[Federal Register Volume 75, Number 38 (Friday, February 26, 2010)]
[Notices]
[Pages 8968-8970]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-3980]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2010-D-0090]
Draft Guidance for Industry on Adaptive Design Clinical Trials
for Drugs and Biologics; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a draft guidance entitled ``Adaptive Design Clinical
Trials for Drugs and Biologics.'' The draft guidance provides sponsors
and the review staff in FDA's Center for Drug Evaluation and Research
(CDER) and Center for Biologics Evaluation and Research (CBER) with
information regarding adaptive design clinical trials when used in drug
development programs. The draft guidance gives advice on various
topics, such as what aspects of adaptive design clinical trials (i.e.,
clinical, statistical, regulatory) call for special consideration, when
to interact with FDA while planning and conducting adaptive design
studies, what information to include in the adaptive design for FDA
review, and issues to consider in the evaluation of a completed
adaptive design study. The draft guidance is intended to assist
sponsors in planning and conducting adaptive design clinical studies,
and to facilitate an efficient FDA review.
DATES: Although you can comment on any guidance at any time (see 21
CFR 10.115(g)(5)), to ensure that the agency considers your comment on
this draft guidance before it begins work on the final version of the
guidance, submit written or electronic comments on the draft guidance
by June 1, 2010.
ADDRESSES: Submit written requests for single copies of the draft
guidance to the Division of Drug Information, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, rm. 2201, Silver Spring, MD 20993-0002, or to
the Office of Communication, Outreach and Development, 1401 Rockville
Pike, suite 200N, Rockville, MD 20852-1448. Send one self-addressed
adhesive label to assist that office in processing your requests. The
draft guidance may also be obtained by mail by calling CBER at 1-800-
835-4709 or 301-827-1800. Submit written comments on the draft guidance
to the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Submit electronic comments to http://www.regulations.gov. See the
SUPPLEMENTARY INFORMATION section for electronic access to the draft
guidance document.
FOR FURTHER INFORMATION CONTACT: Robert T. O'Neill, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 21, rm. 3554, Silver Spring, MD 20993-0002, 301-
796-1700; or
Sue-Jane Wang, Center for Drug Evaluation and Research, Food and
Drug Administration, 10903 New Hampshire Ave., Bldg. 21, rm. 3554,
Silver Spring, MD 20993-0002, 301-796-1700; or
Marc Walton, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 21, rm. 4524, Silver
Spring, MD 20993-0002, 301-796-2600; or
Stephen Ripley, Center for Biologics Evaluation and Research, Food
and Drug Administration, 1401 Rockville Pike, suite 200N, Rockville, MD
20852-1448, 301-827-6210.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a draft guidance for industry
entitled ``Adaptive Design Clinical Trials for Drugs and Biologics.''
This guidance provides information regarding adaptive design trials
when used in drug development programs.
There is great interest in the possibility that clinical trials can
be designed with ``adaptive'' features (i.e., changes in design or
analyses guided by examination of the accumulated data at an interim
point in the trial) that can make the studies more efficient (e.g.,
shorter duration, fewer patients), more likely to demonstrate an effect
of the drug if one exists, or more informative (e.g., by providing
broader dose-response information). The draft guidance discusses
clinical, statistical, and regulatory aspects of a wide range of
adaptive design clinical studies that can be proposed as part of a drug
development program, including both familiar and less familiar
approaches. As more experience is obtained with the less familiar
designs, sponsors can improve their understanding of circumstances
where these designs are most useful or may pose risks to study
integrity and interpretation. The draft guidance describes aspects of
adaptive design trials that deserve special consideration and provides
advice on the information that should be provided to FDA and how best
to interact with FDA to facilitate an efficient review.
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 agency's current thinking on adaptive
design clinical trials for drugs and biologics. It does not create or
confer any rights for or on any person and does not operate to bind FDA
or the public. An alternative approach may be used if such approach
satisfies the requirements of the applicable statutes and regulations.
II. Paperwork Reduction Act of 1995
Under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C.
3501-3520), Federal agencies must obtain
[[Page 8969]]
approval from the Office of Management and Budget (OMB) for each
collection of information that 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 for
each proposed collection of information before submitting the
collection to OMB for approval. To comply with this requirement, FDA is
publishing this notice of the proposed collection of information set
forth in this document.
With respect to the collection of information associated with this
draft guidance, FDA invites comments on the following topics: (1)
Whether the proposed information collected is necessary for the proper
performance of FDA's functions, including whether the information will
have practical utility; (2) the accuracy of FDA's estimated burden of
the proposed information collected, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information collected; and (4) ways to
minimize the burden of information collected on the respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
A. Develop Written Standard Operating Procedures (SOPs) (Reporting and
Recordkeeping Burdens)
In the drug development process, it is particularly important to
protect study blinding of an adaptive design study, where the design is
modified after examination of unblinded interim data, to avoid the
introduction of bias in the study conduct and to maintain confidence in
the validity of the study's result. The draft guidance recommends that
sponsors include in the adaptive design protocol comprehensive and
prospective written SOPs that define who will implement the interim
analysis and adaptation plan, and all monitoring and related procedures
for accomplishing the implementation, providing for the strict control
of access to unblinded data. The draft guidance discusses the
information that should be included in the SOPs and other issues that
should be addressed: (1) Identification of the personnel who will
perform the interim analyses and who will have access to the interim
results; (2) how that access will be controlled and how the interim
analyses will be performed, including how any potential irregularities
in the data (e.g., withdrawals, missing values) will be managed; (3)
how adaptation decisions will be made; (4) whether there are any
foreseeable impediments to complying with the SOPs; (5) how compliance
with the SOPs will be documented and monitored; and (6) what
information, under what circumstances, is permitted to be passed from
the Data Monitoring Committee (DMC) to the sponsor or investigators.
The draft guidance recommends extensively documenting the rules of
operation of the DMC (or other involved groups) and including a
description of the responsibilities of each entity involved in the
process. Based on FDA's data on the number of sponsors that would be
covered by the draft guidance, we estimate that approximately 180 SOPs
related to adequate design will be sent to FDA each year, and that each
SOP will take approximately 6 hours to develop, maintain, and update.
The draft guidance recommends that sponsors document and maintain
records of the SOPs. Documenting and maintaining records is considered
recordkeeping under the PRA. We estimate that 180 SOPs related to
adaptive design will be documented and maintained each year, and that
each SOP will take approximately 30 minutes to document and maintain.
B. Perform Simulations and Analyze Data (Reporting Burden)
The draft guidance discusses study simulations that may be useful
in evaluating different designs. Because patient safety is a concern in
adaptive design dose escalation studies, the draft guidance recommends
that sponsors use simulations to explore the features of different
study designs with regard to the balance of efficiency (study size) and
subject safety. The draft guidance recommends that sponsors include
these simulations and their respective analyses with the selected
design. We estimate that 90 simulations and their respective analyses
will be sent to FDA each year, and that each simulation and its
analysis will take approximately 40 hours to prepare and submit.
This draft guidance also refers to previously approved collections
of information found in FDA regulations. Sections VII, VIII, IX, XI,
and XII of the guidance request that certain information be submitted
to FDA and certain recordkeeping be performed by the sponsor. We may
request this information under 21 CFR 312.23, 312.30, 314.50, 314.126,
and 601.2. The collections of information in 21 CFR parts 312, 314, and
601 have been approved under OMB control numbers 0910-0014, 0910-0001,
and 0910-0338, respectively.
FDA estimates the burden of this collection of information as
follows:
Table 1.--Estimated Reporting Burden\1\
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Number of Number of Responses Hours per
Respondents per Respondent Total Responses Response Total Hours
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Develop written SOPs 30 6 180 6 1,080
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Perform simulations and analyze data 30 3 90 40 3,600
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Total 4,680
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\1\ There are no capital costs or operating and maintenance costs associated with this information collection.
Table 2.--Estimated Recordkeeping Burden\1\
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Number of Number of Records
Recordkeepers per Recordkeeping Total Records Hours per Record Total Hours
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Develop written SOPs 30 6 180 0.5 90
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[[Page 8970]]
Total 90
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\1\ There are no capital costs or operating and maintenance costs associated with this information collection.
III. Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this document.
Submit a single copy of electronic comments or two paper copies of any
mailed comments, except that individuals may submit one paper copy.
Comments are to be identified with the docket number found in brackets
in the heading of this document. Received comments may be seen in the
Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday.
IV. Electronic Access
Persons with access to the Internet may obtain the document at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm, or http://www.regulations.gov.
Dated: February 22, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-3980 Filed 2-25-10; 8:45 am]
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