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Multi-Regional Clinical Trials: The Latest Guidance from FDA

Planning and designing clinical trials conducted in multiple geographic or regulatory regions

The FDA recently released draft guidance on the use of multi-regional clinical trials (MRCTs) in oncology research. The guidance, titled "Consideration for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs," extends the current guidance on MRCTs to further improve their design, implementation, and analysis with specific considerations for oncology research. While many of the recommendations within the guidance may be considered as good practice for MRCT in any therapeutic area, the implementation of these practices within oncology research is particularly important due to regional factors, inclusive of environmental and demographic characteristics, that can impact both tumor expression and response to treatments.

The guidance is geared toward sponsors conducting oncology therapy clinical trials in more than one country under a single protocol. Executing studies in multiple countries can provide greater access to patients, particularly for rare oncology indications, and can expedite the global development program for new therapies. The FDA reported observing a decreasing proportion of U.S. participants in oncology MRCTs in recent years. With greater proportions of the MRCT study samples being enrolled from outside the U.S., there is a risk that the underlying demographic or disease characteristics of the overall sample may differ substantially from those of the U.S. disease population. As a result, the conclusions from the MRCT may not be generalizable within the U.S. population, possibly limiting the effectiveness of an MRCT in support of a U.S. marketing authorization.

Differential response to treatment by regional, environmental, or demographic characteristics is unknown until either the execution of region-specific studies allowing the comparison of results between regions or the execution of an MRCT. A varied sample with representation within and across regions is required to support conclusions on any measured differences between such factors.

The new guidance provides considerations to aid sponsors in running MRCTs such that the data will be relevant and interpretable for the U.S. patient population. The considerations should also be considered for ex-U.S. regions in an MRCT where sampling is more strongly focused within the U.S.  It is worth noting that a thorough, multi-regional clinical development program may require more than one study to first identify that such differences exist and then inform conclusions.

đŸ‘‰  Ensuring Reliable and Applicable Trial Results Across Regions and Patient Populations

MRCTs can be an efficient way to advance the testing, evaluation, and availability of oncology treatments for patients worldwide, rather than conducting separate clinical trials within each of a number of geographic regions. However, differences may exist among patients enrolled across geographic regions that limit the interpretability and generalizability of the multiregional data.

At Veristat, our recommendations when considering MRCTs and the recent guidance include:

  • Targeting enrollment with well-represented subgroups, including a distribution of demographic and baseline disease characteristics that represent the underlying population of patients within each region.
  • For controlled studies, a randomized design is critical to demonstrate conclusive evidence of the clinical impact of a treatment without bias at the end of the study. Available and appropriate standards of care may differ by region and need to be accounted for within the randomization schedule and analysis methods.
  • Patient stratification by geographic location, prior therapies, and/or standard of care may be critical to providing interpretable results, especially when differences exist by region; however, the inclusion will likely increase the sample size of the study. 
  • Statistical analysis of subpopulations should be planned to provide descriptive numeric evidence of differences in study results by geographic locations as well as other baseline factors.

The planning for enrollment in multiple regions should be included in the protocol and statistical analysis plan. The protocol may also include targeted enrollment percentages within a region and should state limitations on standards of care that are available in only small percentages of the regions under study. For by-region conclusions, multiple testing must also be addressed in the study protocol to ensure the type I error rate is well controlled.

đŸ‘‰  Supporting the Full Lifecycle of Your Clinical Development Program

The goal of any clinical development program is to determine a treatment’s efficacy and safety within the targeted population. Understanding and adhering to the latest regulatory recommendations, including the recent FDA draft guidance on MRCTs, and developing thorough study protocols are critical to enable sponsors to achieve success in advancing their clinical development program within a global landscape. The regulatory recommendations should be considered across regions, with consideration to ensure a representative patient population is studied with relevant control arm(s) to provide clear evidence of clinically meaningful treatment effect. Similar considerations should be made for single-arm studies when a comparison arm is not available and rare disease studies where a randomized control arm is not feasible.

 With the global regulatory landscape for the planning and design of clinical trials becoming more complex, Veristat’s integrated teams of regulatory, statistical, clinical, and medical experts can work closely with you to understand your planning and development goals and to meet or exceed your regulatory timelines when performing multi-regional clinical trials.

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