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 1 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 September 30, 2022.

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.

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.

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 examples of CIDs being used in trials intended to support regulatory decision making is one of the motivations behind creating the 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.

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.

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.

Response: There is no restriction on the number of submissions by company or compound.

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.

Response: The FDA will not publicly provide information on meeting requests/proposals that are not accepted into the CID Pilot Meeting Program.

Response: FDA will not disclose publicly that a sponsor has been accepted into the CID pilot meeting program. If the sponsor chooses to publicly disclose that it has been accepted into the CID pilot meeting program, FDA may reference the sponsor as a participant in discussions about the CID pilot meeting program. FDA will share the overall number of CID pilot meeting program requests made and the number of requests selected for inclusion in the pilot meeting program. FDA will also share study design elements permitted under the disclosure agreement with the sponsor. However, the timing and medium of study design element disclosure have not been determined.

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

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.

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.

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 two 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.

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.

The CID pilot program website states the briefing package for the follow-up meeting is due 90 days before the follow-up meeting; the follow-up meeting takes place approximately 120 days after the initial meeting and will focus on new information resulting from the incorporation of the initial feedback. This leaves 30 days between the initial meeting and the due date for the follow-up meeting package. Thirty days is not much time to generate substantial new information to inform the follow-up meeting.

Response: The FDA understands that the specified timelines may prove challenging; however, our expectation is that substantial simulations will have already been conducted prior to the first meeting thus lessening the amount of time needed to generate new information for the second meeting. The FDA will assess the timelines as the program matures and consider changes as needed to maximize the utility of the CID Pilot Meeting Program. Any changes will be disseminated via the CID website.

Response: The Office of Biostatistics (OB) (CDER or CBER, depending on the product) is the lead for the CID Pilot Meeting Program. OB manages the meeting process, including logistics, and takes the lead throughout the CID Pilot Meeting Program process.

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.

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.

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.

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.

Response: The simulation report should primarily focus on the selected design. However, an overview of the candidate designs including top-line results and the rationale for not moving the designs forward can allow for a more comprehensive understanding of the development strategy.

Response: If a sponsor believes that the feedback received at the first CID meeting is sufficient and does not want a second CID meeting before initiating a trial, the sponsor may choose to finalize the protocol, submit it to the IND, and begin enrolling patients.

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 [email protected]. FDA will provide written responses.