FDA Issues Guidance to Modernize and Diversify Clinical Trials

The U.S. Food and Drug Administration (FDA) has recently issued a series of guidance documents aimed at modernizing clinical trial designs, enhancing clinical evidence, and improving diversity in clinical trial populations. These guidances address decentralized clinical trials (DCTs), integrating randomized controlled trials (RCTs) into routine clinical practice, and multiregional clinical trials (MRCTs) in oncology.

Decentralized Clinical Trials (DCTs)

On September 18, 2024, the FDA issued final guidance on conducting clinical trials with decentralized elements. DCTs allow some or all trial-related activities to occur at locations other than traditional clinical trial sites, such as participants' homes or local healthcare facilities. This approach leverages digital health technologies (DHTs) for remote data collection and telehealth for follow-up assessments.

The FDA emphasizes that DCTs must meet the same regulatory requirements as traditional trials, with additional considerations for decentralized activities. The guidance addresses key aspects such as telehealth visits, the use of local healthcare providers (HCPs), safety monitoring, and data management. Investigators can delegate certain trial activities to local HCPs if those activities are within their clinical practice qualifications and do not require detailed study knowledge. However, obtaining informed consent remotely should only be performed by individuals with detailed knowledge of the protocol.

Sponsors are responsible for ensuring the qualifications of contracted services and maintaining a data management plan to track data flow. The FDA recommends a risk-based monitoring plan to ensure data integrity and compliance with the protocol.

Integrating Randomized Controlled Trials into Routine Clinical Practice

The FDA also issued draft guidance on integrating RCTs into routine clinical practice, streamlining protocols, and focusing on essential data collection. These "point-of-care trials" or "large simple trials" aim to improve convenience and accessibility for participants while leveraging existing healthcare infrastructures.

This approach is suitable for studies of approved drugs or unapproved drugs with well-characterized safety profiles. Sponsors must execute agreements with healthcare institutions and ensure that local HCPs are appropriately credentialed and qualified. The guidance promotes a Quality by Design (QbD) approach, incorporating quality into the design of clinical trials by identifying critical-to-quality factors and mitigating potential risks.

Multiregional Clinical Trials in Oncology

In a move to ensure the applicability of clinical trial data to the U.S. population, the FDA issued draft guidance on conducting MRCTs in oncology. MRCTs are clinical trials conducted in multiple regions under a single protocol. The FDA is concerned about the decreasing proportion of U.S. participants in oncology MRCTs, which may limit the generalizability of the results to U.S. patients.

The guidance recommends that sponsors carefully consider patient-related, disease-related, healthcare system, and socio-cultural factors when planning an MRCT. It emphasizes the importance of enrolling a sufficient number of U.S. participants that reflect the diversity of the U.S. population. Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence, stated, “It is important that data from multi-regional clinical trials are applicable to patients in the United States who may use the drug and our current standards of oncological care.”

Sponsors should also ensure that the control arm reflects the U.S. standard of care and develop an analysis plan that includes an estimation of regional treatment effects. Early consultation with the FDA is recommended to maximize efficiency and address potential issues.

Impact and Future Directions

These guidance documents reflect the FDA's commitment to modernizing clinical trials, promoting flexibility in trial design, and increasing clinical trial diversity. By embracing decentralized elements, integrating trials into routine clinical practice, and ensuring the representativeness of study populations, the FDA aims to enhance the efficiency and generalizability of clinical research. These changes are expected to facilitate drug development, improve patient access to clinical trials, and generate more robust evidence for regulatory decision-making.