Aiming to expedite drug development, enhance the body of clinical evidence supporting new and existing therapies, and improve participation and diversity in clinical trial populations, the US Food and Drug Administration (FDA) recently issued three guidance documents that impacted the clinical trial landscape and established a new hub for clinical trial innovation.
FDA’s recently established new hub within the Center for Drug Evaluation and Research (CDER)—the CDER Center for Clinical Trial Innovation (C3TI)—is intended to serve as nexus for internal and external experts to collaborate on designing and conducting innovative clinical drug trials efficiently and effectively. C3TI will also oversee a demonstration program that will provide sponsors of innovative clinical trials more opportunities to work with CDER with an initial focus on point-of-care or pragmatic trials, Bayesian analyses, and trials using selective safety data collection. (The C3TI Demonstration Program is only accepting up to nine proposals, on a rolling basis, within a 12-month period, so sponsors are encouraged to submit their proposals as soon as possible.)
These new guidance documents and FDA’s centralized clinical trial hub reflect FDA’s continued push for innovation in trial designs, coupled with efforts to ensure the generation of useful and generalizable data from these trials. These include a final guidance on conducting decentralized clinical trials (DCTs), a draft guidance on integrating randomized controlled trials (RCTs) into routine clinical practice, and a draft guidance on multiregional clinical trials in oncology.
Decentralized Clinical Trials
In line with our previous discussion of the draft guidance, FDA’s final guidance on Conducting Clinical Trials with Decentralized Elements provides recommendations on the use of decentralized components in clinical trials, signaling its acceptance and support of a shift in how trials are conducted by allowing study-related activities to take place at least in part in non-traditional settings, such as a patient’s home, local pharmacies, and healthcare provider offices.
This includes shifts in trial design, conduct, and oversight elements such as use of decentralized health technologies and software, roles and responsibilities for sponsors and investigators, and using local healthcare providers, as well as remote clinical trial visits.
FDA notes that the use of DCTs may improve, among other things, clinical trial participation and generalizability of resulting data. While striving to enable DCTs, FDA emphasized that the overarching regulatory requirements applicable to DCTs remain the same as for more traditional trial designs.
The final DCT guidance addresses key issues raised by clinical experts and industry in comments, including clarifying inspection requirements and agency expectations on data variability. The final guidance emphasizes that the agency expects sponsors to design trials to consider and minimize the inherent variability that may be introduced from having trial-related activities conducted by healthcare providers, trial personnel, and participants performing tasks at home in DCT design. Further, FDA notes that certain statistical approaches may be challenging to implement in the context of DCTs and, for example, encourages sponsors to consult with the agency when implementing a non-inferiority trial as a DCT.
The final guidance also outlines FDA’s expectations for informed consent and institutional review board (IRB) oversight, when local healthcare practitioners may (or may not) qualify as sub-investigators, packaging and shipping of investigational products, and patient safety processes and procedures.
Integrating Randomized Controlled Trials Into Clinical Practice
FDA’s draft guidance, Integrating Randomized Controlled Trials for Drugs and Biological Products Into Routine Clinical Practice, is part of a series of guidance under the agency’s Real-World Evidence (RWE) Program that is intended to streamline RCTs and integrate research into real-world clinical practice. The draft guidance offers recommendations on “point-of-care trials” or “large simple trials,” which, like DCTs, “aim to bring trial-related activities to patients’ homes or other convenient locations,” with the hope of leveraging existing healthcare infrastructures to reduce RCT start-up times, expanding trial populations, and improving data collection.
The guidance applies most naturally to studies of already-approved FDA drugs, but (in certain instances) may also be applied to studies of unapproved products. As with the DCT guidance described above, while this guidance is intended to reduce barriers to uptake of these innovative trial designs, FDA notes that the existing and underlying regulatory framework applicable to clinical trial design and conduct remains unchanged and applies to the trials described in the guidance.
The draft guidance outlines responsibilities for sponsors, clinical investigators, and local healthcare providers involved in integrating RCTs into clinical practice and promotes the use of a Quality by Design (QbD) process. FDA defines QbD as “incorporating quality into the design of clinical trials by identifying critical-to-quality factors (i.e., those that are likely to have a meaningful impact on participant’s rights, safety and well-being and the reliability of the results), while eliminating procedures and processes that do not contribute to these primary goals.” Per FDA, using a QbD approval approach will ensure data integrity and participant safety, while simplifying trial processes and allowing the design of trials suitable for integration into clinical practice.
The draft guidance provides guidance on designing these trials with respect to the intended trial population, informed consent, using suitable investigational drugs, randomization and blinding, the management of comorbidities and concomitant medications, endpoints, adverse events, data privacy and security, and inspections.
Multiregional Clinical Trials in Oncology
FDA’s draft guidance, Considerations for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs, provides recommendations for conducting MCTs in support of applications for drugs intended to treat cancer. The draft guidance defines an MCT as “a trial that is conducted in more than one region under a single protocol.” While this draft guidance is specific to oncology trials, its underlying concepts aimed at ensuring the applicability of trial data to the intended US treatment population are generally applicable.
The draft guidance notes that a “decreasing proportion” of US participants in oncology MCTs in recent years poses challenges in assessing the consistency of treatment effects among US participants. Non-US participants in multiregional clinical trials (MCTs) may exhibit significantly different demographic or clinical characteristics from those in the United States, potentially leading to data that “may not be appropriate to support and FDA regulatory decision.”
In working to ensure the applicability of clinical trial data to the US population, the draft guidance stresses that a sponsor’s multiregional clinical development program should account for various patient-specific factors, including disease risk related to exposure and genetic background, disease characteristics such as subtype prevalence and molecular drivers of oncogenesis, and socio-cultural factors such as dietary habits and cultural beliefs surrounding alternative cancer therapies. Similarly, healthcare system considerations, such as access to healthcare facilities screenings, treatments, and the affordability and availability of these resources for the patient population should also be factored into the design.
Moreover, adequate regional representation should reflect the incidence or prevalence of the specific cancer type in the United States. FDA advises using a “strategic allocation approach” that considers cancer incidence and prevalence across the US and major geographical regions, rather than focusing on individual countries. FDA recommends that clinical trial sponsors consult with FDA early in the planning stage of single or multi MCTs in oncology.
Key Takeaways
Each of the new guidance documents discussed in this article aligns with FDA’s ongoing effort to enhance clinical trial innovation, participation, and diversity. FDA continues to stress the importance of enrolling a participant population that is reflective of broader US population to ensure the data is generalizable to real-world patient populations. The recommendations in these newly issued guidance documents echo FDA’s prior advocacy for innovative trial designs as a means to achieve greater diversity in clinical trials.
FDA’s receptivity to new technologies, decentralization, and the outsourcing of clinical trial functions does not indicate that the agency intends to reduce the need for oversight over these innovations. Sponsors will need to continue to meet FDA’s existing regulatory requirements in these new and evolving settings, with sponsors, contract research organizations, and third parties ensuring ongoing compliance with FDA’s good clinical practice requirements.
FDA encourages early engagement during the study design phase. Stakeholders should provide a comprehensive outline of their clinical design from the outset, setting forth aspects such as access to relevant datasets, data consistency, recordkeeping, and trial variability.
