Adaptive Designs for Clinical Trials of Drugs and Biologics; Draft Guidance for Industry; Availability, 49400-49403 [2018-21314]
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Federal Register / Vol. 83, No. 190 / Monday, October 1, 2018 / Notices
Dated: September 25, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018–21313 Filed 9–28–18; 8:45 am]
BILLING CODE 4164–01–P
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Drugs and Biologics; Draft Guidance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.
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announcing the availability of a draft
guidance for industry entitled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 The draft guidance will replace the
2010 draft guidance for industry entitled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written comments on the draft guidance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draft guidance before it begins work on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:
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SUMMARY:
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
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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
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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 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
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Federal Register / Vol. 83, No. 190 / Monday, October 1, 2018 / Notices
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.
amozie on DSK3GDR082PROD with NOTICES
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
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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 earlyphase 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 endof-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 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 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
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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
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Federal Register / Vol. 83, No. 190 / Monday, October 1, 2018 / Notices
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:
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;
Æ A description of the set of
parameter configurations used for the
simulation scenarios, including a
justification of the adequacy of the
choices;
Æ Simulation results detailing the
estimated Type I error probability and
power 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;
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 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 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.
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 clinical trials of drugs
and biologics
Number of
respondents
Number of
responses per
respondent
Total
annual
responses
Average
burden 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
are no capital costs or operating and maintenance costs associated with this collection of information.
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Federal Register / Vol. 83, No. 190 / Monday, October 1, 2018 / Notices
III. Electronic Access
Persons with access to the internet
may obtain the draft guidance at https://
www.regulations.gov, https://
www.fda.gov/Drugs/Guidance
ComplianceRegulatoryInformation/
Guidances/default.htm, or https://
www.fda.gov/BiologicsBloodVaccines/
GuidanceComplianceRegulatory
Information/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
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Substance Abuse and Mental Health
Services Administration
amozie on DSK3GDR082PROD with NOTICES
Agency Information Collection
Activities: Submission for OMB
Review; Comment Request
substance abuse treatment and mental
health treatment facilities known to
SAMHSA. (The N–MHSS data
collection is covered under OMB No.
0930–0119.)
The information in I–BHS and
N–SSATS is needed to assess the nature
and extent of these resources, to identify
gaps in services, and to provide a
database for treatment referrals. Both
I–BHS and N–SSATS are components of
the Behavioral Health Services
Information System (BHSIS).
The request for OMB approval will
include a request to update the I–BHS
facility listing on a continuous basis and
to conduct the N–SSATS and the
between cycle N–SSATS (N–SSATS BC)
in 2019, 2020, and 2021. The N–SSATS
BC is a procedure for collecting services
data from newly identified facilities
between main cycles of the survey and
will be used to improve the listing of
treatment facilities in the online
Behavioral Health Treatment Services
Locator.
Periodically, the Substance Abuse and
Mental Health Services Administration
(SAMHSA) will publish a summary of
information collection requests under
OMB review, in compliance with the
Paperwork Reduction Act (44 U.S.C.
Chapter 35). To request a copy of these
documents, call the SAMHSA Reports
Clearance Officer on (240) 276–1243.
Planned Changes
I–BHS: Only minor form changes
corresponding with updated technology
are planned.
N–SSATS: The N–SSATS with client
counts will continue to be conducted in
alternate years, as in the past, and the
Treatment Locator will be updated
monthly.
Project: National Survey of Substance
Abuse Treatment Services (N–SSATS)
(OMB No. 0930–0106)—Revision
The Substance Abuse and Mental
Health Services Administration
(SAMHSA) is requesting a revision of
the National Survey of Substance Abuse
Treatment (N–SSATS) data collection
(OMB No. 0930–0106), which expires
on December 31, 2018. N–SSATS
provides both national and state-level
data on the numbers and types of
patients treated and the characteristics
of facilities providing substance abuse
treatment services. It is conducted
under the authority of Section 505 of the
Public Health Service Act (42 U.S.C.
290aa-4) to meet the specific mandates
for annual information about public and
private substance abuse treatment
providers and the clients they serve.
This request includes:
• Collection of N–SSATS, which is an
annual survey of substance abuse
treatment facilities; and
• Updating of the Inventory of
Behavioral Health Services (I–BHS)
which is the facility universe for the
N–SSATS as well as the annual survey
of mental health treatment facilities, the
National Mental Health Services Survey
(N–MHSS). The I–BHS includes all
Version A (2019 and 2021)
The following items have been added
compared to the 2017 N–SSATS: Add
questions about: Where clients obtain
their medications for opioid use
disorder if they originate elsewhere;
how facilities treat alcohol use disorder;
where clients obtain their medications
for alcohol use disorder if they originate
elsewhere; whether the facility only
treats alcohol use disorder;
detoxification from opioids of abuse
with lofexidine or clonidine; the percent
of clients on MAT for opioid use
disorder that receive maintenance
services, detoxification, and relapse
prevention; testing for metabolic
syndrome; drug and alcohol oral fluid
testing; professional interventionist/
educational consultant; recovery coach;
vocational training or educational
support; Naloxone and overdose
education; ‘‘Outcome follow-up after
discharge’’ which was moved from
another question; medications for HIV
treatment; medications for Hepatitis C
treatment; the medications lofexidine
and clonidine; Hepatitis A and B
vaccinations; Buprenorphine (extendedrelease, injectable, for example,
Sublocade®)’’; clients with co-occurring
pain and substance use; Federally
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49403
Qualified Health Centers (FQHC);
Disulfiram, Naltrexone, or Acamprosate
for alcohol use disorder for outpatient,
inpatient, and residential. Also,
response categories were added to select
that services are not provided, and for
medication services provided, an
‘‘other’’ category was added.
The following items have been
deleted compared to the 2017
N–SSATS: Questions about religious
affiliation, standard operating
procedures, outpatient capacity, how
(paper/electronic/both) a facility
performs selected activities, and the
item asking about Access To Recovery
(ATR) client payments have been
deleted.
The following additional changes
have been made compared to the 2017
N–SSATS: Removed the asterisk from
the question about primary focus of
facilities, which means the information
will no longer be published on the
N–SSATS treatment locator; reorganized
the question about services offered;
moved the question on types of
counseling to the question about
services offered; changed the wording
from Screening for Hepatitis B and C to
Testing for Hepatitis B and C; changed
‘‘Screening for mental health disorders’’
to ‘‘Screening for mental disorders’’;
changed the question about clinical/
therapeutic approaches to a ‘‘mark all
that apply’’ format; changed the
wording from ‘‘Computerized substance
abuse treatment/telemedicine’’ to
‘‘Telemedicine/telehealth’’; changed the
question wording about the number of
outpatient clients so it states, ‘‘As of
March 29, 2019, how many active
clients were receiving each of the
following outpatient substance abuse
services at this facility?’’ and changed
the instructions to state ‘‘An active
client is a client who received treatment
in March and is still enrolled in
treatment on March 29, 2019.’’; and
changed the question about halfway
houses so it states, ‘‘Does this facility
operate transitional housing, a halfway
house, or a sober home for substance
abuse clients at this location, that is, the
location listed on the front cover?’’
For the question about how facilities
treat opioid use disorder, information
was added about the question that
states, ‘‘For this question, MAT refers to
any or all of these medications unless
specified.’’ Also, category 5 was
reworded to say ‘‘This facility
administers naltrexone to treat opioid
use disorder. Naltrexone use is
authorized through any medical staff
who have prescribing privileges.’’ In
addition, a category was added, ‘‘This
facility prescribes buprenorphine to
treat opioid use disorder.
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]]>Agencies
[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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\
----------------------------------------------------------------------------------------------------------------
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
----------------------------------------------------------------------------------------------------------------
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..
-------------------------------------------------------------------------------
Total....................... .............. .............. .............. .............. 13,000
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
[[Page 49403]]
III. Electronic Access
Persons with access to the internet may obtain the draft guidance
at https://www.regulations.gov, https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, or
https://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
