In a Federal Register announcement today, the FDA announced that it will continue a meeting program intended to support the development of drugs using complex or innovative clinical trial designs. While the program itself is supposed to support cutting-edge development efforts, the FDA’s announcement is largely recycled from existing sources of information.
Regulatory background and context
- Simple vs. complex trials: Many clinical trial designs are relatively simple and involve a head-to-head matchup between an investigational product and either a placebo or a standard of care (such as the best available treatment for that condition). However, other trial designs are considerably more involved. These trials are sometimes referred to as having “complex,” “innovative” or “novel” trial designs.
- The FDA refers to these trial designs collectively as “Complex Innovative Clinical Trial Designs,” or CID. Features of trials that qualify them as CIDs include adaptive designs, Bayesian statistical methods or what the FDA calls “other features requiring simulations to determine statistical properties.”
- However, there is no standard definition for CIDs. As explained by Greg Levin, Deputy Director of the FDA’s Division of Biometrics III, “there is no fixed definition of complex innovative trial design because what is considered innovative or novel can change over time.” Instead, the FDA typically defines CIDs in terms of what they are not. They are trial designs that have “rarely or never been used to date,” according to Levin. FDA’s guidance on CIDs also explains that the definition may include “the novel application of complex trial design features to a given indication even when those design features have been used in other indications.”
- A quick background on Adaptive Designs: According to the FDA, adaptive designs for clinical trials allow “for prospectively planned modifications to one or aspects of the design based on accumulating data from subjects in the trial.” For example, a trial might plan for an interim analysis to determine if a treatment arm is not working and shift those patients instead to a different treatment arm. FDA’s guidance document on adaptive designs for clinical trials identifies four principles for adaptive clinical trials including: Adequately controlling the chance of erroneous conclusions, reliably estimating treatment effects, prespecifying details of the design, and appropriately maintaining trial integrity.
- A quick background on Bayesian approaches: Bayesian statistical approaches allow a trial to learn from the evidence it generates while the research is still ongoing. The benefit of a Bayesian approach is that, when combined with high-quality information, it can allow a clinical trial to be completed more quickly and with fewer patients. To quote the FDA’s explanation from a 2010 guidance document on the subject: “In clinical trials, traditional (frequentist) statistical methods may use information from previous studies only at the design stage. Then, at the data analysis stage, the information from these studies is considered as a complement to, but not part of, the formal analysis. In contrast, the Bayesian approach uses Bayes’ Theorem to formally combine prior information with current information on a quantity of interest. The Bayesian idea is to consider the prior information and the trial results as part of a continual data stream, in which inferences are being updated each time new data become available.”
- Significant efforts have been made over the last decade to advance the use of CIDs. For example, in 2016 Congress passed the 21st Century Cures Act. Section 3021 of the law instructed the FDA to take action on “novel clinical trial designs” for drugs and biological product. Specifically, FDA was asked to hold a public meeting on CIDs and to issue a guidance document addressing the use of “complex adaptive and other novel trial design in the development and regulatory review and approval or licensure” of medical products. The goal of the guidance would be to define how the CID could satisfy the FDA’s evidentiary requirements and define the way in which companies could obtain feedback from the FDA on CIDs prior to the initiation of a trial.
- The FDA also committed to “enhancing capacity to review complex innovative designs” as part of the Prescription Drug User Fee Act (PDUFA) reauthorization process. That commitment, outlined in a public letter, explained that FDA will develop staff capacity and expertise, conduct a pilot program, hold a workshop, and release Manuals of Policies and Procedures and templates describing how the agency will evaluate CIDs that rely on computer simulations to determine operating characteristics.
- FDA has since taken action on many of these commitments, including the launch of a CID Pilot Meeting Program in August 2018 to assess the innovative features of participants’ trial designs. However, it has not yet released a Manual of Policies and Procedures Document (MaPP) related to CIDs, which was supposed to be released by the end of FY2020 (September 31, 2020).
- Guidance on the CID Pilot Meeting Program: In September 2019 the FDA released a draft guidance document describing how companies could “interact” with the agency to obtain feedback on CIDs for drugs and biological products. The guidance, finalized in December 2020, describes the processes through which companies may obtain early feedback on trials as well as feedback on trials that have already been initiated. As explained in the guidance, a key concern for the FDA is the possibility that a complex, novel design might result in “erroneous conclusions.”
- For industry, CID-related interactions with the FDA involve several meeting types that are already common to sponsors, including Types A (used to help a stalled product), B (used to discuss phases of development) and C (used for all other purposes). One key challenge for regulators is that compared to an ordinary meeting, the review of a CID proposal “often involves challenging evaluations of design operating characteristics,” which “may make it difficult for FDA to adequately review such designs under short timelines.”
- In cases where the review is especially complex, the FDA said that it might grant multiple Type C meetings “to provide more detailed feedback, especially when the investigational product could fulfill an unmet medical need or treat a serious or life-threatening condition.” To determine the appropriate meeting type, FDA asked sponsors requesting a review of their CID to indicate how the proposal “fits into the overall clinical development program and in what ways it may improve the efficiency of the study or the generalizability of its results compared to a simpler or conventional clinical trial design.”
- The guidance also described the types of information that should be included in a request to review a CID, including a discussion of the statistical analysis considerations, the choice of trial design, important aspects of the design and any prior information used. Sponsors are asked to include an explanation “of how the proposed design meets the goals of the development program better than relevant conventional designs.”
Regulatory Context on CID and PDUFA VII
- Changes to CID from PDUFA: In September 2022, Congress reauthorized the FDA’s Prescription Drug User Fee Program (PDUFA), including a series of negotiated commitments between the FDA and industry. These commitments are contained within the PDUFA VII “ Commitment Letter.” The letter notes that the FDA will “continue to advance modern approaches to enhance the efficiency of the drug development and review processes, such as complex adaptive, Bayesian, and other novel clinical trial designs and model-informed drug development (MIDD).”
- Specifically, the PDUFA VII Commitment Letter calls on the FDA to enhance “capacity to review Complex Innovative Designs” in several different ways. These include adding “staff capacity to enable processes to facilitate appropriate use of these types of methods,” engaging with external experts with extensive knowledge in CID “to support the review of complex innovative designs,” and to maintain the FDA’s Paired Meeting Program.
- As part of the Paired Meeting Program commitments, the FDA is supposed to select one or two “eligible and appropriate” CID proposals each quarter “for highly innovative trial designs for which analytically derived properties may not be feasible, and simulations are necessary to determine trial operating characteristics.”
- Per the letter, the Paired Meeting Program consists of a pair of meetings granted by the FDA – an initial meeting and a follow-up meeting – focused on an innovative trial design. For sponsors, the meetings are intended to offer increased interactions with FDA’s biostatisticians and allow for a “better understanding of the agency’s requirements for trial simulations involved in the use of the pilot study design and allow for iteration of design modifications, if needed.”
- For the FDA, the voluntary pilot program will allow the agency to “publicly discuss example designs as agreed upon with participating sponsors,” which it believes will help clarify the types of trial designs that might be acceptable to regulators and increase their use “in future development programs.” The publication of example designs may take place through guidance, at public workshops, conferences, or on FDA’s website. Sponsors will typically be notified in advance that their study will be the focus of public attention, the FDA said. The agency has already released three case studies on its website related to master protocols, lupus and diffuse large B-cell lymphoma.
FDA’s latest announcement: The program is getting renewed (but we already knew that)
- Under the Commitment Letter, one of the FDA’s specific commitments , no later than December 31, 2022, to “publish 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.”
- On October 19, 2022, the FDA published that Federal Register notice, for the most part repeating details that were originally provided either within the Commitment Letter or on the FDA’s website for the Complex Innovative Trial Design Meeting Program.
- For example, the notice talks about the eligibility criteria for the program, how CIDs will be selected for participation, the submission process, the content and format of the meeting request and the meeting information package, information that FDA may disclose, and how companies may obtain assistance with the program. The information in FDA’s Federal Register notice is taken nearly word-for-word from its existing website on the CID pilot program.
- That webpage has been online since at least May 2022, meaning the information in the Federal Register notice has been available for nearly half a year already.
- However, FDA’s program is now open for public comment as part of the Federal Register notice. Interested parties may submit comments through November 3, 2022.
- Despite this announcement coming on the heels of PDUFA VII, there’s still no word about one of FDA’s PDUFA VI commitments: To release a MAPP and/or SOPP on CIDs. AgencyIQ reviewed CDER and CBER’s databases for documents that might have fulfilled this requirement but were unable to find any such document. As noted above, this document was to have been released by the end of FY2020.
- Additional FDA obligations related to the PDUFA VII Commitment Letter are set to happen in the next few years. According to the letter, FDA is to convene “a public workshop to discuss aspects of complex adaptive, Bayesian, and other novel clinical trial designs” by April 1, 2024. Then, by September 30, 2025, the FDA is supposed to publish draft guidance on the Use of Bayesian Methodology in Clinical Trials of Drugs and Biologics, with a final guidance published within 18 months of the close of the public comment period (unless revisions to the draft are necessary).
To contact the author of this piece, please contact Alec Gaffney ( [email protected])
To contact the editor of this piece, please email Kari Oakes ( [email protected])