FDA’s Center for Drug Evaluation and Research (CDER) has a new initiative to advance clinical trials
- Quick background: The push for “innovation” in clinical trial design. The traditional model of clinical trials is well-established, and in particular the two-armed, double-blind placebo-controlled randomized control trial, run out of centralized clinical trial sites. However, advancements in both the types of products under development and the technologies, tools and methods employed have led to changes in trial designs. As the FDA’s Center for Drug Evaluation and Research (CDER) characterized it in a 2023 call for comments: “Evolving understanding of disease biology and molecular pharmacology, advancements in drug discovery, and growth in novel therapeutic platforms (i.e., beyond small molecule drugs) have the potential to transform the development of promising new therapies for patients with rare and common chronic diseases. These changes in the drug development landscape require novel clinical trial designs and innovative strategies for trial execution, an expanding range of drug development tools, and wider application in regulatory drug development of real-world data sources.”
- The conduct and infrastructure of clinical trials is heavily regulated, and updates to the methods, approaches, designs, or technologies employed can have regulatory implications. In particular, regulations in both the U.S. and E.U. set specific standards and expectations for discrete components of clinical trials (e.g., informed consent of participants, recordkeeping practices, delegation of tasks and research staff oversight) that might need to be adjusted when a trial is designed differently from the traditional model upon which the regulations were built. Further, regulatory confidence in the data produced by some more novel methods is still under construction, even as best practices are still evolving (e.g., how to interpret data from more advanced statistical methods or how to identify, define and adjust for potential biases introduced by these new methods).
Meet the CDER Center for Clinical Trial Innovation (C3TI)
- Announced on April 15, the initiative is meant to serve as “a central hub within CDER to support the implementation of innovative approaches to clinical trial design and conduct. C3TI’s mission is to promote existing and future CDER clinical trial innovation through enhanced communication and collaboration.”
- C3TI will be housed within CDER, not as a center of excellence (COE) like the Oncology Center of Excellence or the Digital Health Center of Excellence, but will instead serve as a main point of organization and contact “to engage stakeholders and assist with non-product-specific questions on innovative clinical trial approaches.” Further, it “will coordinate and act as a liaison to facilitate information sharing with external stakeholders, as appropriate and permitted by law, when they engage CDER on general clinical trial innovation matters” and will support internal FDA communications, and serve as a “centralized knowledge repository.”
- In short, it seems that C3TI will be more of a coordinating center than a COE, housing the demonstration projects (more on that below) and as an internal point of contact on clinical trial initiatives at CDER.
- The establishment of the new center comes amidst other clinical trials policy efforts from CDER. In particular, the drug center opened a docket for public comment “on the barriers and facilitators to incorporating successful or promising innovative clinical trial approaches in drug development programs” – and hosted a meeting on the subject with Duke-Margolis in March 2024. As AgencyIQ discussed at the time, speakers at the Duke-Margolis hosted meeting highlighted the ongoing barriers and challenges to adopting innovative approaches, and in particular the different paces at which methods and regulations develop. The C3TI announcement also captures some key themes from that meeting, highlighting discussions on patient-centric designs, global “regulatory collaboration” on trial policy advancements, and “infrastructure and organizational considerations.” [Read AgencyIQ’s full analysis of that meeting here.]
- KEVIN BUGIN will serve as C3TI Director. Bugin is also the deputy director of operations in the CDER Office of New Drugs (OND), and has been with the agency since 2008 with the exception of a short stint to serve as Chief of Staff for Operation Warp Speed during the pandemic. Bugin described C3TI’s role as serving as “a central hub within CDER to support the implementation of innovative approaches to clinical trial design and conduct. C3TI’s mission is to promote existing and future CDER clinical trial innovation through enhanced communication and collaboration.” There are three specific goals for C3TI, according to Bugin: To coordinate across CDER; to communicate externally about these efforts; and to run demonstration programs on innovative clinical trials (see below).
- Notably, Bugin was a key contributor to the March Duke-Margolis-hosted meeting on trial innovation, outlining his perspective on the current challenges with and barriers to adoption of more innovative approaches. “I think drug development is really—when you boil it down—all about managing uncertainty over the course of development, and we’re all doing what we can in our own spaces to manage that uncertainty,” he said at that meeting. “And I think we take comfort in keeping certain aspects of that process under control, with as little change as possible. So, adding new drug development tools is naturally, maybe not going to go over so well.” He summed it up by referencing a phrase attributed to former FDA director Janet Woodcock: advancement is held back by a “crisis of the timid.”
What, exactly, will C3TI be doing? Meet the demonstration projects
- In addition to its role in coordinating and communicating information about clinical trial innovation, C3TI will host several demonstration projects. The projects will be open to participation by relevant research programs. Interested sponsors will need to submit proposals to the projects, and “if a proposal is accepted, the information provided in the proposal submission will be used as a basis for guiding subsequent steps and potential discussions.” The proposals should be submitted with the “relevant application (i.e., pre-[Investigational New Drug] IND, IND)” and specify which of the demonstration programs, outlined below, they seek to participate in.
- C3TI is starting with three demonstration projects: Bayesian statistics, pragmatic trials and selective safety data collection. Per the announcement, “C3TI selected three initial demonstration project areas, which were prioritized given their alignment with the broader objectives of C3TI, their expected readiness of implementation and scalability, and the opportunity to improve lessons learned. C3TI intends to launch additional demonstration project areas as the C3TI Demonstration Program evolves.”
- First up: the Bayesian Supplemental Analysis (BSA) Demonstration Project. The ICH E9 Guideline on statistical approaches for clinical trials (1998) defines “Bayesian Approaches” as an approach to data analysis that “provides a posterior probability distribution for some parameter (e.g. treatment effect), derived from the observed data and a prior probability distribution for the parameter. The posterior distribution is then used as the basis for statistical inference.” In other words, Bayesian statistical approaches allow for prior data to be “borrowed” for use in current analyses.
- Interest in using Bayesian methods has been ramping up in recent years. Even as the FDA addressed a section on Bayesian adaptive designs in its 2019 final guidance on adaptive trial designs, questions about how to leverage these methods and how regulators will consider these approaches remain – including, for example, what exactly counts as a Bayesian design. As AgencyIQ recently noted, the use of Bayesian methods has been a key focus of the FDA’s Complex Innovative Design (CID) Paired Meeting program. Under C3TI’s Bayesian methods demonstration project, “C3TI will partner with sponsors to integrate Bayesian analysis in parallel to frequentist analysis during their trial, providing an opportunity for both CDER and sponsors to learn new methods without impacting review criteria.” This is separate from the CID program, as it will focus instead on “simple non-adaptive trial designs that do not incorporate data from previous trials” – and, under the project, “the Bayesian analyses would be supplementary descriptive analyses that would not change the primary analysis methods or decision criteria (e.g., frequentist null hypothesis testing at 1-sided 0.025) for the trial” during the application’s review. In effect, the new demonstration project will focus more on using Bayesian methods as a kind of voluntary supplement to their regular development program, to help advance methods and understanding.
- Participation criteria: “For consideration and selection to participate within this demonstration project, the trial must be a phase 3 efficacy, safety, or non-inferiority standalone trial (i.e., not incorporating data from previous trials beyond informing the non-inferiority margin) with a simple non-adaptive design. The Bayesian analysis should supplement the primary analysis and may be used to evaluate the primary endpoint in the overall study population and/or in relevant subgroups (i.e., for subgroup analysis). Participating sponsors would support the conduct of the supplementary descriptive Bayesian analyses.”
- Second: The Selective Safety Data Collection (SSDC) Demonstration Project. Per C3TI, this project “offers an innovative approach to facilitate the conduct of large-scale efficacy and safety trials through the purposeful reduction in the collection of certain types of data for drugs or biologics with a well-characterized safety profile.” The goal of the project is to “strategically streamline data collection,” and will focus on establishing best practices in such streamlined data collection, “creating benefits such as reducing the burden of collecting unnecessary safety data, eliminating unnecessary expense and allocating resources to the relevant objectives of a study, and facilitating trial conduct to answer important scientific questions on long-term efficacy and safety of drugs and biologics.”
- The participants in this project “would receive additional CDER engagement support for trial design and implementation aspects, which includes leaders across several CDER offices (e.g., Office of New Drugs, Office of Medical Policy, Office of Translational Sciences),” as well as “access to additional coordination support with CDER subject matter experts and an inspection process that is fit-for-purpose for the innovative design (i.e., focused on a quality by design approach).” Notably, quality by design (QbD) approaches are outlined under the ICH E6(R3) guideline, which is currently undergoing a revision. This area was a key focus of a January 2024 meeting hosted by FDA and Duke-Margolis, at which regulators from FDA and EMA described the current regulatory challenges to implementing such approaches, including documentation and organizational challenges.
- Participation criteria: To participate, sponsors should have an active pre-IND or IND for the specific product for which they are seeking participation, and the trial “must be a late-stage pre- or post-marketing trial for a drug product where the safety profile, with respect to commonly occurring adverse events, is well understood and documented.” These could include trials seeking new indications or label expansions (new populations or additional endpoints in the same population), studies on specific safety concerns or “trial[s] designed to provide additional evidence of efficacy when current data support a well-characterized safety profile.” If selected, sponsors “will be expected to share select details of their clinical trials and the implementation of clinical trial innovation as they progress.”
- And finally, the Streamlined Trials Embedded in clinical Practice (STEP) Demonstration Project. This project will focus on research programs where certain trial activities are conducted at the point of care (POC), which are also called “pragmatic” trials or pragmatic elements of a trial. C3TI “will partner with sponsors on trials that include limited procedures outside of routine clinical care, decentralization of procedures that can be done outside of designated research sites, the use of real-world data to obtain outcomes, and, where appropriate, the integration into point-of-care practice” for this project. STEP will focus on “pragmatic/point-of-care trials” and will, through the demonstration project, “provide an opportunity to address and resolve issues (e.g., statistical analyses, incorporation of real-world data and evidence, trial endpoint selection, inspectional approaches) around trial design and conduct.” The learnings of the projects will “inform updates to relevant CDER guidance,” says C3TI.
- The STEP project highlights “benefits” of participation similar to those for the SSDC program, specifically “additional CDER engagement support for trial design and implementation aspects, which includes leaders across several CDER offices (e.g., Office of Medical Policy, Office of New Drugs, Office of Translational Sciences). Engagement may include access to additional coordination support with CDER subject matter experts and an inspection process that is fit-for-purpose for the innovative design (i.e., focused on a quality by design approach).”
- Participation criteria: Interested sponsors should have a pre-IND or IND for the relevant product, and the trial should either be in later pre-market development with a “reasonably well-defined” safety profile or a post-approval trial. The relevant trials should be those that incorporate “pragmatic design elements that are reflective of routine clinical practice to improve trial efficiency and enhance patient centricity while maintaining patient safety and data integrity,” with the agency specifically citing “broad eligibility criteria, limited visits and procedures outside of what might occur in routine care, including incorporation of decentralized procedures, and limited safety data collection consistent with ICH E19” as potential elements. Those “with narrow entry criteria, complex procedures, complex drug administration, or challenging endpoint collection will likely NOT be appropriate.” Once again, the agency notes that learnings from the demonstration program will be shared, so participating sponsors will need to agree to public disclosure.
Analysis and what’s next
- It doesn’t seem that C3TI will be involved in reviews more broadly – for now. Unlike the Oncology Center of Excellence (OCE) or the Digital Health Center of Excellence (DHCoE) it doesn’t seem that C3TI will be called in to consult on individual product applications outside of the scope of the specific projects that it will oversee. It more seems that the C3TI will be a project lead on clinical trial innovation demonstration projects, providing support to the sponsors directly participating, and then will be responsible for communicating those learnings out to the FDA and other stakeholders more broadly. Going forward, it’s not entirely clear if the C3TI team will be directly involved in the development of any new guidance that might come from these demonstration projects – for example, new or updated guidance on decentralized trials or the use of real-world data – or how the demonstration project learnings compiled and communicated by this project team will be relied on by the FDA’s policy staff.
- C3TI does “aspire” to help train FDA staff on novel development programs. Per Bugin, who leads C3TI, “CDER staff noted they would benefit from greater exposure to or experience with the use of innovations in their regular review work.” Therefore, C3TI will aspire to create more opportunities for staff to participate in development programs planning to implement novel trial approaches to gain experience with a given innovation” in the demonstration projects, and “will also explore how to create new opportunities for CDER staff to receive training and exposure to new clinical trial methods, technologies, and tools.” The demonstration projects seem to be both a way to develop best practices, but also expose CDER staff and its Offices to the issues that will be raised during reviews of submissions incorporating these elements. This could help build a foundation for regulatory consistency as these applications start to come into the FDA, although this depends on the outcomes of the projects.
- One key update compared to previous work: Moving from pilots to programs. At the March 2024 workshop on clinical trial innovation, CDER chief PATRIZIA CAVAZZONI made the comment that “I think it’s time to stop the pilots,” when it comes to FDA’s strategies for encouraging sponsors to adopt innovative approaches more readily. The work from C3TI seem to be more hand-over-hand operational help in these specific subject areas, for participating sponsors, than proof-in-concept pilot programs. At that same meeting, AMY BERTHA (Bayer, representing trade association BIO), suggested that FDA could work to develop best practices and lessons learned across the agency, and “When the time is right to transition from a pilot to routine regulatory review, FDA can help ensure that the pilot mindset is successfully integrated into day-to-day review practices,” calling for cross-FDA consistency. While the goals of the C3TI projects seem lofty, it does appear that this is exactly what CDER is trying to do – build out its own practices and make sure there is a coordinated hub to warehouse information and provide answers to these questions for reviewers going forward.
- Will CDER’s latest initiative revitalize efforts on complex and innovative trial design? One challenging aspect in discussing the relative success of CDER’s previous and ongoing efforts related to “innovative” trial design is that the term itself is imprecise. Technically, though several of CDER’s existing programs have different aims (e.g., to further rare disease drug development, encourage the use of mechanistic modeling approaches, support the incorporation of Bayesian methodologies, etc.) many overlap with the goals of this latest initiative. While it’s challenging to compare their success relative to one another, one of the Center’s more recent efforts which very closely aligns with the new Center was its CID Paired Meeting Program. Despite FDA’s steady increase in resources dedicated to the program, industry’s interest seemed to stall; no new proposals have been accepted by the FDA since 2021, and those which had been accepted were narrow in scope. The C3TI Bayesian Supplemental Analysis demonstration project page specifically calls out the differences between this new project and the CID program, noting that the new demonstration project is specifically for “simple non-adaptive trials designs” that “would not change the primary analysis method or decision criteria” – in effect, taking a step back to pressure test methods alongside the frequentist analysis as a learning experience.
Featuring previous research by Rachel Coe.
To contact the author of this item, please email Laura DiAngelo ( [email protected]).
To contact the editor of this item, please email Alexander Gaffney ( [email protected])
Key Documents and Dates
- CDER Launches a Center for Clinical Trial Innovation
- Center for Drug Evaluation and Research Center for Clinical Trial Innovation
- C3TI Demonstration Program Proposal Submission
- About CDER Center for Clinical Trial Innovation (C3TI)
- AgencyIQ Analysis: Stakeholders identify opportunities, challenges in innovative clinical trial design