Use of Data Monitoring Committees in Clinical Trials; Draft Guidance for Industry; Availability; Agency Information Collection Activities; Proposed Collection; Comment Request, 10084-10087 [2024-02849]
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Federal Register / Vol. 89, No. 30 / Tuesday, February 13, 2024 / Notices
Recipients are required to submit their
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ANNUAL BURDEN ESTIMATES
Average
burden hours
per response
Annual
burden
hours
Pre-Expenditure Report Form .........................................................................
Intended Use Plan ...........................................................................................
Post-Expenditure Reporting Form ...................................................................
57
57
57
1
1
1
2
40
110
114
2,280
6,270
Estimated Total Annual Burden Hours: ....................................................
........................
........................
........................
8,664
Authority: 42 U.S.C. 1397–1397e.
Mary C. Jones,
ACF/OPRE Certifying Officer.
[FR Doc. 2024–02851 Filed 2–12–24; 8:45 am]
BILLING CODE 4184–24–P
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Clinical Trials; Draft Guidance for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.
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announcing the availability of a draft
guidance for industry entitled ‘‘Use of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.
SUMMARY:
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Annual
number of
responses per
respondent
Total
number of
respondents
Instrument
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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 This draft guidance is not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
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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
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Federal Register / Vol. 89, No. 30 / Tuesday, February 13, 2024 / Notices
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-201509-18/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 selfaddressed adhesive label to assist that
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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, PRAStaff@fda.hhs.gov.
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
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10085
(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 § 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
§ 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:
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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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Section of guidance;
reporting activity
Number of
responses per
respondent
Number of
respondents
Total annual
responses
Average
burden
per response
Total
hours
Section VIII; Sponsor reporting to
FDA on DMC recommendations
related to safety.
74
1
74
0.5 (30 minutes) ...............................
37
Total ...........................................
........................
........................
........................
...........................................................
37
1 There
are no capital costs or operating and maintenance costs associated with this collection of information.
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Federal Register / Vol. 89, No. 30 / Tuesday, February 13, 2024 / Notices
TABLE 2—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1
Section of guidance;
recordkeeping activity
Number of
records per
recordkeeper
Number of
recordkeepers
Average
burden per
recordkeeping
Total annual
records
Total
hours
Sections VI and VII; Charters and
SOPs for DMCs ..................................
Section VI.6.C.4.b.; DMC meeting
records ...............................................
74
1
74
8
592
740
1
740
2
1,480
Total ................................................
..............................
..............................
..............................
..............................
2,072
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
Section of guidance;
disclosure activity
Number of
respondents
Number of
disclosures
per
respondent
Total annual
disclosures
Average
burden per
disclosure
Total
hours
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 ThirdParty 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
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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.
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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-regulatoryinformation/guidances-drugs, https://
www.fda.gov/vaccines-blood-biologics/
guidance-compliance-regulatoryinformation-biologics/biologicsguidances, https://www.fda.gov/
medical-devices/device-advicecomprehensive-regulatory-assistance/
guidance-documents-medical-devicesand-radiation-emitting-products,
https://www.fda.gov/regulatoryinformation/search-fda-guidancedocuments, 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
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Health Resources and Services
Administration
Update to the Bright Futures
Periodicity Schedule as Part of the
HRSA-Supported Preventive Services
Guidelines for Infants, Children, and
Adolescents; Correction
Health Resources and Services
Administration (HRSA), Department of
Health and Human Services (HHS).
ACTION: Notices; correction.
AGENCY:
HRSA published documents
in the Federal Register of October 24,
SUMMARY:
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]]>Agencies
[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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\
----------------------------------------------------------------------------------------------------------------
Number of
Section of guidance; reporting Number of responses per Total annual Average burden Total hours
activity respondents respondent responses per response
----------------------------------------------------------------------------------------------------------------
Section VIII; Sponsor 74 1 74 0.5 (30 minutes) 37
reporting to FDA on DMC
recommendations related to
safety.
---------------------------------------------------------------------------------
Total..................... .............. .............. .............. ................ 37
----------------------------------------------------------------------------------------------------------------
\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\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Number of records Total annual Average burden
Section of guidance; recordkeeping activity recordkeepers per recordkeeper records per recordkeeping Total hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
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
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
Section of guidance; disclosure activity Number of disclosures per Total annual Average burden Total hours
respondents respondent disclosures per disclosure
--------------------------------------------------------------------------------------------------------------------------------------------------------
Section VI.C.4.; DMC reports of meeting minutes to the sponsor..... 740 2 1,480 1 1,480
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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
