Adaptive Designs for Clinical Trials of Drugs and Biologics; Guidance for Industry; Availability, 65983-65985 [2019-25986]
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Federal Register / Vol. 84, No. 231 / Monday, December 2, 2019 / Notices
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.
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guidance finalizes the draft guidance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–
jbell on DSKJLSW7X2PROD with NOTICES
SUMMARY:
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395–7285, or emailed to oira_
submission@omb.eop.gov. 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.
PO 00000
Frm 00019
Fmt 4703
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65983
• 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/201523389.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.
E:\FR\FM\02DEN1.SGM
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65984
Federal Register / Vol. 84, No. 231 / Monday, December 2, 2019 / Notices
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, PRAStaff@
fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
jbell on DSKJLSW7X2PROD with NOTICES
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
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17:10 Nov 29, 2019
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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
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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:
Æ An overall description of the trial
design;
Æ 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.;
Æ 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;
Æ Simulation results detailing the
estimated operating characteristics
under the various scenarios;
Æ Simulation code that is readable
and adequately commented and should
include the random seeds used to
generate the simulation results; and
Æ 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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Federal Register / Vol. 84, No. 231 / Monday, December 2, 2019 / Notices
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
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:
estimates should adequately take the
design into account, or if naı¨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-ofphase-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
TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1
Guidance for industry on adaptive designs for clinical trials
of drugs and biologics
Number of
responses per
respondent
Total annual
responses
Hours per
response
Total hours
Clinical trial protocols and related submissions to FDA
with an adaptive design and analysis plan should contain the information in section VIII.B. ...............................
Marketing applications that rely on studies with an adaptive design should contain the information in section
VIII.C. ................................................................................
40
6
240
50
12,000
15
1.33
20
50
1,000
Total ..............................................................................
........................
........................
........................
........................
13,000
1 There
jbell on DSKJLSW7X2PROD with NOTICES
Number of
respondents
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
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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.
ComplianceRegulatoryInformation/
Guidances/default.htm, https://
www.fda.gov/vaccines-blood-biologics/
guidance-compliance-regulatoryinformation-biologics/biologicsguidances, 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
III. Electronic Access
Persons with access to the internet
may obtain the guidance at https://
www.fda.gov/Drugs/Guidance
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Agencies
[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]]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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.
[[Page 65985]]
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\
----------------------------------------------------------------------------------------------------------------
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
----------------------------------------------------------------------------------------------------------------
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
----------------------------------------------------------------------------------------------------------------
\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