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The FDA recently released a draft guidance on the use of multi-regional clinical trials (MRCTs) in oncology research. A well-planned MRCT can be an efficient approach to the global clinical development of a novel product, allowing for access to a wider sampling population and the potential to approach multiple regulatory agencies for advice during the development planning and, after safety and efficacy are established, for eventual marketing authorization.
The guidance, titled “Considerations for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs,” extends the E17 FDA guidance on MRCTs, providing specific recommendations by the FDA for the planning and implementation of MRCTs to support the assessment of cancer drugs for use in the U.S. population. While the draft guidance on oncology MRCT is specific to the U.S. approval process, thereby ensuring interpretable results within the context of FDA requirements, many of the recommendations can be generalized to a global perspective for multi-jurisdiction approval. In our last blog on this topic, we provided key considerations for supporting an MRCT in oncology research with considerations specific to the U.S. regulations. In this post, we make recommendations to enhance the planning and use of MRCT to facilitate a clear interpretation of study safety and efficacy results within a global perspective to ultimately support marketing authorization applications across multiple countries.
Many factors can impact disease latency, severity and response to treatments, including intrinsic characteristics such as demographics or genetic variations, and extrinsic factors such as environmental exposures and access to/standards of care. Intrinsic and extrinsic factors often vary by geographic region. When performed across a pre-planned diverse population, early-phase clinical trials can help to delineate regional differences in the study population and identify possible differences in response to experimental treatments by region. Differences identified in the early-phase trials can be incorporated into the later-phase MRCT planning.
Clinical development programs planned with MRCT can support access to a more diverse patient population and provide valuable information on variations in treatment effect. A well-designed MRCT, supported by early-phase clinical trials, can successfully support applications for marketing authorization across multiple regions.
👉 Recommendations for Incorporating an MRCT in a Global Development Program
Consider the following key recommendations to effectively design a clinical development program that seamlessly includes an MRCT:
1 - Explore intrinsic and extrinsic differences in population in early-phase studies.
Differences may exist in pharmacokinetic and pharmacodynamic response, preliminary evidence of efficacy, and safety performance of the experimental treatment in varying populations early in the development program. When these variations are identified, Sponsor companies can better plan for sample size and relative representation within the study. If there are subpopulations that are more prevalent in some regions, the identifying factor of the subpopulation can be included in design elements (such as stratification by presence/absence of the subpopulation factor) or included to represent a targeted percentage of the sample to ensure that evidence of efficacy and safety can be determined. When the subpopulation is closely associated with the region of the participant, region can be used as a stratification factor or for targeted enrollment percentages.
2 - When possible, identify a single primary efficacy endpoint for the MRCT that is accepted as primary evidence of efficacy by regional regulatory authorities where marketing access will be sought.
Gathering input and agreement from regional regulatory agencies on the selected primary endpoint and, to the extent possible, a clinically meaningful benefit that would support a successful marketing application, will help Sponsors plan an appropriate sample size for the study and create an efficient application for marketing authorization across geographic regions. When regulatory authorities have different preferences for primary endpoint for demonstration of efficacy across regions, the Sponsor can address this through application of a region-specific primary endpoint, as can be defined within the study protocol. Further detail on this occurrence is provided in the E17 FDA guidance.
In oncology research with randomized controlled trials, the primary efficacy endpoint is often a time-to-event endpoint, either overall survival or progression free survival. However, single arm oncology studies often use overall response rate or complete response rate according to disease response criteria (e.g., RECIST) criteria as a primary efficacy endpoint
3 - Identify a single control product for comparison, with consistent treatment and dose level across locations.
If a single control product cannot be identified, a set of controls can be implemented with stratification by control-product. If there are substantial differences across regions in standard of care, approved products that can be used as control, or regulatory agency requirements to a placebo-controlled study in some (but not all) regions, one or more regions may be excluded or a more complex design may be considered. For different controls by regions, for example, an MRCT can be designed with region-specific control arms and, as needed, pre-specified minimum number(s) of participants to be randomized to each product to allow comparisons within-region and against each control arm.
4 - Stratify randomization.
For a randomized controlled trial, if by-region differences exist (#1) or a single control arm cannot be selected across regions (#3), by-region or by-control arm stratification factors can be included in the randomization scheme. If there are hypothesized differences or observed differences in disease severity or response to treatment by baseline disease status or demographic factors (e.g., age, sex), stratification by these factors would also be appropriate.
5 - Pre-specify the analysis methods, including the sample to be analyzed for primary and supportive efficacy analysis.
MRCT with a single control arm: The pre-specified primary assessment of efficacy and safety should be in the overall sample with by-region assessments as supportive analyses. If the randomization scheme is stratified, the stratification factors should be accounted for in the analysis method applied. By-region analysis can be performed as a descriptive summary to illustrate the consistency and any deviations in the overall treatment effect and safety findings across geographic locations. If substantial variation is observed, further analysis may be required.
MRCT with multiple control arms: Depending on the design and hypothesized differences in the control arms, the pre-specified primary efficacy analysis may be performed comparing against all controls pooled together or may be performed by control arm. Additional complexities, including whether all participants treated with the experimental product can be pooled for the primary analysis also need to be pre-specified.
Additional by-region assessments may be appropriate, as with MRCT with a single control arm.
Hypothesis testing: The hypothesis testing algorithm should be pre-specified to control the type I error rate for primary and secondary conclusions. When type I error is not controlled or analyses are performed to demonstrate consistency in trend across multiple groups, the interpretations should be made with caution to not overly assert efficacy or safety findings without sufficient control
👉 Determining MRCT Suitability for Global Clinical Development
Sponsors considering late-phase MRCTs to support an efficient global clinical development program should request scientific advice from regulatory agencies for each of the targeted regions for eventual application for marketing authorization prior to the implementation of the MRCT. The advice may include a minimum percentage of the sample that should be enrolled within the region of interest, as well as items listed above (#2).
While MRCTs can increase efficiency in a clinical development program, they are not without risk. If there are substantial regional differences due to intrinsic or extrinsic factors that impact the disease severity or the response to treatment, or if there are substantial differences in response to control product(s) by region, it will be difficult to make generalizable conclusions due to the diversity of the population. The best risk mitigation is to perform early-phase clinical research within a representative and diverse sample to better understand the relative effect of treatment and variability of the underlying population. With sufficient information, researchers can identify whether an MRCT can support generalized conclusions in a global clinical development program.
When prepared with sufficient region-specific preplanning and the considerations of intrinsic and extrinsic factors that may impact treatment effect, late-phase MRCT designed and executed according to the E17 guidance can create an efficient development program with the opportunity to apply for marketing authorization in multiple regions simultaneously.
Veristat experts are ready to help you assess whether an MRCT is suitable for your development program, offering deep expertise in global regulatory requirements, how to assess regional variability, and multi-regional clinical trial design. Our team provides strategic guidance backed by extensive experience in clinical trial implementation, ensuring that your MRCT is designed to support regulatory approval across multiple regions.
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