2010-3980. Draft Guidance for Industry on Adaptive Design Clinical Trials for Drugs and Biologics; Availability

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The Food and Drug Administration (FDA) is announcing the availability of a draft guidance entitled “Adaptive Design Clinical Trials for Drugs and Biologics.” The draft guidance provides sponsors and the review staff in FDA's Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) with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 The draft guidance gives advice on various topics, such as what aspects of adaptive design clinical trials (i.e., clinical, statistical, regulatory) call for special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 The draft guidance is intended to assist sponsors in planning and conducting adaptive design clinical studies, and to facilitate an efficient FDA review.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comment on any guidance at any time (see 21 CFR 10.115(g)(5)), to ensure that the agency considers your comment on this draft guidance before it begins work on the final version of the guidance, submit written or electronic comments on the draft guidance by June 1, 2010.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Submit written requests for single copies of the draft guidance to the Division of Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 2201,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 The draft guidance may also be obtained by mail by calling CBER at 1-800-835-4709 or 301-827-1800. Submit written comments on the draft guidance to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.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 See the SUPPLEMENTARY INFORMATION section for electronic access to the draft guidance document.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 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 Burden¹

	Number of Respondents	Number of Responses per Respondent	Total Responses	Hours per 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 Burden¹

	Number of Recordkeepers	Number of Records per Recordkeeping	Total Records	Hours per Record	Total Hours
Develop written SOPs	30	6	180	0.5	90
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.