FDA releases draft guidance on oncology multiregional clinical trials (MRCTs): Key considerations for global drug development
This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.
The U.S. Food and Drug Administration (FDA) released a new draft guidance on September 16th titled "Considerations for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs”.1 Recognizing that most drug development is global, the guidance explains how drug developers should address requirements for ensuring that oncology MRCTs include populations that enable interpretability and relevance of the results to U.S. patients. The guidance also clarifies the FDA’s position on the use of foreign data to support marketing applications for cancer therapies in the U.S.
The FDA will no longer accept data from clinical trials conducted in only one country or single geographical region as sufficient to support a marketing application, since these data will not enable understanding of any differences in treatment effect for the diverse U.S. population. While FDA regulations allow for the use of foreign data to support a marketing application2,3, the regulations, along with the guidances4,5,6 focused on ensuring diversity in clinical trials, state that foreign data are acceptable only if the patient population is representative in terms of criteria such as demographics and disease characteristics.
Consequently, companies developing therapies for oncology indications who have already conducted their clinical trials in a single country or geographical region may have to conduct additional trials to ensure their clinical program is representative of the target U.S. patient population.
The guidance also means that companies must begin their Diversity Action Plan as early as Phase 1 and well before their Phase 3 pivotal studies. In many instances, companies rely upon their Phase 2 oncology study(ies) to support their marketing application, with the Phase 3 trial(s) serving as confirmatory and completed post-approval.
The guidance's overall goal is to ensure that data from oncology MRCTs are applicable to the U.S. population and medical practice while maintaining the efficiencies of global trials.
Oncology drug developers will need to carefully plan trial designs and populations to meet these new expectations. Below, we highlight five key recommendations and associated actions (noting that the guidance implies there may be flexibility in expectations for rare cancers):
1. Increased focus on U.S. population representation:
- Sponsors should enroll sufficient U.S. participants to allow robust assessment of drug safety and efficacy in the target U.S. patient population.
- The trial population should adequately represent the diversity of the U.S. population affected by the cancer that the investigational product is intended to treat.
2. Careful consideration of regional allocation of study patients:
- For cancers that are common in the U.S., equal allocation of study participants across major geographical regions is highly recommended.
- For cancers that are rare in the U.S., proportional allocation (i.e., allocation of participants to regions in proportion to size of region and disease prevalence) is recommended, but potential regional differences should be carefully evaluated.
3. Emphasis on diversity of selected study sites:
- Sites should be selected to help achieve demographic representativeness.
- FDA expects clinical trial sites to be actively expanded beyond tertiary and academic centers (e.g., to community hospitals), and possibly into countries/regions that have traditionally not been considered.
- Sponsors of oncology MRCTs must be prepared for the very real potential for increased clinical site inspections related to the diversification of sites, countries and regions.
4. Comprehensive evaluation of regional differences in patient characteristics and clinical practice:
- To determine if an MRCT approach is appropriate, sponsors must assess regional differences in disease characteristics, standard of care (SOC), and available treatments.
- As trials should be conducted in regions where the clinical practice for that indication is comparable to the U.S. and the trials should include SOC that is similar to the U.S., this will:
- either limit where MRCTs can be conducted (e.g., to Western Europe);
- or necessitate that sponsors/their CROs expand to and invest in sites located in non-Western countries/regions (e.g., Africa, Latin America), and ensure that these sites meet GCP requirements and other qualifying criteria.
- When there are important regional differences relating to acceptable SOC, seeking scientific advice from the regulatory agencies is recommended.
- Sponsors should monitor for changes in the SOC during trials and consult the FDA on incorporating new treatments. Trials with an outdated control arm or backbone may get regulatory pushback.
- Because regulators in each region will require that the clinical study population is representative of that region, companies with global oncology development plans must expect to meet region-specific and population-specific requirements for all countries in scope. Consequently, sponsors may have to consider a ‘blended’ approach to development with several trials – i.e., conduct an MRCT that will enroll a substantial proportion of participants in a single foreign geographical region but must also have one or more additional pivotal trials that will enroll a population that is representative of the U.S. population.
5. Analysis considerations:
- Regional treatment effects should be estimated and the approach to analyze for geographical regional effects should be pre-specified.
- The guidance implies that the MRCTs need not be powered to assess for efficacy in the US subgroup, but the FDA wants enough U.S. patients to allow for robust sub-group analyses.
Although the guidance doesn’t state a timeframe in which FDA will begin to implement these expectations, we should anticipate that this will be immediate and sponsors should prepare accordingly. Additionally, while the updated draft Guidance on Diversity Action Plans indicates that the guidelines will not apply until 180 days after the final guidance is issued, the current guidance on oncology MRCTs strongly implies that the FDA expects oncology drug sponsors to start incorporating diversity planning now.
Comments on the draft guidance will be accepted until November 18, 2024, before the FDA begins work on the final version.
As a leading global Phase 1-4 clinical research organization, Parexel leverages our breadth of regulatory, clinical trial, and therapeutic expertise to optimize clinical development programs. Our team of ex-regulators can help you navigate the requirements of the major regulatory agencies, including an assessment of this new FDA draft guidance and its implications for your global oncology development program. Please contact us, we are always available for a conversation.
References:
1. U.S Food & Drug Administration (2024, September 16). Considerations for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-generating-clinical-evidence-oncology-multiregional-clinical-development-programs [accessed September 17, 2024]
2. Code of Federal Regulations. 21 CFR 314.106 Foreign data. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314/subpart-D/section-314.106 [accessed September 20, 2024]
3. U.S Food & Drug Administration (2012, March). FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND: Frequently Asked Questions: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-acceptance-foreign-clinical-studies-not-conducted-under-ind-frequently-asked-questions [accessed September 20, 2024]
U.S Food & Drug Administration (2024, June). Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diversity-action-plans-improve-enrollment-participants-underrepresented-populations-clinical-studies [accessed September 20, 2024]
4. U.S Food & Drug Administration (2020, November). Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enhancing-diversity-clinical-trial-populations-eligibility-criteria-enrollment-practices-and-trial [accessed September 20, 2024]
5. U.S Food & Drug Administration (2024, January). Collection of Race and Ethnicity Data in Clinical Trials and Clinical Studies for FDA-Regulated Medical Products: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/collection-race-and-ethnicity-data-clinical-trials-and-clinical-studies-fda-regulated-medical [accessed September 20, 2024]