Notice: Draft Guidance for Industry on Adaptive Design Clinical Trials 
for Drugs and Biologics; Availability

Federal Register: February 26, 2010 (Volume 75, Number 38)            
                  Page 8968-8970

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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availability of a draft guidance entitled ``Adaptive Design Clinical 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 The draft guidance provides sponsors 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 The draft guidance gives advice on various 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 The draft guidance is intended to assist 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this draft guidance before it begins work on the final version of the 
guidance, submit written or electronic comments on the draft guidance 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ADDRESSES: Submit written requests for single copies of the draft 
guidance to the Division of Drug Information, Center for Drug 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draft guidance may also be obtained by mail by calling CBER at 1-800-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 Submit written comments on the draft guidance 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SUPPLEMENTARY INFORMATION section for electronic access to the draft 
guidance document.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\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                            Number of       Number of Responses                         Hours per
                                                           Respondents        per Respondent      Total Responses        Response         Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
Develop written SOPs                                                   30                     6                180                  6              1,080
--------------------------------------------------------------------------------------------------------------------------------------------------------
Perform simulations and analyze data                                   30                     3                 90                 40              3,600
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                              4,680
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this information collection.


                                                       Table 2.--Estimated Recordkeeping Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                            Number of        Number of Records
                                                          Recordkeepers      per Recordkeeping     Total Records    Hours per  Record     Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
Develop written SOPs                                                   30                     6                180                0.5                 90
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 8970]]


Total                                                                                                                                                 90
--------------------------------------------------------------------------------------------------------------------------------------------------------
\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]
BILLING CODE 4160-01-S