The Food and Drug Administration (FDA) has recently issued a series of guidance documents aimed at modernizing clinical trials, enhancing participant diversity, and integrating real-world evidence to improve drug development and regulatory decision-making. These guidances address decentralized clinical trials, diversity action plans, multiregional clinical trials in oncology, and the integration of randomized controlled trials into routine clinical practice.
Decentralized Clinical Trials (DCTs)
The FDA finalized its guidance on conducting clinical trials with decentralized elements, embracing a shift towards conducting study-related activities at locations other than traditional clinical sites. This includes the patient’s home, local healthcare providers' offices, or even local pharmacies. The aim is to enhance convenience for study participants, facilitate research on diseases affecting populations with limited mobility, and reduce the burden on caregivers.
Key recommendations in the guidance cover various aspects of DCT implementation:
- DCT Design, Conduct, and Oversight: Recommendations for designing, conducting, and overseeing DCTs to ensure data integrity and participant safety.
- Remote Clinical Trial Visits: Guidance on conducting remote clinical trial visits and activities, including the use of local healthcare providers (HCPs).
- Digital Health Technologies: Recommendations for using digital health technologies in DCTs to acquire data remotely.
- Roles of Sponsors and Investigators: Clarification of the roles and responsibilities of sponsors and investigators in DCTs.
- Informed Consent and IRB Oversight: Guidance on informed consent processes and institutional review board (IRB) oversight of DCTs.
- Investigational Products: Considerations for the types of investigational products suitable for study in DCTs.
- Packaging and Shipping: Recommendations for packaging and shipping investigational products in DCTs.
- Participant Safety: Processes and procedures to ensure participant safety in DCTs.
- Software Use: Guidance on the use of software in DCTs.
Diversity Action Plans (DAPs)
The FDA is placing increased emphasis on the diversity of study participants and plans to soon require “Diversity Action Plans” (DAPs) from sponsors. These plans aim to improve the enrollment of participants from underrepresented populations in clinical studies. The guidance specifies that DAPs should include enrollment goals disaggregated by race, ethnicity, sex, and age, reflecting the prevalence or incidence of the disease in the U.S. population.
The DAP should include:
- Enrollment Goals: Goals disaggregated by race, ethnicity, sex, and age group, reflecting the estimated prevalence or incidence of the disease in the US population.
- Rationale for Enrollment Goals: Background information on the disease or condition, including a detailed explanation if the goals deviate from the estimated disease prevalence or incidence in the intended population.
- Measures to Meet Enrollment Goals: Strategies to achieve these goals, such as community engagement, cultural competency training for investigators, improved participant communication materials, reducing participant burden, and improving access to study sites.
Multiregional Clinical Trials (MRCTs) in Oncology
The FDA is encouraging oncology sponsors to conduct multiregional clinical trials (MRCTs) to support marketing applications for new drugs and biologics. However, the agency emphasizes that the results of these trials must be applicable to the intended use population and standard cancer care practices in the U.S. The FDA expressed concern that a “decreasing proportion of US participants” in cancer drug trials limits the generalizability of data to the U.S. population.
Key recommendations for oncology MRCTs include:
- Strategic Allocation Approach: Utilizing a strategic allocation approach based on cancer incidence or prevalence in the U.S., with regions defined by major geographical regions rather than single countries or regions.
- Consideration of Specific Factors: Crafting a multiregional clinical development program (CDP) that considers patient-related factors (e.g., exposure to disease risk factors and genetic background), disease-related factors (e.g., disease subtype prevalence and molecular drivers of oncogenesis), socio-cultural factors (e.g., diets and cultural beliefs), and health care system factors (e.g., access to health care facilities and treatments).
Integrating Randomized Controlled Trials (RCTs) into Routine Clinical Practice
The FDA issued draft guidance on integrating randomized controlled trials (RCTs) for drug and biological products into routine clinical practice. This guidance is part of the FDA’s Real-World Evidence (RWE) Program and provides recommendations on “point of care trials” or “large similar trials,” which aim to bring trial-related activities to more convenient locations for patients.
The draft guidance outlines responsibilities for sponsors, clinical investigators, and local healthcare providers (HCPs). Sponsors are encouraged to engage healthcare institutions in clinical trials integrated into clinical practice, which can facilitate participant enrollment by improving convenience and accessibility. Clinical investigators are responsible for ensuring that a trial is conducted according to the signed investigator statement, the investigational plan, and applicable regulations. Local HCPs should perform tasks that align with their qualifications in routine clinical practice.
The RCT integration draft guidance emphasizes the importance of employing a “quality by design” (QbD) approach in the design of point of care and large-scale clinical trials. This involves identifying critical-to-quality factors and eliminating procedures and processes that do not contribute to these primary goals.
Impact and Next Steps
These new guidances reflect the FDA's commitment to modernizing clinical trials, enhancing diversity, and integrating real-world evidence to improve drug development and regulatory decision-making. By implementing these recommendations, sponsors can design more efficient and inclusive clinical trials that generate data applicable to diverse populations and real-world healthcare settings.
The FDA has invited comments on the DAP guidance through September 26, the multiregional trials guidance through November 18, and the trial integration guidance through December 17, 2024. Stakeholders are encouraged to provide feedback to help shape the final versions of these important guidance documents.
