Multi-Regional Clinical Trials 102: Clinical Trial Design & Protocol-Related Issues
Additional information on the guidance document is available in our preceding FDA News article entitled “Multi-Regional Clinical Trials 101: Value, Requirements, and Key Considerations Associated with MRCTs.”
In June of this year, the International Council for Harmonisation (ICH) published a document containing a number of guidelines regarding the planning and design of multi-regional clinical trials (MRCTs). The draft guidance, entitled “E17 General Principles for Planning and Design of Multi-Regional Clinical Trials,” was developed with the goal of “increasing the acceptability of MRCTs in global regulatory submissions.” On September 9th, the FDA announced the availability of this draft guidance.
Impact of Regional Variations
It is important for sponsors to take regional variability (and the extent to which it can be explained by both intrinsic and extrinsic factors) into consideration during the planning stage and when determining the role that MRCTs can play in the development strategy. Some factors may vary from region to region and could have an impact on study results. One such factor is the distribution of baseline demographics, which includes body weight and age. In addition, the guidance notes that sponsors should consider cultural differences such as the use of contraceptives and preferences for a particular route of administration, as this can differ drastically from one region to another.
“Additionally, factors such as cultural or socio-economic factors and access to healthcare may impact study results and also recruitment, compliance, and retention, as well as the approaches that could be used to retain subjects,” states the draft guidance.
Selection of Subjects
Sponsors should take careful consideration when selecting subjects for participation in MRCTs, taking additional time to better understand and possibly mitigate potential sources of regional variability and their impact on the results of the trial. The draft guidance notes that the protocol for selecting subjects should include clear and specific inclusion and exclusion criteria that are acceptable and can be applied across all regions.
The draft guidance provides a number of recommendations regarding the selection of subjects and various measures that should be taken. Some of these include:
- Implementation of uniform criteria for classification and diagnosis of the disease, or definition of the at-risk population
- Clear specification of diagnostic tools that are needed to select subjects, and the degree to which locally validated tools and qualified labs may be used.
- Availability of recommended tools (validated imaging instruments and measurements of biomarkers) in all regions when needed for subject selection.
- Specification of methods for specimen collection, handling, and storage.
Dose Selection in Confirmatory MRCTs
In order to select the appropriate dose for confirmatory MRCTs, it is necessary to have a well planned development program that includes PK and/or PK/PD studies during phase I and II. This is critical in order to identify important regional differences that could have an impact on dose selection. The draft guidance states that, in principle, dose regimens in confirmatory MRCTs should be the same in all participating regions. “However, if early trial data show a clearly defined dose/exposure/response relationship that differs for a region, it may be appropriate to use a different dosing regimen in that region, provided that the regimen is expected to produce similar therapeutic effects with an acceptable safety margin, and is fully justified and clearly described in the study protocol.”
Choice of Endpoints
The draft guidance states that the general principles regarding endpoint selection and definition that are provided in ICH E9 are also applicable to MRCTs. Additionally, the following aspects are of particular importance to MRCTs:
According to the document, “an ideal study endpoint is one that is clinically meaningful, accepted in medical practice (by regulatory guidance or professional society guidelines) and sufficiently sensitive and specific to detect the anticipated effect of the treatment.” In addition to these criteria, the primary endpoint should also be acceptable to all concerned regulatory authorities. This will ensure that interpretation of the trial’s success or failure is consistent across all regions and regulatory authorities.
In order to maintain the feasibility and improve the quality of trial conduct, sponsors are encouraged to harmonize secondary endpoints whenever possible. In some cases, this may not be possible, as individual regulatory authorities may sometimes require different secondary endpoints that best match their interests and experiences. The document states that, even in these circumstances, “all secondary endpoints including those selected only for a particular regulatory authority should be described in the protocol.”
Other Considerations & Recommendations
The draft guidance provides a number of additional recommendations and factors for sponsors to take into consideration during the planning and design of MRCTs. These include, but are not limited to:
- “The overall sample-size for MRCTs is determined by a treatment effect that is considered clinically meaningful and relevant to all regions based on knowledge of the disease, the mechanism of action of the drug, on a priori knowledge about ethnic factors and their potential impact on drug response in each region, as well as any data available from early exploratory trials with the new drug.”
- “The MRCT should also be designed to provide sufficient information for an evaluation of the extent to which the overall treatment effect applies to subjects from different regions.”
Allocation to Regions
- “Proper planning for sample size allocation to region is needed in order to describe the treatment effect in the multi-regional setting.”
Collection & Handling of Safety & Efficacy Information
- Methods for the collection and handling of safety and efficacy information should be standardized across all participating regions.
- “Safety reporting should be conducted in accordance with ICH E2.”
- “When local regulations specify different requirements, such as timelines for expedited reporting, these should also be adhered to locally.”
For additional information on the ICH guidelines, view the full draft guidance.