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Multi-Regional Clinical Trials – Challenges in Applying Data to the US Population

Interpretation of Guidance: Considerations for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs [1]– The FDA has issued a draft guidance that provides key insights into their expectations for the use of clinical data generated in multiregional clinical trials to support US filings.

1. Background

Providing the right treatment to the right population and individual is critical. This requires robust assessment of a drug’s safety and efficacy in the populations that will use it, ensuring that clinical evidence generated from clinical trials is applicable to them.   The rapid development of drugs to address urgent medical needs, coupled with the increasing reliance on international clinical trials, has introduced additional complexities in meeting these needs. While these international trials can expedite global drug development, they may challenge the generalizability and interpretability of those clinical results to US patients and medical practices.

Particularly, in oncology, multiregional clinical trials (MRCTs) are increasingly used for their ability to efficiently collect safety and efficacy data across diverse populations, accelerating approvals and broadening access to innovative therapies. MRCTs are also particularly advantageous in rare diseases, where larger patient pools are essential. Additionally, if a multiregional development program is in place earlier, it can enable early identification of factors that may predict regional differences in outcomes that could inform the design of future pivotal MRCTs. However, the FDA has noted a declining proportion of US participants in oncology MRCTs. This reduction can hinder the assessment of treatment effects between participants enrolled in the US and the overall study population.  Furthermore, there may be significant disparities in the demographic and clinical characteristics of participants.  These deficiencies can affect the FDA’s ability to evaluate the generalizability and applicability of trial results to the US population and medical practices. Sponsors must ensure that study populations provide evidence that is generalizable and applicable within the context of US medical practices. This new draft guidance builds on principles outlined in existing FDA guidance documents [1],[2] and offers further recommendations for planning, designing, and analyzing MRCTs to enhance their relevance to US populations.

[1] https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-generating-clinical-evidence-oncology-multiregional-clinical-development-programs

[2] E5 – Ethnic Factors in the Acceptability of Foreign Clinical Data – Questions and Answers (September 2006),

[3] E17 General Principles for Planning and Design of Multiregional Clinical Trials (July 2018).

2. Recommendations

2.1 Factors to Consider

 The Agency has outlined key principles for assessing the appropriateness of an MRCT approach by considering various scientific, clinical, and other factors. The Agency recommends that the Sponsor should, at a minimum, take into account the following factors:

  • Patient-related factors, such as exposure to disease risk and genetic backgrounds
  • Disease-related factors, including the prevalence of subtypes and molecular drivers
  • Healthcare system factors, such as access to specialized oncology care and available treatments.
  • Socio-cultural factors, like dietary habits and beliefs about alternative therapies.

Sponsors should consider the incidence and prevalence of the disease within different populations, as well as patient-related factors such as risk factors (e.g., age, gender, comorbidities) and genetic background, which may influence disease development.  It’s also crucial to consider the age at presentation, and the distribution of cancer histologies, subtypes.  For example, if a particular cancer subtype is prevalent in the US, sponsors should prioritize selecting clinical trial sites that can recruit a significant number of patients with that specific subtype to ensure the trial’s relevance.

In addition to disease characteristics, sponsors should assess available therapies across regions, including the consistency of standard treatments and the overall treatment landscape. Variations in these factors can influence trial design and outcomes. For example, the availability of different therapies affects the selection of control groups in clinical trials.  Prior treatments, such as chemotherapy versus immunotherapy, may significantly affect study results. Additionally, understanding the treatment options available after disease progression is crucial, especially when overall survival (OS) is the primary endpoint, as differences in these therapies can affect total survival time assessments and influence the design of cross-over studies.

2.2 Adequate Representation of US Patients

To ensure adequate representation of US patients in clinical trials, the FDA recommends distributing participants based on disease incidence and prevalence. For trials targeting common cancers in the US, such as colorectal and breast cancer, participants should be evenly distributed across the geographical areas where the trials will be conducted, including North America. For rarer cancers that may be more prevalent in other regions, like squamous cell esophageal cancer, a proportional distribution approach is generally advised. However, this approach should be used with caution. The sponsor should assess its appropriateness by considering whether the drug’s effect may be altered by factors that differ across regions. A narrower indication that reflects the population studied may be warranted if there are significant differences across the trial population (e.g., different risk factors in major geographical regions). The FDA also allows flexibility in trial design, permitting a trial to be conducted in a single region while using additional trials to confirm its applicability to the US population. For example, a sponsor may conduct an MRCT with the majority of participants from a single foreign region if it is part of a program that includes other pivotal trials enrolling a population representative of the US.

2.3 Clinical Site Selection

When selecting clinical trial sites, the FDA recommends conducting trials across multiple regions instead of limiting them to a single location. Sponsors should evaluate differences and similarities in patient characteristics, disease manifestations, and healthcare systems across these regions to ensure the data reflects the demographics and clinical characteristics of patients in the US.  Additionally, sponsors must provide a rationale for the chosen geographical areas and sample size distribution. Sponsors should assess each site’s contribution to population representativeness, including historical recruitment record of diverse demographics. The FDA also supports trials in non-traditional settings, like community hospitals, to enhance diversity and accessibility.

2.4 Clinical Trial Conduct

Clinical trial sites need to comply with ICH E6 Good Clinical Practice (GCP) standards and be ready for regulatory inspections. Centralized and risk-based monitoring should be implemented by Sponsors to identify and address emerging regional differences, and timely, accurate information exchange among sites must be ensured to facilitate effective trial conduct.

2.5 Early Identification of Potential Differences in Drug Effects Across Populations

To help with MRCT design, particularly for pivotal MRCTs, the FDA advises early identification of potential differences in drug effects across populations by conducting early-phase studies in diverse groups or regions. These studies help detect variability in drug response among different populations and provide preliminary insights into how intrinsic and extrinsic factors like pharmacokinetics, diet, alternative medicine use, genetics, race, age, ethnicity, and sex may impact clinical outcomes.

However, due to small sample sizes in early studies, a lack of observed differences may not justify limiting pivotal trials to a single non-US region.

3. Regulatory Communication

Companies should engage with the FDA early in the clinical development process, ideally before starting pivotal trials that provide the definitive assessment of the drug’s safety and efficacy. Ensuring that the clinical data from these pivotal trials are generalizable and applicable to the US patient population and medical practices is essential for approval. Furthermore, aligning key elements of the overall development plan with the FDA and other regulatory bodies, either simultaneously or nearly concurrently, is important to ensure coordination and consistency across regions.

4. Summary

The key points regarding the generalizability and applicability of clinical evidence to the US patient population and medical practice are:

  • Engage early with regulatory agencies and align with different agencies during the early stages of drug development.
  • Identify intrinsic (e.g., age, race, body weight, and disease stage) and extrinsic factors (e.g., smoking status, diets) related to the drug and evaluate their potential impact early to support the robust design of confirmatory MRCTs.
  • Plan for a reasonable distribution of clinical trial sites in the MRCT to recruit a population that represents US disease demographics.
  • Ensure sufficient US participation in the MRCTs. Allocation strategies are proposed by the Agency.
  • The absence of observed differences between different populations or regions in early-phase studies should not be used as a justification for restricting trials to a single non-US country or region.

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