ultiregional clinical trials (MRCTs) enable simultaneous drug evaluation across diverse populations while meeting international regulatory standards. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guideline on MRCTs introduced in 2017 provides a framework for optimizing MRCT design and execution. In recent years, China has emerged as a key player in implementing these guidelines, integrating international standards into its regulatory framework and industry practices. Through collaboration among regulators, academia, and industry, China is strengthening its role in advancing simultaneous global drug development. Since the introduction of ICH E17, progress has been evident in the global implementation of MRCTs, although certain obstacles remain.

Drug development has transformed into a global endeavor aimed at providing patients worldwide with early access to innovative therapies. MRCTs have become a pivotal strategy in this process, enabling the simultaneous development of new drugs while adhering to the rigorous scientific standards required for regulatory approvals across diverse regions. The release of the Multi-Regional Clinical Trials, E17 guideline was a major milestone, offering principles to design, plan, and conduct MRCTs in a manner acceptable to multiple regulatory bodies.

Implementing ICH E17 in MRCTs faces several challenges, including complex trial design, regional differences in clinical practices, inconsistent regulatory requirements, and ethical concerns. To address these challenges, the Research and Development-based Pharmaceutical Association Committee (RDPAC) has played a vital role in promoting ICH E17 implementation in China and worldwide. Building on a consensus Bluebook collectively developed by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NPMA), academia, and industry (the first collaboration of its kind in China), this article provides examples that highlight key developments in core aspects such as pooling strategies, regional sample size allocation, and the holistic assessment of regional benefit-risk profiles. These recent advances reflect a collaborative effort through a tripartite model involving the regulatory agency, academia, and industry, marking an important step in China’s contribution to and leadership in global standards within the broader context of the globalization of drug development.

Advancing Pooling Strategies in MRCTs

ICH E17 emphasizes pooling strategies that enhance flexibility in sample size allocation, facilitate benefit-risk consistency evaluations across regions or subpopulations, and support regulatory decision-making. However, a lack of understanding and application of pooling strategies has been recognized. Surveys conducted by the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Japan Pharmaceutical Manufacturers Association (JPMA) identified the lack of clarity in defining pooling strategies as one of the major reasons for the limited understanding of the guidelines. The Bluebook articulates the process for determining the appropriate pooling strategy using two main approaches: pooled regions (grouping geographical regions, countries, or regulatory regions) and pooled subpopulations (grouping subsets of subjects who share key characteristics such as biomarkers or ethnicity). This process follows a two-step data-driven approach for identifying true effect modifiers (EMs)—intrinsic and/or extrinsic factors (as defined in Ethnic Factors in the Acceptability of Foreign Clinical Data, ICH E5) that significantly impact treatment effects and can be used to define subpopulations.

1. Data collection step: Sources can include medical and scientific literature, public databases, regulatory guidelines, and insights from local healthcare professionals.
2. Data evaluation step: Analyze the collected data to determine whether these factors are true EMs. This evaluation often involves early-phase clinical trials, exposure-response analysis, and pharmacokinetics (PK) and pharmacodynamics (PD) modeling.

When true EMs are difficult to determine*, pooling by geographic regions may serve as an alternative. For instance, grouping East Asia can be a reasonable approach when the region shows internal consistency, though it may still be necessary to focus on a single population (e.g., China) when meaningful differences exist. Early communication with regulatory authorities remains vital to ensure that pooling decisions and associated analytical plans are clearly documented.

* Identifying true EMs requires extensive data collection and evaluation from diverse sources, such as biomarkers, genetic data, clinical practices, and epidemiology. Even with thorough analysis, residual confounding factors may remain, and, in some cases, EMs are only revealed after pivotal trials, necessitating further investigation or additional trials.

Sample Size Allocation to Regions: A Case Example in Conjunction with Pooled Regions

The ICH E17 guideline outlines five approaches to regional sample size allocation, each with its own advantages and disadvantages. A balanced approach is generally recommended by the ICH E17 to facilitate recruitment, ensure timely trial completion, and provide sufficient data for assessing benefit-risk profile consistency across regions:

• proportional allocation: allocation of subjects to regions in proportion to the size of region and disease prevalence
• equal allocation: allocation of equal numbers of subjects to each region

The same allocation recommendations remain applicable when pooling strategies, such as pooled regions, are used. The following hypothetical example illustrates how these recommendations, combined with pooling strategies, justify the sample size allocation for an experimental drug targeting tumor mutation–positive cancer patients.

• An estimated 2,600,000 patients worldwide are affected by this cancer.
• East Asia has the highest prevalence (1,180,000), followed by North America and Europe (910,000), Africa (50,000), and the rest of the world (460,000).
• The tumor mutation rate is 3% in East Asia, 16% in North America and Europe, 10.3% in Africa, and 5% in the rest of the world.
• The proportion of tumor mutation–positive patients is highest in North America and Europe (69%), while East Asia accounts for 17.3%, Africa 2.5%, and the rest of the world 11.1%.
• The planned enrollment for an MRCT allocates approximately 20% to East Asia, 65% to North America and Europe, 3% to Africa, and 15% to the rest of the world.

Additionally, it is important to ensure that no single region is significantly overrepresented or underrepresented, as this can hinder health authorities’ ability to evaluate regional benefit-risk profiles if trial results are dominated by one area. In this example, China plans to enroll at least half of the East Asian patients, providing a representative portion of participants from the region.

Regional Benefit-Risk Profile Consistency Evaluation: A Holistic Approach Based on Totality of Evidence

Under ICH E17, evaluating regional benefit-risk profile consistency in MRCTs involves assessing whether a drug’s benefit-risk profile remains consistent across various (pooled) regions. Regional consistency is evaluated using descriptive methods, forest plots, and statistical models that adjust for covariates. In the spirit of ICH E17, the Bluebook recommends a holistic approach: considering the totality of evidence rather than relying on a single criterion or endpoint. In practice, observing regional differences in MRCTs is not uncommon. When they arise, a structured exploratory framework is advocated to identify potential causes and ensure a systematic evaluation. Key aspects include:

• Clinical relevance: Determines whether regional differences impact real-world treatment, considering factors such as disease burden and medical practices. Numerical differences alone do not always indicate clinical significance.
• Disease and treatment factors: Reviews variations in epidemiology, diagnostics, and treatment approaches. Changes in clinical guidelines during a trial can affect outcomes.
• Clinical pharmacology: Examines drug absorption, metabolism, and elimination differences using PK and PD modeling. Genetic factors and body weight may also play a role.
• Biological plausibility: Ensures observed differences align with scientific knowledge. If discrepancies lack a clear biological explanation, confounding factors or trial biases should be investigated.
• Internal consistency: Checks whether treatment effects are consistent across endpoints and subgroups within a region.
• External consistency: Compares findings with other trials or real-world data to ensure results are not isolated to a single study.
• Statistical uncertainty: Assesses whether differences arise from random variation, especially in small sample sizes, using tools like funnel plots.

This structured framework helps interpret regional differences by integrating biological, clinical, and statistical evidence. It supports regulatory decision-making and ensures that MRCTs contribute to reliable global drug development.

Conclusion

The implementation of the ICH E17 guideline has reshaped MRCTs, promoting global regulatory alignment and improving patient access to new therapies. In the past few years, progress has been made in integrating ICH E17 principles into drug development, strengthening scientific rigor and regulatory acceptance while reducing inefficiencies. Recently, the CDE released a draft guidance (in Chinese) on benefit-risk assessment based on MRCTs in simultaneous global new drug development, reflecting the regulator’s expectation of advancing innovative drugs through MRCTs.

As global drug development evolves, emerging trends will influence MRCTs. Multinational companies have already started using the Bluebook to re-evaluate relevant MRCT strategies (e.g., regional/country sample size allocation, streamlined NDA submission dossier strategy, etc.) to further enhance drug development efficiencies. Enhancing diversity in clinical trials will improve generalizability, with MRCTs playing a key role in broader inclusion. Decentralized clinical trials (DCTs) will streamline operations through remote participation, while adaptive trial designs will enable real-time modifications for efficiency. Advances in digital technologies, including artificial intelligence, real-world evidence, and predictive analytics, will further optimize trial execution and regulatory decision-making. As demonstrated by this collaborative RDPAC Bluebook effort, these new trends will require even closer collaboration among stakeholders to further advance simultaneous global drug development in China.