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Complex Innovative Trial Designs Pilot Program

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As displayed in the Federal Register notice on August 29, 2018, FDA is conducting a Complex Innovative Trial Design (CID) Pilot Meeting Program to support the goal of facilitating and advancing the use of complex adaptive, Bayesian, and other novel clinical trial designs. The CID Pilot Meeting Program fulfills a performance goal agreed to under PDUFA VI, included as part of the FDA Reauthorization Act of 2017.

This pilot meeting program offers sponsors whose meeting requests are granted the opportunity for increased interaction  with FDA staff to discuss their proposed  CID approach.

Meetings will be conducted by FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) during fiscal years 2019 to 2022. 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 trial designs for medical products  that have not yet been approved by FDA.

Goals of the CID Pilot Meeting Program

The CID Pilot Program is designed to:

  • Facilitate the use of CID approaches in late-stage drug development.
  • Promote innovation by allowing FDA to publicly discuss the trial designs considered through the pilot program, including trial designs for medical products that have not yet been approved by FDA.

Procedures and Submission Information

CID Pilot Meeting Program
Quarterly meeting request submission deadlines

March 31

June 30

Sept. 30

Dec. 31

Applicants will be notified of eligibility to proceed to disclosure discussions approximately 45 days after submission deadlines.

Under the CID pilot meeting program, FDA will accept two primary meeting requests and two alternates per quarter. For each meeting request granted as part of the pilot, FDA will conduct an initial meeting and a follow-up meeting on the same CID and medical product within a span of approximately 120 days.

  • The sponsor must have an Investigational New Drug (IND) or pre-IND number for the medical product in the CID proposal.
  • 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 to inform the proposed CID.
  • The sponsor and FDA are able to reach agreement on the trial design information to be publicly disclosed.

FDA welcomes submissions related to any eligible CID. However, given that FDA expects to grant up to two meeting requests per quarter as part of the pilot program, FDA will select requests based on:

  • Innovative features of the trial design, particularly whether the innovation may provide advantages over alternative approaches. Initial priority will be given to trial designs for which (1) analytically derived properties (e.g., type I error) may not be feasible and (2) 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).

Sponsors may request to participate in the program on a rolling basis through June 30, 2022. Only those requests received by the last day of each quarter of the fiscal year will be considered for the following quarter. Meeting-granted and -denied decisions and notifications will be made within 45 days after the quarterly closing date.

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. Please review the information about providing regulatory submissions in electronic format.

Include the following information in the meeting request (25 pages or fewer):

  1. Product name.
  2. Application number.
  3. Proposed indication(s) or context of product development.
  4. 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 handling missing data, and decision criteria. These key features 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) should include several plausible hypothetical scenarios.
  10. Elements of the study design that the sponsor considers nondisclosable, along with a rationale for exclusion.
  11. A list of issues for discussion with FDA 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.

Within 45 days after the quarterly closing date, FDA will review the meeting requests, select up to four meeting requests each quarter (two primary and two alternates) to proceed to disclosure discussions, and notify sponsors of their status. Before FDA grants the initial meeting under the CID pilot meeting program, FDA and the sponsor must discuss and agree on the information that FDA may include in public case studies. The specific information to be disclosed will depend on the content of each meeting request and associated CID. 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.  FDA anticipates 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 criterial to add/drop a dose, etc.)
  • If a Bayesian approach, how Bayesian methods are being used for design and/or analysis purposes

 

Sponsors whose meeting requests are granted as part of the pilot program should submit a meeting information package electronically no later than 30 days before the initial meeting and no later than 90 days before the follow-up meeting. Include “CID Pilot Program Meeting Package for CDER” (CDER applications) or “CID Pilot Program Meeting 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 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 handling missing data, and decision criteria.
  6. Detailed simulation report that includes the following:
    1. Example trials in which a small number of hypothetical trials are described with different conclusions.
    2. Description of the set of parameter configurations used for the simulation scenarios, including a justification of the adequacy of the choices.
    3. Simulation results detailing the simulated type I error probability and power under various scenarios.
    4. Simulation code that is readable, is adequately commented on, and includes the random seeds. The code should 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 follow-up 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 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.

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

For more information regarding a submission inquiry to CDER please use the subject line:
CID Pilot Meeting Program for CDER

For more information regarding a submission inquiry to CBER please use the subject line:
CID Pilot Meeting Program for CBER

  1. What is the Complex Innovative Trial Design (CID) Pilot Meeting Program?

    Response: Officially launched with the publication of a Federal Register Notice in August 2018, the CID Pilot Meeting Program is a U.S. Food and Drug Administration (FDA)-led pilot meeting program which supports the goal of facilitating and advancing the use of complex adaptive, Bayesian, and other novel clinical trial designs. Under the sixth iteration of the Prescription Drugs User Fee Amendments (PDUFA VI), FDA agreed to conduct a pilot meeting program for highly innovative trial designs for which analytically derived properties may not be feasible, and simulations are necessary to determine trial operating characteristics (e.g., Type I error).

    This program offers sponsors who are selected an opportunity for increased engagement with FDA experts from the Center for Drug Evaluation and Research (CDER) and/or Center for Biologics Evaluation and Research (CBER) to discuss CID and analyses in medical product development. The pilot program period will be conducted through U.S. government fiscal year 2022.

  2. What is Type I error?

    Response: Clinical trials are conducted to provide evidence that a medical product is both safe and effective. The FDA’s evaluation of clinical trials often includes an assessment of the type I error, which is the probability of falsely concluding that a medical product has an effect when it does not.

  3. How can CIDs streamline the drug development process?

    Response: CIDs and analyses can help streamline the drug development process by increasing the efficiency of clinical trials. For example, clinical trials with adaptive designs may allow for a greater chance of detecting a drug effect at a given expected sample size by allowing for dropping a less effective treatment arm. Other adaptive designs may allow for stopping a trial early if there is persuasive evidence that the drug is highly effective.

  4. Has the FDA approved any drugs using CIDs?

    Response: A CID was used in the Partnership for Research on Ebola Virus in Liberia II (PREVAIL II) trial to test potential Ebola therapies under a single protocol; this trial was stopped as the Ebola outbreak waned, and no drugs were approved using data from this trial. The few number of examples of CIDs being used in trials intended to support regulatory decision making is one of the motivations behind creating the pilot meeting program.

  5. When is FDA accepting proposals (meeting requests) for the CID pilot meeting program?

    Response: To apply for the CID pilot, sponsors should submit a meeting request to the CID Pilot Meeting Program. The FDA began accepting meeting requests with the publication of the Federal Register Notice on August 30, 2018. Meeting requests received by the end of each quarter (e.g., March 31, June 30, September 30, December 31) will be screened for eligibility and reviewed in the following quarter. Within 45 days after the quarter closing date, FDA will notify the sponsor whether their request will proceed to disclosure discussions or is denied. For those meeting requests that FDA grants, the initial meeting will occur in the following quarter and a follow-up meeting will occur in the subsequent quarter.

  6. At what point in the drug development process should an applicant submit a meeting request?

    Response: The pilot program is designed to facilitate meeting discussion for CIDs intended to provide substantial evidence of effectiveness to support regulatory approval. Sponsors need to consider the optimal time during their drug development program to submit a meeting request.

  7. Is it acceptable to submit a Type C meeting request in parallel with a CID Pilot Program meeting request for the same trial?

    Response: FDA understands that the purpose of submitting a Type C meeting request in parallel with a CID Pilot Program meeting request is likely based on concerns regarding timing of the development program and uncertainty about whether the CID pilot program meeting will be granted. FDA discourages parallel submissions, as it is an inefficient use of FDA resources. The CID Pilot Meeting Program selection committee, which includes staff from medical product and statistics review divisions, will assess meeting requests and make selections. Those requests not selected can subsequently choose to pursue a traditional path forward.

  8. If a sponsor has requested and been denied a Type C meeting, is the sponsor still eligible to submit a meeting request for the CID Pilot Meeting Program?

    Response: If the Type C meeting request to discuss a CID was denied, eligibility for the CID Pilot Meeting Program will depend on the rationale for the Type C meeting denial. Sponsors should include a justification for acceptance into the CID Pilot Meeting Program. Submission of an identical trial design and analysis that FDA has already provided feedback on during a Type C meeting will not be eligible for the CID Pilot Meeting Program.

  9. Should the Investigational New Drug (IND) application be planned concurrent with the CID pilot program initial meeting or after the follow-up CID meeting?

    Response: An already filed IND or pre-IND is required to be eligible to submit a CID Pilot meeting request.

  10. What information will sponsors need to disclose about their CID to be selected into the pilot program?

    Response: The specific information to be disclosed will depend on the content of each proposed CID, 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. Please refer to the CID website for additional details. To promote innovation in the area of CIDs, 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 trial designs for drugs that have not yet been approved by FDA.

  11. Can the amount of information disclosed to the public change as the CID trial in the CID Pilot Meeting Program progresses?

    Response: FDA and the sponsor will discuss and must agree on the information to be disclosed prior to FDA’s granting of the CID meeting request. The elements to be disclosed about a trial design accepted into the CID Pilot Meeting Program will be determined on a case-by-case basis to account for the innovative aspects of the proposed design. FDA expects that disclosure agreements will capture the iterative process.

  12. The FDA CID Pilot Meeting Program notice in the Federal Register states that for each sponsor whose meeting request is granted, FDA will conduct two meetings to discuss regulatory approaches for the specific CID. How will these meetings differ, and is there a recommended structure?

    Response: The FDA envisions an iterative process and will utilize the first meeting to focus on a discussion of the 1) rationale for the proposed design and analysis, 2) statistical analysis plan, and 3) simulations. Sufficient details should be provided in the initial meeting package to allow for a fruitful discussion. The outcome of the initial meeting will be to summarize important discussion points, areas of alignment, clarifications, and action items. The subsequent follow-up meeting will be conducted approximately 120 days after the initial meeting and will focus on new information resulting from incorporation of the initial feedback.

  13. When should meeting packages be submitted for the initial and follow-up CID pilot program meetings?

    Response: The initial meeting package should be submitted no later than 30 days prior to the initial meeting. The follow-up meeting package should be submitted no later than 90 days prior to the follow-up meeting.

  14. Who processes CID meeting requests and manages the meetings, if granted?

    Response: Meetings conducted as part of the CID Pilot Meeting Program will include statistical and clinical review staff from the relevant disciplines and therapeutic areas.

  15. For the CID pilot meetings, will the sponsor be meeting with the review division responsible for reviewing the final new drug application?

    Response: Meetings conducted as part of the CID Pilot Meeting Program will include statistical and clinical review staff from the relevant disciplines and therapeutic areas.

  16. How binding is the advice that FDA provides during the initial and follow-up CID meetings? Is it akin to a Special Protocol Assessment (SPA)?

    Response: As with other FDA/sponsor meetings, the outcome will be to summarize important discussion points, areas of alignment, clarifications, and action items. While FDA may agree generally during the meetings that a sponsor’s proposed design and methodology is appropriate for the specified context of use within a development program, that is not akin to the SPA provisions in the Federal Food, Drug, and Cosmetic Act. For FDA policy around SPAs, see Guidance for Industry, Special Protocol Assessment, available at https://www.fda.gov/downloads/Drugs/Guidances/UCM498793.pdf.

  17. In the study design process, it is typical for the sponsor to consider many design options as circumstances evolve over time and then to select a final design with the optimal operating characteristics and operational features. To what extent is FDA interested in knowing the history of the evolution of design options and associated simulation results in support of the choice of final design?

    Response: Sponsors should include a brief summary of the evolution of design options and associated simulations in the meeting package. Such a summary will serve to better inform FDA of options considered by the sponsor.

  18. Can a sponsor set up teleconferences with FDA to discuss the CID pilot meeting program?

    Response: FDA does not have the resources to accommodate requests for pre-proposal teleconferences. If a sponsor has specific questions pertaining to the CID Pilot Meeting Program, FDA encourages the sponsor to submit the questions via email to CID@fda.hhs.gov. FDA will provide written responses.

For submission assistance and inquiries about the CID Pilot Meeting Program, email: CID@fda.hhs.gov

Learn More about CID:

Adaptive Design Clinical Trials for Drugs and Biologics (PDF - 623KB)

Public Meeting: Promoting the Use of Complex Innovative Designs in Clinical Trials

FDA in Brief: FDA launches new pilot to advance innovative clinical trial designs as part of agency’s broader program to modernize drug development and promote innovation in drugs targeted to unmet needs

 

Page Last Updated: 02/06/2019
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