[Federal Register Volume 87, Number 202 (Thursday, October 20, 2022)]
[Notices]
[Pages 63787-63790]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-22794]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2022-N-1400]


Complex Innovative Design Paired Meeting Program

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The seventh iteration of the Prescription Drug User Amendments 
(PDUFA VII), included as part of the FDA User Fee Reauthorization Act 
of 2022, highlights the goal of facilitating and advancing the use of 
complex adaptive, Bayesian, and other novel clinical trial designs. The 
Food and Drug Administration (FDA or Agency) is announcing the 
continuation of the paired meeting program established under the sixth 
iteration of PDUFA that affords sponsors, who are selected, the 
opportunity to meet with Agency staff to discuss the use of complex 
innovative trial design (CID) approaches in medical product 
development. Meetings under the program will be conducted by FDA's 
Center for Drug Evaluation and Research (CDER) or Center for Biologics 
Evaluation and Research (CBER) during fiscal years 2023 to 2027. For 
each sponsor whose meeting request is granted, two meetings will be 
held between the sponsor and CDER or CBER that will provide an 
opportunity for medical product developers to discuss their CID 
proposals. To promote innovation in this area, trial designs developed 
through the paired meeting program may be presented by FDA (e.g., in a 
guidance or public workshop) as case studies, including trial designs 
for drugs that have not yet been approved by FDA.

DATES: The CID Paired Meeting Program will proceed from October 1, 
2022, through September 30, 2027. Sponsors may submit meeting requests 
for the program through June 30, 2027. Either electronic or written 
comments about this meeting program must be submitted by November 3, 
2022.

ADDRESSES: You may submit comments about the CID paired meetings 
program as follows. Please note that late, untimely filed comments will 
not be considered. The https://www.regulations.gov electronic filing 
system will accept comments until 11:59 p.m. Eastern Time at the end of 
November 3, 2022. Comments received by mail/hand delivery/courier (for 
written/paper submissions) will be considered timely if they are 
received on or before that date.

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-2022-N-1400 for ``Complex Innovative Design Paired Meeting 
Program.'' Received comments, those filed in a timely manner (see 
ADDRESSES), 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, 240-402-7500.
     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.govinfo.gov/content/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, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: 
    CDER: Scott Goldie, Center for Drug Evaluation and Research, Food 
and Drug Administration, 10903 New

[[Page 63788]]

Hampshire Ave., Bldg. 21, Rm. 3557, Silver Spring, MD 20993-0002, 301-
796-2055, [email protected], with the subject line ``CID Paired 
Meeting Program for CDER.''
    CBER: 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

    In connection with the seventh iteration of PDUFA, FDA committed to 
continue the paired meeting program established under PDUFA VI for 
highly innovative trial designs, with a particular focus on trial 
designs for which simulations are necessary to evaluate the trial 
operating characteristics. The Agency also committed to issue a Federal 
Register notice announcing the continuation of the paired meeting 
program, outlining program eligibility, and describing the proposal 
submission, selection process, and example topics that will advance the 
use of complex innovative designs and inform the development of a 
guidance document (see PDUFA Reauthorization Performance Goals and 
Procedures Fiscal Years 2023 Through 2027, section I.L.4.b, https://www.fda.gov/media/151712/download).
    FDA is announcing the continuation of the paired meeting program to 
satisfy the above-mentioned commitments. The goals of the early meeting 
discussions granted under this program are to provide advice on how a 
proposed CID approach can be used in a specific drug development 
program and to promote innovation by allowing FDA to publicly present 
the trial designs considered through the program, including trial 
designs for drugs that have not yet been approved by FDA. FDA has 
committed to accepting up to eight proposals each fiscal year.
    Meeting requests may be submitted on a rolling basis; however, only 
those received by the quarterly closing date, which will be the last 
day of each quarter of the fiscal year (i.e., December 31, March 31, 
June 30, September 30), will be considered for selection in the 
following quarter. Within 45 days after the quarterly closing date, FDA 
will review the submissions, select meeting requests to proceed to 
disclosure discussions, and notify sponsors of their status. When 
disclosure discussions are complete, FDA will grant the paired meetings 
request.
    The Meeting Request Granted letter will include the date for an 
initial meeting. The follow-up meeting will occur approximately 90 days 
after receiving the follow-up meeting package. Being granted a meeting 
as part of the paired meeting program does not mean that the proposed 
CID is appropriate for regulatory decision making. Likewise, being 
denied a meeting as part of the paired meeting program does not mean 
that the proposed CID is unacceptable for regulatory decision making. 
Sponsors who do not participate in the paired meeting program may seek 
Agency interaction on their clinical development plan through 
traditional channels (e.g., Type C meeting requests, Critical Path 
Innovation Meetings).
    The listed eligibility factors and procedures outlined in this 
notice reflect the current thinking at the time of publication. 
Processes may be revised and will be communicated on the following web 
page: https://www.fda.gov/drugs/development-resources/complex-innovative-trial-design-meeting-program.

II. Eligibility and Selection for Participation in the CID Paired 
Meeting Program

    To be eligible for the CID Paired Meeting Program:
     The sponsor must have a pre-investigational new drug (IND) 
application or IND number for the medical product(s) included in the 
CID meeting request with the intent of implementing the CID proposed in 
the meeting request.
     The trial is not a first in human study, and there is 
sufficient clinical information available to inform the proposed CID.
     The sponsor and FDA are able to reach agreement on the 
trial design information to be publicly disclosed.
    Example CIDs include, but are not limited to:
     Trials with adaptations to multiple design features such 
as treatment arm selection or patient allocation.
     Formal incorporation of prior information such as placebo 
augmentation using an external control or other data sources, or other 
approaches to leverage information internal or external to the trial.
     Use of posterior probability or decision-theoretic 
approaches to determine trial success criteria.
     Trials with novel application of complex design features 
for a given indication (even when those design features have been used 
in other indications), such as use of an active-controlled, non-
inferiority design in a setting where placebo-controlled designs have 
typically been used and where there is a novel or complex approach for 
determining the non-inferiority margin.
     Master protocols.
     Sequential multiple assignment randomized trial designs.
    The Agency currently plans to accept requests based on the 
following:
     Innovative features of the trial design, particularly if 
the innovation may provide advantages over alternative approaches.
     Therapeutic need (i.e., therapies being developed for use 
in disease areas where there are no or limited treatment options).
     Priority will be given to trial designs for which 
analytically derived properties (e.g., Type I error) may not be 
feasible and simulations are necessary to determine operating 
characteristics.
     Priority will also be given to proposed CIDs intended to 
provide substantial evidence of effectiveness to support regulatory 
approval of the medical product.

III. Procedures and Submission Information

A. General Information

    The CID Paired Meeting Program will be jointly administered by the 
following Centers:
     CDER: CDER's Office of Biostatistics, in the Office of 
Translational Sciences, which is the point of contact for CID Paired 
Meeting Program communications for CDER products.
     CBER: CBER's Division of Biostatistics, in the Office of 
Biostatistics and Pharmacovigilance, which is the point of contact for 
CID Paired Meeting Program communications for CBER products.

B. How To Submit a Meeting Request and Meeting Package

    Meeting requests should be submitted electronically to the relevant 
application (i.e., Pre-IND, IND) with ``CID Program Meeting Request for 
CDER'' (CDER applications) or ``CID Program Meeting Request for CBER'' 
(CBER applications) in the subject line. Information about providing 
regulatory submissions in electronic format is available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/providing-regulatory-submissions-electronic-format-certain-human-pharmaceutical-product-applications.

C. Content and Format of the Meeting Request

    Include the following information in the meeting request (25 pages 
or less):
    1. Product Name.
    2. Application Number.

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    3. Proposed indication(s) or context of product development.
    4. A background section that provides a brief history of the 
development program and the status of product development.
    5. Trial objectives.
    6. Brief rationale for the choice of the proposed CID.
    7. Description of study design, including study schema with 
treatment arms, randomization strategy, and endpoints.
    8. Key features of the statistical analysis plan including, but not 
limited to, the analyses, model, analysis population, approach to 
handle missing data, and decision criteria. These should include 
aspects of the design that may be modified and the corresponding rules 
for decisions, if adaptive.
    9. Simulation plan, including the set of parameter configurations 
that will be used for the scenarios to be simulated and preliminary 
evaluation and discussion of design operating characteristics. 
Preliminary simulation results of the operating characteristics (e.g., 
Type I error, power, etc.) should include several hypothetical 
plausible scenarios.
    10. Elements of the study design that the sponsor considers non-
disclosable, along with a rationale for exclusion.
    11. A list of issues for discussion with the Agency about the 
specific proposed CID approach for the applicable drug development 
program.

D. Content and Format of the Meeting Information Package

    Sponsors whose meeting requests are granted as part of the program 
should submit a meeting information package electronically with ``CID 
Paired Meeting Program Package for CDER'' (CDER applications) or ``CID 
Paired Meeting Program Package for CBER'' (CBER applications) in the 
subject line.
    The initial meeting package should include the following 
information:
    1. Product name.
    2. Application number.
    3. Proposed agenda, including estimated time needed for discussion 
of each agenda item.
    4. List of questions for discussion along with a brief summary of 
each question that explains the need or context for the question.
    5. Detailed description of the statistical methodology including, 
but not limited to, the analyses, model, analysis population, approach 
to handle missing data, and decision criteria.
    6. Detailed simulation report that includes the following:
    a. Example trials in which a small number of hypothetical trials 
are described with different conclusions.
    b. Description of the set of parameter configurations used for the 
simulation scenarios, including a justification of the adequacy of the 
choices.
    c. Simulation results, including operating characteristics such as 
Type I error probability, power, expected sample size/duration, and 
estimation properties under various scenarios.
    d. Simulation code that is readable, adequately commented on, and 
includes the random seeds. The code should preferably be written in 
widely used programming languages such as R or SAS to facilitate the 
simulation review.
    e. Overall conclusions, including a brief summary of the simulated 
operating characteristics based on the design features and analyses and 
a discussion of the utility of the CID given the simulation results.
    The followup meeting package should include the following 
information:
    1. Product name.
    2. Application number.
    3. Updated background section that includes a brief history of the 
development program and the status of product development and clinical 
data to date, if applicable.
    4. Proposed agenda, including estimated times needed for discussion 
of each agenda item.
    5. List of questions for discussion along with a brief summary of 
each question that explains the need or context for the question.
    6. Updated programs/shells for simulations, if applicable.
    7. Summary of new information that is available to support 
discussions.

E. Meeting Summary

    A meeting summary will be sent to the sponsor within 60 days of 
each meeting.

F. Disclosure

    To promote innovation in this area, trial designs developed through 
the paired meeting program may be presented by FDA (e.g., in a 
guidance, at public workshops and conferences, or on FDA's website) as 
case studies, including while the drug studied in the trial has not yet 
been approved by FDA. Accordingly, before FDA grants the initial 
meeting under the program, FDA and the sponsor must agree on the 
information that FDA may include in these public case studies. The 
specific information to be disclosed will depend on the content of each 
CID proposal, but FDA intends to focus on information that is 
beneficial to advancing the use of CIDs, and those elements relevant to 
understanding of the CID and its potential use in a clinical trial 
intended to support regulatory approval. Generally, the Agency does not 
anticipate that the case studies will need to include information such 
as molecular structure, the sponsor's name, product name, subject-level 
data, recruitment strategies, or a complete description of study 
eligibility criteria. FDA does anticipate that the following 
information will generally be disclosed to facilitate discussion of the 
proposed CID:
    1. Rationale for the selected design.
    2. Study design characteristics:
    a. Randomization.
    b. Blinding.
    c. Study schema.
    d. Study endpoints.
    e. Target population.
    f. Sample size determination, including assumptions.
    g. Choice of controls (external/historical, concurrent).
    h. Estimand(s) of interest.
    i. Adaptive elements, including aspects of the design that can be 
modified.
    3. Analysis plan:
    a. Model(s), including underlying assumptions and any prior 
distributions.
    b. Null and alternative hypotheses.
    c. Statistical test(s).
    d. Approaches to handle missing data and multiplicity.
    e. Decision criteria throughout the trial, including rules for 
adaptive decisions.
    4. Simulations:
    a. Objectives and assumptions.
    b. Scenarios, including parameter configurations and the rationale 
for parameter values considered, and hypothetical examples of trials 
for a given simulation scenario.
    c. Simulation results, including operating characteristics such as 
Type I error probability, power, expected sample size/duration, and 
estimation properties.
    5. Data access plan components and any other approaches to minimize 
impacts on trial integrity imposed by the innovative design.
    6. Any modifications or amendments to any of the above that occur 
during interactions about the proposed CID between Submitter and FDA.
    It is important that sponsors wishing to participate in the program 
identify aspects of the design and analysis that they consider non-
disclosable and provide a rationale for withholding the information. 
Participation in the program, including any agreement on information 
disclosure, will be voluntary and at the discretion of the sponsor. 
Sponsors that do not wish to make such disclosures may seek regulatory 
input through other existing channels.

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IV. Paperwork Reduction Act of 1995

    This notice refers to collections of information that are subject 
to review by the Office of Management and Budget (OMB) under the 
Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521). The collection 
of information resulting from formal meetings between sponsors or 
applicants and FDA has been approved under OMB control number 0910-
0429. The collection of information in 21 CFR part 312 (investigational 
new drug applications) has been approved under OMB control number 0910-
0014.

    Dated: October 17, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-22794 Filed 10-19-22; 8:45 am]
BILLING CODE 4164-01-P