his is the first in a series of articles introducing perspectives from the public and private sectors on identifying and addressing challenges in adopting innovative trial approaches into clinical evidence generation and FDA’s medical product approval processes.

Clinical trial design complexity has risen dramatically over the past several decades. To combat these pressures, approaches to trial design have evolved to include development of adaptive study designs, recognized standards for real-world evidence acquisition, and streamlined methodologies for safety data collection. One notable barrier to broad adoption of novel designs is the ability and willingness of regulatory bodies to be open to these innovations and to provide timely guidance on the best ways for these innovations to contribute to the therapeutic product development and approval processes.

On April 15, 2024, the FDA’s Center for Drug Evaluation and Research (CDER) launched the CDER Center for Clinical Trial Innovation (C3TI), paving the way for subsequent regulatory innovation initiatives. C3TI has several objectives: 1) accelerating development of safe and effective drugs, 2) improving trial efficiency and effectiveness, 3) assisting stakeholders in implementing trial innovations, 4) enhancing trial data quality, and 5) increasing participation diversity in trials. C3TI’s primary “novel” contribution is establishing several demonstration projects that will allow FDA staff to collaborate with industry experts to test, implement, and scale the integration of specified innovative approaches. The first three demonstration projects are “Bayesian Supplementary Analysis,” “Selective Safety Data Collection,” and “Streamlined Trials Embedded in Practice.”

Is C3TI’s approach unique? FDA centers already interact with relevant stakeholders on specific problems through working groups/partnerships, and organizations submitting drug applications already work across divisions where relevant. C3TI formalizes what is happening behind the scenes (see “FDA’s History of Partnerships” below). Therefore, these demonstration projects will be most effective if they influence how the FDA regulates product review processes. Perhaps the greatest utility of C3TI is for FDA introspection on how it approaches partnerships with external stakeholders—that is to say, beyond the perspective of solely a regulatory steward to that of a learner in a changing industry landscape in the face of rapid scientific evolution.

CDER and CBER (the Center for Biologics Evaluation and Research) have also begun a close collaboration in rare diseases, culminating in the development of the FDA Rare Diseases Innovation Hub. Rare diseases were represented in more than half of all approved FDA submissions in 2023. Since the program’s announcement, numerous public sessions have been held to discuss how the role of this new structure, similar to C3TI, seeks to advance patient outcomes by enhancing innovation. Most recently, in December 2024, CDER introduced the Center for Real-World Evidence Innovation (CCRI), which intends to advance integration of real-world data and evidence into regulatory decision-making across the center, further highlighting the FDA’s changing structure.

FDA’s History of Partnerships

Over the years, FDA has evolved to show deep flexibility while engaging the broader market in its regulatory approach, seeing the organizations and stakeholders it regulates as partners rather than adversaries. Its centers have participated in numerous Public-Private Partnerships (PPP) or consortia, multistakeholder groups convening at least one nonprofit (e.g., academia, government, or foundation) and one for-profit organization (e.g., pharmaceutical, biotechnology, or medical device company). One notable example is the Reagan-Udall Foundation for the FDA, a private nonprofit organization born out of congressional legislation to equip FDA staff with high-quality regulatory science and technology to perform its trademark “safe and effective” mission. Other such PPPs are the large initiatives managed by the Foundation for the NIH (FNIH), such as the Accelerating Medicines Partnership and the Biomarkers Consortium, which convene the NIH, FDA, multiple biopharmaceutical and life science companies, nonprofit and other organizations to reimagine development of diagnostics and treatments.

More recently, the FDA has turned its focus to include patients and patient advocates in discussions and now convenes a Patient Engagement Advisory Committee. In collaboration with the Clinical Trial Transformation Initiative aimed at improving trial efficiency and quality, the FDA has played an important role in standing up the Patient Engagement Collaborative to include the patient perspective in the drug regulatory process.

As the number and complexity of these partnerships multiply, expanding into even more niche areas like drug supply chain security and biomarkers, the need to build on existing collaborations grows.

Evolving Innovation through Ongoing Partnerships

With this extensive history of collaboration, why develop C3TI, the Rare Disease Innovation Hub, and CCRI now?

First, increasing trial design complexity requires higher quantities of data from multiple sources. In the case of rare diseases, clinical development has shifted further to solve the unmet medical needs through narrower patient population targeted drug development, requiring higher statistical power to reach significant conclusions. At the same time, multiple drugs for common diseases have been approved in competitive markets like oncology and rheumatology. Furthermore, focus has shifted to study narrower subpopulations of patients for common chronic diseases. Adaptive trial designs through Bayesian statistical approaches are increasingly prevalent across various therapeutic areas to study more complex questions. Real-world evidence (RWE) is now being incorporated into pragmatic trial and hybrid design. C3TI’s announced pilot programs capture several of these ideas (e.g., RWE and Bayesian statistical approaches).

Second, it is important to consider our evolving understanding of the human body and scientific principles. Society’s understanding of genetics, genomics, immunology, and molecular drivers—the molecular underpinnings of diseases and disease subtypes—is rapidly expanding. New platforms now exist to target previously undruggable targets: siRNA, ASOs, bispecific antibodies, ADCs, and cellular or gene therapies. And over the last few years, AI applications to life sciences and in silico modeling in drug development have become commonplace. Such approaches allow us to “connect the dots”—not just looking for solutions in one disease therapeutic area at a time but looking to solve problems at the system level. At the translational level, smart technologies have eased collection of real-world data and will be an area of focus for CCRI as its functions are developed.

Third, patient perspectives need to be increasingly considered with patient advocacy organizations playing larger roles creating patient registries, designing collaborative clinical trial protocols, and collecting data directly from patients, not only from clinical sites. Currently, there is a push toward moving clinical research forward through integration with patient care which may be addressed through C3TI’s Streamlined Trials Embedded in Clinical Practice Demonstration Program in tandem with CCRI’s efforts to include RWE in trial design.

Fundamentally, what these new FDA structures can do best is highlight the need for additional case studies and input on the demonstration projects from the entire community of stakeholders—to ensure that regulators are focused on what is important to the relevant stakeholder groups and ultimately to public health. Simultaneously, C3TI, the Rare Disease Innovation Hub, and CCRI should develop regulatory policies contingent on the science, first by clarifying their own internal structures, which would enable relevant stakeholders to understand how to interact with these entities while getting the benefit of cross-team and cross-divisional collaborations within FDA. For instance, a stakeholder developing a therapeutic for a rare disease using Bayesian statistical approaches based on RWE may require assistance from all three centers. Instructions around how this stakeholder would interact with each center, as well as how these engagements will affect the product’s overall ability to be approved, should be developed to assist such stakeholders.

Carving a Path Forward

In the upcoming series of articles, several authors will contribute perspectives from the public (regulatory) and private (industry) perspectives to unpack how the current climate can motivate regulatory innovation by and with the FDA. While regulatory bodies are sometimes superficially or unfairly regarded as a barrier to innovation, they are also a gateway for how new innovations can safely and effectively plug into the existing ecosystem of medical products. External stakeholder engagement with C3TI, the Rare Disease Innovation Hub, and CCRI will be key because it will leverage where the science is headed while simultaneously driving regulatory processes to keep pace with the evolution of clinical trials. Given the nascent stages of development for these centers, relevant stakeholders have an opportunity to guide their continued developmental priorities through discussion in forums that converge regulatory and industry stakeholders (e.g., DIA Annual and Specialty Meetings) as well as through participation in relevant center activities (e.g., participation in C3TI demonstration programs). FDA can also lead the way in global regulatory harmonization initiatives while adapting its regulatory process to match the increasing speed of medical product innovation.

The next article in this series will continue this discussion from the regulatory perspective; look for it in an upcoming issue of Global Forum.

To learn more about these topics, plan to attend DIA’s Biostatistics and Clinical Innovation Industry and Regulator Forum.