[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This guidance finalizes the draft guidance entitled ``Adaptive Designs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