[Federal Register Volume 83, Number 190 (Monday, October 1, 2018)]
[Notices]
[Pages 49400-49403]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-21314]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-D-3124]


Adaptive Designs for Clinical Trials of Drugs and Biologics; 
Draft Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a draft guidance for industry entitled ``Adaptive 
Designs for Clinical Trials of Drugs and Biologics.'' This document 
provides guidance to sponsors and applicants submitting investigational 
new drug applications (INDs), new drug applications (NDAs), biologics 
license applications (BLAs), or supplemental applications on the 
appropriate use of adaptive designs for clinical trials to provide 
evidence of the effectiveness and safety of a drug or biologic. The 
guidance describes the basic principles for designing, conducting, and 
reporting the results from an adaptive clinical trial. The draft 
guidance will replace the 2010 draft guidance for industry entitled 
``Adaptive Design Clinical Trials for Drugs and Biologics.''

DATES: Submit either electronic or written comments on the draft 
guidance by November 30, 2018 to ensure that the Agency considers your 
comment on this draft guidance before it begins work on the final 
version of the guidance.

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-2018-D-3124 for ``Adaptive Designs for Clinical Trials of Drugs and 
Biologics; Draft Guidance for Industry.'' 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 office between 9 a.m. and 4 p.m., Monday 
through Friday.
     Confidential Submissions--To submit a comment with 
confidential 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.gpo.gov/fdsys/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.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    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, 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, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002. Send 
one self-addressed adhesive label to assist that office in processing 
your requests. The guidance may also be obtained by mail by calling 
CBER at 1-800-835-4709 or 240-402-8010. See the SUPPLEMENTARY 
INFORMATION section for electronic access to the draft guidance 
document.

FOR FURTHER INFORMATION CONTACT: Scott Goldie, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 21, Rm. 3557, Silver Spring, MD 20993-0002, 301-
794-2055; or Stephen Ripley, Center for Biologics Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
71, Rm. 7301, Silver Spring, MD 20993-0002, 240-402-7911.

SUPPLEMENTARY INFORMATION: 

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``Adaptive Designs for Clinical Trials of Drugs and 
Biologics.'' This document provides guidance to sponsors and applicants 
submitting INDs, NDAs, BLAs, or supplemental applications on the 
appropriate use of adaptive designs

[[Page 49401]]

for clinical trials to provide evidence of the effectiveness and safety 
of a drug or biologic. The guidance describes the basic principles for 
designing, conducting, and reporting the results from an adaptive 
clinical trial. The guidance also advises sponsors on the types of 
information FDA needs to evaluate the results from clinical trials with 
adaptive designs, including Bayesian adaptive designs and complex 
designs that rely on computer simulations for their design. This 
guidance meets FDA's performance commitment under PDUFA (Prescription 
Drug User Fee Act) VI to publish draft guidance on complex adaptive 
(including Bayesian adaptive) trial designs by the end of fiscal year 
2018.
    The primary focus of this guidance is on adaptive designs for 
clinical trials intended to support the effectiveness and safety of 
drugs or biologics. The concepts discussed are also useful for early 
phase or exploratory clinical trials as well as trials conducted to 
satisfy postmarketing commitments or requirements. The draft guidance 
will replace the 2010 draft guidance for industry entitled ``Adaptive 
Design Clinical Trials for Drugs and Biologics.''
    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 ``Adaptive 
Designs for Clinical Trials of Drugs and Biologics.'' 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. This guidance 
is not subject to Executive Order 12866.

II. Paperwork Reduction Act of 1995

    Under the Paperwork Reduction Act of 1995 (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.
    The draft guidance discusses several collections of information 
that have been approved by OMB. For example, the draft guidance 
explains that sponsors who have questions about adaptive design 
elements in an early-phase exploratory trial should seek FDA feedback 
by either identifying specific questions in a submission containing the 
protocol or by requesting a meeting to discuss those questions. 
Discussion of the plans for an adaptive trial can be the basis for 
requesting a Type C meeting. Regulatory mechanisms for obtaining 
formal, substantive feedback from FDA on clinical trials may also 
include end-of-phase 2 meetings. The draft guidance also recommends 
that special protocol assessments (given the 45-day response timeline) 
are submitted for trials with complex adaptive designs only if there 
has been extensive previous discussion between FDA and the sponsor 
regarding the proposed trial and design. The draft guidance explains 
that in their submissions, the sponsors should pre-specify the details 
of the adaptive design and provide justification that the chances of 
erroneous conclusions will be adequately controlled, estimation of 
treatment effects will be sufficiently reliable, and trial integrity 
will be appropriately maintained. The draft guidance notes that the 
sponsor should advise FDA during the course of a trial of any proposed 
changes to the trial design (usually through protocol amendments), and 
that FDA may request that the sponsor submit minutes from open sessions 
of a monitoring committee during an ongoing trial.
    FDA has OMB approval under the PRA for the submission of INDs, 
including protocol amendments and information amendments, in 21 CFR 
part 312, subpart B, and sponsors may request comment and advice on an 
IND as well as request meetings with FDA under subpart C (OMB control 
number 0910-0014). In addition, the following collections of 
information that have been approved by OMB would cover other 
submissions discussed in the draft guidance:
     Guidance for industry on formal meetings with sponsors and 
applicants for PDUFA products (OMB control number 0910-0429);
     Guidance for Industry on special protocol assessment (OMB 
control number 0910-0470);
     Guidance for industry on clinical trial data monitoring 
committees (OMB control number 0910-0581);
     Guidance for industry on oversight of clinical 
investigations (OMB control number 0910-0733);
     International Council for Harmonization guidance for 
industry ``E6(R2) Good Clinical Practice'' (OMB control number 0910-
0843);
     Protection of Human Subjects: Informed Consent; 
Institutional Review Boards (21 CFR parts 50 and 56) (OMB control 
number 0910-0755);
     Institutional Review Boards (21 CFR 56.115) (OMB control 
number 0910-0130); and
     Requirements on Content and Format of Labeling for Human 
Prescription Drug and Biological Products (OMB control number 0910-
0572).
    In addition, the submission of NDAs, including 21 CFR 314.50(d)(5) 
(clinical data section) and (d)(6) (statistical section), has been 
approved under OMB control number 0910-0001. The submission of BLAs and 
their supplements has been approved under OMB control number 0910-0338.
    The draft guidance also requests the submission of information that 
has not been approved by OMB under the PRA.
    In section VIII.B, the draft guidance states that the documented 
plan for a clinical trial with a proposed adaptive design should 
include the information described below. The information could be 
included in the clinical trial protocol and/or in separate documents, 
such as a statistical analysis plan, a data monitoring committee (DMC) 
charter, or an adaptation committee charter. Although different types 
of information might be included in different documents, all important 
information described below should be submitted to FDA during the 
design stage so that FDA has sufficient time to provide feedback prior 
to initiation of the clinical trial:
     A rationale for the selected design;
     A detailed description of the monitoring and adaptation 
plan, including the anticipated number and

[[Page 49402]]

timing of interim analyses, the specific aspects of the design that may 
be modified, and the specific rule that will be used to make adaptation 
decisions;
     Information on the roles of the bodies responsible for 
implementing the adaptive design, such as the DMC and/or the dedicated 
adaptation committee;
     Pre-specification of the statistical methods that will be 
used to produce interim results and guide adaptation decisions, and to 
carry out hypothesis tests, estimate treatment effects, and estimate 
uncertainty in treatment effect estimates at the end of the trial;
     Evaluation and discussion of the design operating 
characteristics;
     When simulations are the primary or sole technique for 
evaluating trial operating characteristics, a detailed simulation 
report should be submitted, including:
    [cir] An overall description of the trial design;
    [cir] Example trials, in which a small number of hypothetical 
trials are described with different conclusions, such as a positive 
trial with the original sample size, a trial stopped for futility after 
the first interim look, a positive trial after increasing the sample 
size;
    [cir] A description of the set of parameter configurations used for 
the simulation scenarios, including a justification of the adequacy of 
the choices;
    [cir] Simulation results detailing the estimated Type I error 
probability and power under the various scenarios;
    [cir] Simulation code that is readable and adequately commented and 
should include the random seeds used to generate the simulation 
results;
    [cir] A summary providing overall conclusions.
     A comprehensive written data access plan defining how 
trial integrity will be maintained in the presence of the planned 
adaptations. This documentation should include the following 
information: (1) The personnel who will perform the interim analyses; 
(2) the personnel who will have access to interim results; (3) how that 
access will be controlled; (4) how adaptive decisions will be made; and 
(5) what type of information will be disseminated following adaptive 
decisions, and to whom it will be disseminated. The data access plan 
should describe what information, under what circumstances, is 
permitted to be passed to the sponsor or investigators. In addition, it 
is recommended that sponsors establish procedures to evaluate 
compliance with the data access plan and to document all interim 
meetings of the committee tasked with making adaptation decisions, 
i.e., the DMC or other adaptation committee (e.g., with written minutes 
describing what was reviewed, discussed, and decided).
    In section VIII.C, the draft guidance states that a marketing 
application to FDA that relies on a trial with an adaptive design 
should include, in addition to the typical content of that marketing 
application, sufficient information and documentation to allow FDA to 
thoroughly review the results, including:
     All prospective plans, any relevant committee charters 
(e.g., the DMC or adaptation committee charter), and any supporting 
documentation (e.g., literature references, programming code, 
simulation report);
     Information on compliance with the planned adaptation rule 
and with the procedures outlined in the data access plan to maintain 
trial integrity;
     Records of deliberations and participants for any interim 
discussions by any committees involved in the adaptive process;
     Results of the interim analyses used for the adaptation 
decisions;
     Appropriate reporting of the adaptive design and trial 
results in the proposed package insert. For example, the trial summary 
should describe the adaptive design utilized. In addition, treatment 
effect estimates should appropriately take the design into account, or 
if na[iuml]ve estimates such as unadjusted sample means are used, the 
extent of bias should be evaluated and estimates should be presented 
with appropriate cautions regarding their interpretation.
    Based on our review of INDs, NDAs, BLAs, and supplemental 
applications for the use of adaptive designs for clinical trials to 
provide evidence of effectiveness and safety, we estimate that 
approximately 40 sponsors or applicants (``number of respondents'' in 
table 1, row 1) will prepare approximately 240 documented plans for 
clinical trials containing a proposed adaptive design and analysis plan 
and will submit this information to FDA in a clinical trial protocol 
and/or in separate documents such as a statistical analysis plan, a DMC 
charter, or an adaptation committee charter (``total annual responses'' 
in table 1, row 1), and that preparing and submitting this information 
will take approximately 50 hours per sponsor or applicant (``average 
burden per response'' in table 1, row 1).
    In addition, we estimate that approximately 15 sponsors or 
applicants (``number of respondents'' in table 1, row 2) will prepare 
and submit to FDA approximately 20 marketing applications that rely on 
a trial with an adaptive design (``total annual responses'' in table 1, 
row 2), and that preparing and submitting this information will take 
approximately 50 hours per sponsor or applicant (``average burden per 
response'' in table 1, row 2).
    FDA estimates the burden of this collection of information as 
follows:

                                 Table 1--Estimated Annual Reporting Burden \1\
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Guidance on adaptive designs for                     Number of                        Average
  clinical trials of drugs and       Number of     responses per   Total  annual    burden per      Total hours
            biologics               respondents     respondent       responses       response
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Clinical trial protocols and                  40               6             240              50          12,000
 related submissions to FDA with
 an adaptive design and analysis
 plan should contain the
 information in section VIII.B..
Marketing applications that rely              15            1.33              20              50           1,000
 on studies with an adaptive
 design should contain the
 information in section VIII.C..
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    Total.......................  ..............  ..............  ..............  ..............          13,000
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


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III. Electronic Access

    Persons with access to the internet may obtain the draft guidance 
at https://www.regulations.gov, http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, or 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

    Dated: September 25, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-21314 Filed 9-28-18; 8:45 am]
 BILLING CODE 4164-01-P


