GENERAL PRINCIPLES FOR PLANNING AND DESIGN OF MULTI-REGIONAL CLINICAL TRIALSE17

1. INTRODUCTION

1.1. Objectives of the Guideline

The guidance document focuses on enhancing the recognition of data from multi-regional clinical trials (MRCTs) by regulatory bodies worldwide to support drug marketing approvals. It outlines principles for MRCT planning and design, emphasizing its integration with existing ICH recommendations (E5, E6, E8, E9, E10, E18) to address both strategic program matters and specific challenges related to confirmatory MRCTs.

1. Background

It may be difficult to carry out a drug development program internationally in an era of drug development globalisation, partly because regulatory bodies have different and perhaps contradictory requirements.  At the same time, assessing MRCT data for drug approval is becoming more difficult for regulatory bodies.  MRCT data are frequently sent to several regulatory bodies without a prior regulatory assessment of the development program.  Although the ICH E5 guideline addresses concerns about bridging results from one region to another, there are currently no ICH guidelines that expressly address the planning and design of MRCTs.

MRCTs following the current guideline will enable the assessment of treatment effects and safety evaluations across diverse populations, taking into account intrinsic and extrinsic factors. Properly designed MRCTs can streamline drug development processes and facilitate simultaneous marketing authorisation submissions to various regulatory bodies, thereby enabling quicker global access to new medications. Additionally, these studies may enhance understanding of regional variations in treatment effects and the factors influencing them within a unified study framework.

1.3. Scope of the Guideline

MRCT is defined in the present guideline as a clinical trial conducted in more than one region under a single protocol. In this context, a region may refer to a geographical re gion, country or regulatory region (see Section 3. Glossary). The primary focus of this guideline is on MRCTs designed to provide data that will be submitted to multiple regulatory authorities for drug approval (including approval of additional indications, new formulations and new dosing regimens) and for studies conducted to satisfy post-market ing requirements. Certain aspects of this guideline may also be relevant to studies con ducted early in clinical development or in later phases. The present guideline mainly covers drugs including biological products, although some sections may not be applicable to all development programmes (e.g., pharmacokinetics (PK) not used for preventive vac cine dose-finding).

1.4. Basic Principles

Basic principles are described below:

1. When correctly planned and carried out in accordance with this guidance, the strategic use of MRCTs in drug development programs can improve drug development efficiency. MRCTs may facilitate the simultaneous submission of applications for marketing authorisation and help regional regulatory decision-making, so facilitating early global access to new drugs. The potential for regional variations to affect the interpretability of study data should be carefully evaluated, even if MRCTs may often become the preferable method for investigating a new drug for which regulatory submission is expected in various countries.
2. Early identification of the intrinsic and extrinsic elements is crucial for the drug development program. Before designing confirmatory MRCTs, the possible influence of these factors could be investigated in the exploratory stages. In order to assess their influence on treatment outcomes, information about them should also be gathered during the confirmatory trial.
3. MRCTs are designed with the idea that the treatment impact is applicable to the entire target population, especially to the trial’s included regions. The degree to which this assumption is true can be assessed by strategically allocating the sample size to different regions.
4. Based on established knowledge regarding similarities, pre-specified pooling of regions or subpopulations may improve regulatory decision-making, allow for flexibility in sample size allocation to regions, and make it easier to evaluate consistency in treatment effects across regions.
5. To ensure that it is acceptable to all relevant regulatory agencies, a single primary analysis approach for hypothesis testing and calculation of the overall treatment effect should be planned. It is necessary to plan a systematic investigation to look at how treatment effects are consistent across subpopulations and regions.
6. To ensure that the study results are interpretable, it is crucial to establish high-quality study design and conduct in accordance with ICH E6 in all regions, given the variety of regional practices.  A successful MRCT requires consistently excellent trial quality, which can be attained with careful attention to quality during trial planning, investigator training, and trial monitoring. 
7. In order to achieve acceptability of a global approach to study design across the various regulatory regions, effective communication between sponsors and regulatory authorities is advised throughout the planning stage of MRCTs.   

• GENERAL RECOMMENDATIONS IN THE PLANNING AND DESIGN OF MRCTS

2.1 Strategy-related Issues

   2.1.1 The Value of MRCTs in Drug Development

Drug development has traditionally relied on regulatory strategies tailored for specific regions. Multiregional clinical trials (MRCTs) have been effective in recruiting trial subjects within a reasonable timeframe, particularly for rare diseases, special populations like the elderly or pediatric groups, and large-scale studies such as cardiovascular outcome study or vaccine efficacy studies. Recently, there has been a shift towards global regulatory strategies to enhance study efficiency and expedite drug availability to patients worldwide.

MRCTs allow for an examination of the applicability of a treatment to diverse populations. The intrinsic and/or extrinsic factors that are believed or suspected to impact upon responses to the drug can be further evaluated based on data from various regions using a single protocol. For example, the impact on the treatment effect of genetic differences or different distribution of gene polymorphisms in drug metabolising enzymes or the molecular target of a drug can be examined in exploratory and/or confirmatory MRCTs that include subjects with different intrinsic factors across regions. Accumulated knowledge of the impact of intrinsic and extrinsic factors and global sharing of experiences in various regions may promote inclusion of additional regions in MRCTs.

The primary reason for performing MRCTs is to evaluate the overall treatment effect

based on data from subjects in all regions.  However, intrinsic and/or extrinsic factors

may be expected to impact subjects’ responses to drugs differently across regions and

should be considered when planning MRCTs.  If major differences in treatment effects

are expected, available data should be assessed to decide, whether it is appropriate and

feasible to conduct the MRCT.  Even in the case of expected major differences in treatment effects, it may still be possible, to conduct MRCTs by excluding some regions or a defined subgroup within a region, after careful consideration.  Additional strategies to study a disease and/or drug in the excluded regions should be considered (see ICH E5). 

If MRCTs are the source of data in the bridging strategy based on the ICH E5 guideline,

MRCTs could provide more robust evidence than single regional trials for extrapolation

of study results.  In some cases, single-region studies may be appropriate, such as in the evaluation of drugs to treat or prevent a disease that is prevalent in a single region (e.g., anti-malarial drugs, vaccines specific to local epidemics, or antibiotics for region-specific strains).

MRCTs enable simultaneous global drug development, decreasing the need for separate clinical studies in each region, thus reducing duplication. While requiring more coordination and potentially increasing start-up time, MRCTs can lead to earlier global access and approval of new drugs worldwide, thereby avoiding significant lag in the availability of new drugs in some regions.

MRCTs facilitate synchronizing clinical drug development timing across various regions, contrasting with independent local studies. They are beneficial in both the exploratory and confirmatory stages of drug programs. Early identification of intrinsic and extrinsic factors is crucial for effectively planning confirmatory MRCTs. See illustrative examples in Figure 1, it also shows the use of MRCTs in the overall design of the drug development programme.

In conclusion, the strategic use of MRCTs that are appropriately planned and carried out in accordance with this guideline will increase drug development efficiency, enable simultaneous submission of marketing authorisation applications and regulatory decision-making in multiple regions, and allow for the investigation of the treatment effect to diverse populations. As a result, MRCTs may typically end up being the best choice for investigating a new drug for which several regions have scheduled regulatory submissions.

2.1.2 Good Clinical Practice (GCP) Requirements and MRCTs

All sites involved in multi-regional clinical trials (MRCTs) must adhere to quality, ethical, and regulatory standards, specifically ICH E6 Good Clinical Practice (GCP). This includes making sites available for GCP inspections and implementing predefined monitoring plans to mitigate risks to participants and ensure reliable study results. Centralized and risk-based monitoring is recommended to address regional variations in subjects’ retention and adverse event reporting. Effective communication of information among sponsors, trial management teams, and participating sites is essential.

2.1.3 Scientific Consultation Meetings with Regulatory Authorities

Sponsors of MRCTs are encouraged to have scientific consultation meetings with rele

vant regulatory authorities.  These interactions should take place during the planning stage

of MRCTs to discuss the regulatory requirements for the overall development plan and

the acceptability of MRCT data to support marketing authorisations.  Conducting such

consultation meetings early in the planning stage of MRCTs will enable the comments

received from regulatory authorities to be taken into consideration.  The sponsor should

prepare the protocol and other relevant documents, and it may be beneficial to include

information as to which authorities are providing regulatory advice, and how that advice

is being taken into consideration.  Consultation with authorities may happen at various

stages affecting different aspects of protocol development.  Inter-authority scientific

discussions are encouraged to allow for harmonisation of study requirements. 

The entire text of ICH E17 could not be presented in this article due to space constraints. To properly grasp GENERAL PRINCIPLES FOR PLANNING AND DESIGN OF MULTI-REGIONAL CLINICAL TRIALS, it is advised that you read the entire guideline. The link is provided below

Reference:

https://database.ich.org/sites/default/files/E17EWG_Step4_2017_1116.pdf

Dr Subramanian S Iyer