FDA Draft Guidance on Multiregional Clinical Development Programs for Oncology

In September 2024, the FDA published the draft guidance titled, Considerations for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs. This draft guidance is intended to address and forestall potential problems that may arise when data from one or more Multiregional Clinical Trials (MRTCs) are used to support oncology drug development in the United States (U.S.), especially regarding New Drug Applications (NDA) and marketing approvals for Biologics License Applications (BLA). The draft guidance is intended to address specific issues affecting oncology trials in the context of the July 2018 Guidance for Industry, E17 General Principles for Planning and Design of Multi-Regional Clinical Trials.  

The key motivating concern addressed in the draft guidance is whether outcomes reported from an MRTC may be considered applicable to the intended use population of cancer patients in the U.S., and whether the results are interpretable in the context of U.S. medical practice. A major concern is that of representativeness of enrolled participants with respect to the U.S. population expected to be treated with the investigation product post approval. The draft guidance indicates that data submitted in support of FDA marketing approval should include results from a substantial number of U.S. participants, even if the sponsor has evidence that enrolled subjects in other regions share clinical or demographic characteristics with the U.S. population.  Depending on how commonly the cancer type occurs in the U.S., either equal or proportional allocation of U.S. participants is recommended.

Another important consideration noted in the draft guidance is evaluation of differences in standard of care treatment at foreign sites compared to standard of care in the U.S. For selection of foreign sites, a critical criterion should be readiness for FDA inspection and for compliance with laws and regulations covering good clinical practice.

When planning clinical trials outside the U.S. with the intention of applying the results to the U.S. population, sponsors and investigators must carefully navigate the landscape of international and U.S. regulatory guidelines. While the International Council for Harmonisation (ICH) guidelines offer a harmonized framework for ethical research conduct globally, it is essential to recognize key differences between these guidelines and U.S.-specific regulations, primarily the Common Rule.

Both ICH and the Common Rule share a foundation in core ethical principles, emphasizing respect for persons, beneficence, and justice. They both mandate obtaining informed consent from participants, ensuring they fully understand the study’s purpose, risks, benefits, and their right to withdraw. Furthermore, both frameworks require independent review and approval of research by an Institutional Review Board (IRB) to uphold ethical standards and prioritize additional protections for vulnerable groups like children, prisoners, and adults lacking capacity.

Despite these fundamental similarities, critical distinctions exist. The ICH guidelines primarily focus on clinical trials for pharmaceuticals, while the Common Rule casts a wider net, covering a broader range of human subjects research. Importantly, the Common Rule is a legally binding regulation in the U.S., whereas ICH guidelines serve as recommendations that are adopted into national laws, carrying varying degrees of legal weight. These frameworks also diverge in specific requirements. For instance, U.S. regulations place a stronger emphasis on diversity within the IRB, requiring representation across race, gender, cultural background, and professional fields. U.S. regulations may also demand more extensive documentation, including financial disclosures and specific forms tailored to different study types. While both mandate ongoing monitoring of research, U.S. regulations offer more flexibility in adapting the approach to the study’s risk level.

While both ICH guidelines and U.S. regulations emphasize the importance of ethical research conduct, a critical challenge arises when applying data from global trials to the U.S. population. The FDA, for instance, expects studies to utilize ‘representative samples’ but does not provide specific guidance on what constitutes such a sample. This ambiguity poses difficulties for sponsors and investigators aiming to ensure their research meets FDA requirements and adequately reflects the diversity of the U.S. population. A lack of clarity on representativeness can inadvertently lead to the exclusion of certain groups, raising concerns about equity and fairness in research participation.

Furthermore, the FDA’s current conception of representativeness appears to potentially undervalue critical factors that influence health outcomes and treatment responses. Social determinants of health, such as socioeconomic status, access to healthcare, education level, environmental factors, can significantly impact an individual’s health profile and experience with a given disease or intervention.

Therefore, relying solely on racial and ethnic categories to establish representativeness may be insufficient and even misleading. For instance, a study population composed of Black individuals residing outside the U.S. may not accurately reflect the experiences and health needs of Black Americans due to differences in social, economic, and environmental contexts. These disparities can influence disease prevalence, access to care, and treatment adherence, ultimately affecting the generalizability of study findings to the U.S. population.

These differences have significant implications for global research intended for U.S. applications. Studies must comply with both ICH guidelines and U.S. regulations, including the Common Rule and FDA requirements. This necessitates careful selection of an IRB, ideally a U.S.-based central IRB or one with expertise in U.S. regulations, to ensure thorough review. Data privacy, particularly adherence to Health Insurance Portability and Accountability Act (HIPAA) standards, must be prioritized even when research is conducted outside the U.S. Finally, researchers should strive for cultural sensitivity in informed consent and study procedures, adapting to the local context while maintaining alignment with U.S. ethical standards.

Conclusion

By understanding the nuances of both ICH guidelines and U.S. regulations, sponsors and investigators can conduct ethical and compliant global research that generates data applicable to the U.S. population. This proactive approach not only ensures the protection of human subjects but also facilitates the development of safe and effective therapies that benefit individuals worldwide.

If you have further questions about navigating the regulatory landscape or ensuring your trial meets FDA expectations, don’t hesitate to reach out to our team of experts. Contact us via the form below.