[Federal Register Volume 84, Number 231 (Monday, December 2, 2019)]
[Notices]
[Pages 65983-65985]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-25986]



[[Page 65983]]

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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; 
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 final guidance for industry entitled ``Adaptive 
Designs for Clinical Trials of Drugs and Biologics.'' This guidance 
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 biological 
product. The guidance describes important principles for designing, 
conducting, and reporting the results from an adaptive clinical trial. 
This guidance finalizes the draft guidance entitled ``Adaptive Designs 
for Clinical Trials of Drugs and Biologics'' issued in October 2018.
    FDA is also announcing that a proposed collection of information 
has been submitted to the Office of Management and Budget (OMB) for 
review and clearance under the Paperwork Reduction Act of 1995.

DATES: The announcement of the guidance is published in the Federal 
Register on December 2, 2019. Submit either electronic or written 
comments on the collection of information by January 2, 2020.

ADDRESSES: To ensure that comments on the information collection are 
received, please note that late, untimely filed comments will not be 
considered. Electronic comments must be submitted on or before January 
2, 2020. The https://www.regulations.gov electronic filing system will 
accept comments until 11:59 p.m. Eastern Time at the end of January 2, 
2020. Comments received by mail/hand delivery/courier (for written/
paper submissions) will be considered timely if they are postmarked or 
the delivery service acceptance receipt is on or before that date. OMB 
recommends that written comments be faxed to the Office of Information 
and Regulatory Affairs, OMB, Attn: FDA Desk Officer, Fax: 202-395-7285, 
or emailed to [email protected]. All comments should be 
identified with the title ``Adaptive Designs for Clinical Trials of 
Drugs and Biologics'' and the OMB control number 0910-0014. Also 
include the FDA docket number found in brackets in the heading of this 
document.

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.'' 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.
     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 this 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. See the SUPPLEMENTARY INFORMATION section for electronic 
access to the guidance document.

[[Page 65984]]


FOR FURTHER INFORMATION CONTACT: Regarding the guidance: 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.
    Regarding the information collection: Domini Bean, Office of 
Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852, 301-796-5733, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a final guidance for industry 
entitled ``Adaptive Designs for Clinical Trials of Drugs and 
Biologics.'' The guidance provides recommendations to sponsors and 
applicants submitting INDs, NDAs, 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. Agency 
regulations in 21 CFR parts 312, 314, and 601 govern the format and 
content of information that must be included in IND, NDA, and BLA 
submissions, respectively, and set forth general requirements regarding 
supporting documentation and recordkeeping associated with the various 
applicable provisions.
    Recommendations found in the guidance describe principles we 
consider important for designing, conducting, and reporting the results 
from an adaptive clinical trial. The guidance also discusses the types 
of information FDA will evaluate from clinical trials with adaptive 
designs, including Bayesian adaptive and complex trials that rely on 
computer simulations for their design. The primary focus of this 
guidance is on adaptive designs for clinical trials intended to support 
the effectiveness and safety of drugs and biological products.
    This guidance finalizes the draft guidance of the same title issued 
on October 1, 2018 (83 FR 49400). FDA considered comments received on 
the draft guidance as the guidance was finalized. Changes from the 
draft to the final guidance include: (1) Reworking the subsection on 
Bayesian adaptive designs to clarify the Agency's recommendations and 
(2) clarifying the extent of prespecification required for the rules 
governing adaptations. In addition, editorial changes were made to 
improve clarity.
    This guidance is being issued consistent with FDA's good guidance 
practices regulation (21 CFR 10.115). The guidance represents 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.

II. Paperwork Reduction Act of 1995

    In compliance with 44 U.S.C. 3507, FDA has submitted the following 
proposed collection of information to OMB for review and clearance.

Investigational New Drug Regulations OMB Control Number 0910-0014--
Revision

    In accordance with 21 CFR 312.145, we are making this guidance 
available under our good guidance practices regulations in 21 CFR 
10.115 to help respondents comply with regulatory requirements 
associated with submitting INDs, NDAs (currently approved under OMB 
control number 0910-0001), and BLAs (currently approved under OMB 
control number 0910-0338). In section VIII.B., the guidance states that 
the documented plan for a clinical trial with a proposed adaptive 
design should include certain information. The information could be 
included in the clinical trial protocol and/or in separate documents, 
such as: (1) A statistical analysis plan, (2) a data monitoring 
committee (DMC) charter, or (3) 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 timing of interim analyses, 
the specific aspects of the design that may be modified, and the 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, if applicable;
     Prespecification of the statistical methods that will be 
used to produce interim results, guide adaptation decisions, 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; and
     In cases where 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, etc.;
    [cir] A description of the set of parameter configurations used for 
the simulation scenarios, including a justification of the adequacy of 
the choices;
    o The number of simulated trials (iterations) evaluated for each 
scenario and a rationale for the adequacy of this number;
    [cir] Simulation results detailing the estimated operating 
characteristics 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; and
    [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 information regarding: 
(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 (and 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). For example, interim 
meetings should be documented with written meeting minutes describing 
what was reviewed, discussed, and decided.

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    In section VIII.C., the guidance states that a marketing 
application to FDA that relies on a trial with an adaptive design 
should include 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 or analyses used for the 
adaptation decisions; and
     Appropriate reporting of the adaptive design and trial 
results in section 14 of the proposed package insert. For example, the 
trial summary should describe the adaptive design utilized. In 
addition, treatment effect estimates should adequately 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.
    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 guidance also recommends that 
special protocol assessments (given the 45-day response timeline) be 
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 guidance explains that in 
their submissions, sponsors should prespecify 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 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.
    As noted above, in the Federal Register of October 1, 2018, FDA 
published a 60-day notice requesting public comment on the proposed 
collection of information.
    There were 21 distinct commenters during this time frame, including 
from industry, drug associations, individuals, and academia, with 
multiple comments from each distinct commenter.
    The majority of comments on the guidance related to format, 
clarity, or word choice, providing specific technical recommendations 
on statistical methodologies. Because we do not believe these 
considerations have any effect on the information collection burden, we 
have made no changes to our estimate.
    We estimate the burden of this collection of information as 
follows:

                                 Table 1--Estimated Annual Reporting Burden \1\
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    Guidance for industry on                         Number of
  adaptive designs for clinical      Number of     responses per   Total annual      Hours per      Total hours
  trials of drugs and 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.

    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 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 data monitoring committee charter, or an 
adaptation committee charter. In addition, we estimate that preparing 
and submitting this information will take approximately 50 hours per 
sponsor or applicant.
    Furthermore, we estimate that approximately 15 sponsors or 
applicants will prepare and submit to FDA approximately 20 marketing 
applications that rely on a trial with an adaptive design and that 
preparing and submitting this information will take approximately 50 
hours per sponsor or applicant.
    FDA is issuing this final guidance subject to OMB approval of the 
collections of information. Before implementing the information 
collection provisions of the guidance, FDA will publish a notice in the 
Federal Register announcing OMB's decision to approve, modify, or 
disapprove the collections of information, including OMB control 
number(s) for newly approved collections.

III. Electronic Access

    Persons with access to the internet may obtain the guidance at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances, or https://www.regulations.gov.

    Dated: November 25, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-25986 Filed 11-29-19; 8:45 am]
 BILLING CODE 4164-01-P