Establishment and Operation of Clinical Trial Data 
Monitoring Committees'' issued on March 28, 2006. Changes to the 
guidance reflect changes in DMC structure and practice since FDA issued 
the 2006 version. When finalized, this guidance will replace the 2006 
guidance.
    Sponsors may be required to monitor clinical studies evaluating 
investigational drugs, biological products, and devices (see 21 CFR 
312.50 and 312.56 (for drugs and biological products) and 21 CFR 
812.2(b)(1)(iv), 812.40, and 812.46 (for devices)). Various groups and/
or individuals play different roles in clinical trial monitoring and 
oversight. One such group is a DMC. A clinical trial DMC is established 
by a sponsor and is composed of a group of individuals with relevant 
expertise that reviews accumulating data on a regular basis from one or 
more clinical trials and recommends to the sponsor whether to continue, 
modify, or stop a trial or trials.
    Consistent with Sec.  312.32(d)(1) (21 CFR 312.32(d)(1)), the 
sponsor must investigate a DMC's recommendation relating to an 
increased rate of serious unanticipated adverse events as potentially 
reportable to FDA under Sec.  312.32. If the sponsor concludes that 
there is a ``reasonable possibility'' that the increased rate of 
serious unanticipated adverse events was associated with use of the 
drug, the finding, and support for it (which could include the DMC 
report, any analyses, and pertinent data) must be submitted to FDA as a 
serious unexpected suspected adverse reaction. Similar considerations 
would also apply if the sponsor concludes that an increased rate of 
adverse events constitutes an unanticipated adverse device effect under 
21 CFR 812.46(b) and 812.150(b)(1).
    In the guidance (section VI.B), FDA recommends that sponsors 
establish a charter describing DMC obligations, responsibilities, and 
standard operating procedures. The charter should address, for example, 
the following:

[[Page 10086]]

    1. Procedures for assessing financial and intellectual conflicts of 
interest of proposed DMC members, including identifying any concurrent 
service of any DMC member on other DMCs for trials of the same, 
related, or competing product;
    2. how unblinded analyses will be prepared (e.g., by an independent 
statistician) for the DMC and at what frequency; and
    3. procedures to maintain the confidentiality of interim 
comparative data in communications between the DMC, the sponsor, and 
(if applicable) outside parties to ensure that such data available to 
the DMC are not inappropriately disclosed or disclosed without 
appropriate protections.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the current thinking of FDA on ``Use of Data 
Monitoring Committees in Clinical Trials.'' It does not establish any 
rights for any person and is not binding on FDA or the public. You can 
use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.

II. Paperwork Reduction Act of 1995

    Under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-
3521), 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 revision 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.

Use of Data Monitoring Committees in Clinical Trials

OMB Control Number 0910-0581--Revision

    This collection of information supports recommendations found in 
the Agency guidance. The draft guidance document entitled ``Use of Data 
Monitoring Committees in Clinical Trials'' addresses the roles, 
responsibilities, and operating procedures of DMCs and describes 
certain reporting and recordkeeping responsibilities, including the 
following: (1) sponsor reporting to FDA on DMC recommendations related 
to safety; (2) standard operating procedures (SOPs) for DMCs; (3) DMC 
meeting records; and (4) DMC reports based on meeting minutes to the 
sponsor. The submission of the requested information provides the 
appropriate parties with essential information regarding the clinical 
trial upon which they may base their recommendations.
1. Sponsor Reporting to FDA on DMC Recommendations Related to Safety
    FDA recommends that sponsors inform FDA about all DMC 
recommendations related to the safety of the investigational product, 
whether or not the adverse events that led to the recommendation meet 
the definition of serious.
2. Charters and SOPs for DMCs
    In section VI.B of the guidance, we outline recommendations for 
establishing a DMC charter describing SOPs. The SOPs ensure that 
established written procedures are followed and proper recordkeeping is 
performed.
    In section VII of the guidance, we outline the relationships of the 
DMC members and the sponsors to address the independence of the DMC 
from the sponsor.
3. DMC Meeting Records
    FDA recommends that the DMC keep minutes of all meetings but use 
separate minutes for open and closed sessions.
4. 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. This 
report should include sufficient information to explain the rationale 
for any recommended changes. Sponsors should establish procedures to 
minimize bias, such as requiring that reports to the sponsor include 
only those data generally available to the sponsor (e.g., number 
screened, number enrolled at each site) (see 21 CFR 314.126(b)(5) and 
860.7(f)(1)). FDA may request copies of DMC meeting records when the 
trial is completed (21 CFR 312.58 and 812.150(b)(10)) and may also 
request access to the electronic data sets used for each set of interim 
analysis. FDA therefore recommends that sponsors arrange for archiving 
such electronic data sets.
    Description of the Respondents: The submission and data collection 
recommendations described in this document affect sponsors of clinical 
trials and DMCs.
    FDA estimates the burden of this collection of information as 
follows:

                                 Table 1--Estimated Annual Reporting Burden \1\
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                                                   Number of
Section of guidance; reporting     Number of     responses per   Total annual    Average burden     Total hours
           activity               respondents     respondent       responses      per response
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Section VIII; Sponsor                       74               1              74  0.5 (30 minutes)              37
 reporting to FDA on DMC
 recommendations related to
 safety.
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    Total.....................  ..............  ..............  ..............  ................              37
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


[[Page 10087]]


                                                   Table 2--Estimated Annual Recordkeeping Burden \1\
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                                                               Number of      Number of records     Total annual      Average burden
       Section of guidance; recordkeeping activity           recordkeepers     per recordkeeper       records       per recordkeeping     Total hours
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Sections VI and VII; Charters and SOPs for DMCs..........                 74                  1                 74                  8                592
Section VI.6.C.4.b.; DMC meeting records.................                740                  1                740                  2              1,480
                                                          ----------------------------------------------------------------------------------------------
    Total................................................  .................  .................  .................  .................              2,072
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.


                                               Table 3--Estimated Annual Third-Party Disclosure Burden \1\
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                                                                                         Number of
              Section of guidance; disclosure activity                  Number of     disclosures per    Total annual    Average burden    Total hours
                                                                       respondents       respondent      disclosures     per disclosure
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Section VI.C.4.; DMC reports of meeting minutes to the sponsor.....             740                2            1,480                1            1,480
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    Reporting, Recordkeeping, and Third-Party Disclosure Burdens: Based 
on our experience and the anticipated increase in DMC use, FDA 
estimates that there are approximately 1,480 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 740 
clinical trials. For the purposes of this information collection, FDA 
estimates that each sponsor is responsible for approximately 10 trials, 
resulting in an estimated 74 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 using a DMC, 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. 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 (closed and open meeting sessions) 
to the sponsor. One set of both of the meeting records should be 
maintained per clinical trial.
    Based on a review of the information collection since our last 
request for OMB approval, our estimated burden for the information 
collection reflects an overall increase in burden of 1,183 hours and a 
corresponding increase of 1,794 responses. We attribute this increase 
generally to an adjustment in respondents based on our experience and 
the anticipated increase in DMC use. In table 3, since we removed the 
language in this draft guidance regarding waivers, we removed the 
``sponsor notification to the DMC regarding waivers'' task from the 
burden table, resulting in a decrease of 1 response. In addition, the 
sections in the draft guidance were changed; therefore, we updated the 
section numbers in the burden tables in accordance with the draft 
guidance.
    This draft guidance also refers to previously approved FDA 
collections of information found in FDA regulations. The collections of 
information in 21 CFR parts 50 and 56 have been approved under OMB 
control number 0910-0130. The collections of information in 21 CFR part 
312 have been approved under OMB control number 0910-0014. The 
collections of information in 21 CFR part 314 have been approved under 
OMB control number 0910-0001. The collections of information pertaining 
to good clinical practice have been approved under OMB control number 
0910-0843. The collections of information in 21 CFR part 812 have been 
approved under OMB control number 0910-0078. The collections of 
information in 21 CFR part 54 pertaining to financial disclosure by 
clinical investigators have been approved under OMB control number 
0910-0396.

III. Electronic Access

    Persons with access to the internet may obtain an electronic 
version of the draft guidance at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances, https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-medical-devices-and-radiation-emitting-products, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.

    Dated: February 6, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-02849 Filed 2-12-24; 8:45 am]
BILLING CODE 4164-01-P