[Federal Register Volume 83, Number 169 (Thursday, August 30, 2018)]
[Notices]
[Pages 44274-44277]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-18801]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-0049]


Complex Innovative Designs Pilot Meeting Program

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The sixth iteration of the Prescription Drug User Fee Act 
(PDUFA VI), incorporated as part of the FDA Reauthorization Act of 2017 
(FDARA), 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 a pilot 
meeting program 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 pilot 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 2018 to 2022. This pilot meeting 
program fulfills FDA's commitment under PDUFA VI. For each sponsor 
whose meeting request is granted as part of the pilot, FDA will grant 
two meetings between the sponsor and CDER or CBER that will provide an 
opportunity for medical product developers and FDA to discuss 
regulatory approaches for CID. To promote innovation in this area, 
trial designs developed through the pilot meeting program may be 
presented by FDA (e.g., in a guidance or public workshop) as case 
studies, including

[[Page 44275]]

trial designs for drugs that have not yet been approved by FDA.

DATES: The CID pilot meeting program will proceed from the date of this 
notice through September 30, 2022. Sponsors may submit meeting requests 
for the pilot program through June 30, 2022. Comments about this pilot 
meeting program can be submitted until October 1, 2018. Please note 
that late, untimely filed comments will not be considered.

ADDRESSES: You may submit comments about the CID pilot meetings program 
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-N-0049 for ``Complex Innovative Designs Pilot Meeting 
Program.'' 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.

FOR FURTHER INFORMATION CONTACT:
    CDER: 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, 301-796-2055, [email protected], 
with the subject line ``CID Pilot Meeting Program for CDER.''
    CBER: Christopher Egelebo, Center for Biologics Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
71, Rm 1043, Silver Spring, MD 20993-0002, 240-402-8625, 
[email protected], with the subject line ``CID Pilot 
Meeting Program for CBER.''

SUPPLEMENTARY INFORMATION:

I. Background

    In connection with the sixth iteration of PDUFA, FDA committed to 
conduct a pilot program for highly innovative trial designs for which 
analytically derived properties (e.g., Type I error) may not be 
feasible, and simulations are necessary to determine trial operating 
characteristics. The Agency also committed to issue a Federal Register 
Notice announcing the pilot program, clarifying pilot program 
eligibility, and describing the proposal submission and selection 
process (see PDUFA Reauthorization Performance Goals and Procedures 
Fiscal Years 2018 Through 2022, section I.J.4.b. (https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM511438.pdf)).
    FDA is announcing this pilot meeting program to satisfy the above-
mentioned commitments. The goal of the early meeting discussions 
granted under this pilot program is 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 pilot program, including trial designs 
for drugs that have not yet been approved by FDA. FDA has committed to 
accepting up to two meeting requests quarterly each fiscal year.
    Meeting requests may be submitted on a rolling basis; however, only 
those requests 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 up to four meeting requests 
each quarter, two primary and two alternates to proceed to disclosure 
discussions, and notify sponsors of their status. If FDA and the 
sponsor of a meeting request selected as primary are unable to reach an 
agreement on the elements for public disclosure, the Agency will 
proceed with an alternate submission. When disclosure discussions are 
complete, FDA will grant up to two meetings per quarter under the 
pilot.
    The meetings granted will include an initial and followup meeting 
on the same CID and medical product within the span of approximately 
120 days. Being granted a meeting as part of the pilot meeting program 
does not mean that the proposed CID is appropriate for

[[Page 44276]]

regulatory decision making. Likewise, being denied a meeting as part of 
the pilot meeting program does not mean that the proposed CID is 
unacceptable for regulatory decision making. Sponsors who do not 
participate in the pilot program may seek Agency interaction on their 
clinical development plan through existing channels (e.g., Type C 
meeting requests, Critical Path Innovation Meetings).
    The listed eligibility factors and procedures outlined in this 
Federal Register notice reflect the current thinking at the time of 
publication. Processes may be revised as this pilot program evolves and 
will be communicated on the CID Pilot Meeting Program website: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM617212.htm.

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

    To be eligible for the CID Pilot Meeting Program:
     The sponsor must have a pre-IND or IND number for the 
medical product(s) included in the CID proposal with the intent of 
implementing the CID in the pilot program application.
     The proposed CID is intended to provide substantial 
evidence of effectiveness to support regulatory approval of the medical 
product.
     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.
    Recognizing that the FDA will learn both from the number and types 
of submissions received, FDA welcomes submissions related to any 
eligible CID. However, given that the Agency expects to grant up to two 
meeting requests per quarter as part of the pilot program, the Agency 
currently intends to select requests based on the following:
     Innovative features of the trial design, particularly if 
the innovation may provide advantages over alternative approaches. 
Initial 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.
     Therapeutic need (i.e., therapies being developed for use 
in disease areas where there are no or limited treatments).

III. Procedures and Submission Information

A. General Information

    The CID pilot 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 all 
communications for CDER products.
     CBER: CBER's Office of Biostatistics and Epidemiology, 
which is the point of contact for all 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 Pilot Program Meeting 
Request for CDER'' (CDER applications) or ``CID Pilot 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/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/%20ElectronicSubmissions/ucm153574.htm.

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.
    3. Proposed indication(s) or context of product development.
    4. A background section that includes 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, models, 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 1 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 CID proposed approach for the applicable drug development 
program and a summarized list of next steps in the regulatory decision 
making process along with any supporting data relevant to the 
discussion.

D. Content and Format of the Meeting Information Package

    Sponsors whose meeting requests are granted as part of the pilot 
program should submit a meeting information package electronically with 
``CID Pilot Program Meeting Package for CDER'' (CDER applications) or 
``CID Pilot Program Meeting Package for CBER'' (CBER applications) in 
the subject line no later than 30 days before the initial meeting and 
no later than 90 days before the followup meeting.
    The initial meeting package should include the following 
information:
    1. Product name.
    2. Application number.
    3. Proposed agenda, including estimated times 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, models, 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 detailing the simulated type I error 
probability and power 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.
    7. Overall conclusions including a brief summary of the simulated 
operating characteristics based on 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.

[[Page 44277]]

    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 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 Summaries

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

F. Disclosure

    To promote innovation and to provide better clarity on the 
acceptance of different types of trial designs, trial designs developed 
through the pilot program may be presented by FDA (e.g., in a guidance 
or public workshop) 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 this pilot 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 application, but FDA intends to focus on 
information that is beneficial to advancing the use of CIDs, and those 
elements relevant to the 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, adverse 
events, or a complete description of study eligibility criteria. FDA 
does anticipate that the following information will generally need to 
be disclosed to facilitate discussion of the proposed CID: Study 
endpoints to the degree necessary to describe the design (e.g., overall 
survival in the context of a time to event analysis), target 
population, sample size and power determination, null and alternative 
hypotheses, key operating characteristics, assumed rates for 
dichotomous outcomes or mean and variance for continuous outcomes, 
simulation objectives, simulation scenarios, assumptions (e.g., dropout 
rate, rate of enrollment), modeling characteristics, critical study 
design characteristics including any adaptive elements (e.g., decision 
criteria to add/drop a dose, etc.), and, if a Bayesian approach, how 
Bayesian methods are being used for design and/or analysis purposes.
    It is important that sponsors wishing to participate in the pilot 
program identify aspects of the design and analysis that they consider 
non-disclosable and provide a rationale for withholding the 
information. Participation in the pilot 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.

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. 3501-3520). 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: August 24, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-18801 Filed 8-29-18; 8:45 am]
 BILLING CODE 4164-01-P


