Multi-regional clinical trials and global drug development.

The landscape of drug development evolves with the globalization of the health industry as an integral part of the economy as well as public health worldwide. It is recognized that there are major advantages of being involved in conducting Multi-Regional Clinical Trials (MRCTs) as a part of it: Increasing drug development efficiency, promoting local or regional clinical research, providing local regulatory authorities a large body of data including their own patients studied under the same standard to evaluate the medical product, benefiting citizen patients to access new drugs around the same times as other nations. For these reasons, participating in various MRCTs globally is a rising trend for China as an emergent country in its biopharmaceutical industry and medical-health policy. China has joined the ICH as a member country in 2017. ICH E-17 contains general principles of MRCTs but lacks specifics. In this article, we highlight pertinent design and analysis issues with MRCTs and discuss current common approaches from the statistical aspects.

Proposal for the revision of guidelines for clinical trials of vaccines to prevent infectious diseases in Japan

ABSTRACTThe primary objective of a multiregional clinical trial (MRCT) is to assess the efficacy of all participating regions and evaluate the probability of applying the overall results to a specific region. The consistency assessment of the target region with the overall results is the most common way of evaluating the efficacy in a specific region. Recently, Huang et al. (2012) proposed an additional trial in the target region to an MRCT to evaluate the efficacy in the target ethnic (TE) population under the framework of simultaneous global drug development program (SGDDP). However, the operating characteristics of this statistical framework were not well considered. Therefore, a nested group sequential program for regional efficacy evaluation is proposed in this paper. It is an extension of Huang’s SGDDP framework and allows interim analysis after MRCT and in the course of local clinical trial (LCT) phase. It is able to well control the family-wise type I error in the program level and enhances the flexibility of the program. In LCT sample size estimation, we introduce virtual trial, which is transformed from the original program by using discounting factor, and an iteration method is employed to calculate the sample size and stopping boundaries of interim analyses. The proposed sample size estimation method is validated in the simulations and the effect of varied weight, effect size of TE population, and design setting is explored. Examples with normal end point, binary end point, and survival end point are shown to illustrate the application of the proposed nested group sequential program.

In order to encourage innovative medicine to address Chinese unmet medical needs, China has changed its drug regulatory landscape to speed up access to new medicines. In order to understand the fast‐changing landscape and to enable planning of more global drug development programs and study designs in China, we reviewed 15 published clinical pharmacology‐related guidances by the National Medical Products Administration (NMPA), and compared them with reference guidances from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the International Conference on Harmonization (ICH), to understand the similarities and differences, especially any China‐specific requirements, such as ethnic sensitivity analysis. Overall, by reviewing these clinical pharmacology‐related NMPA guidances, it is clear that NMPA guidances are very similar to FDA, EMA, and ICH guidances. There are no relevant differences in the major principles, but some differences in structure, contents, and focus were noted. The NMPA is adapting flexibility statements into newly published guidances. Ethnic sensitivity analysis needs to be implemented early in drug development plans. The NMPA encourages sponsors to conduct early clinical trials in China or include China early in multiregional clinical trials, and to obtain safety, efficacy, and pharmacokinetic data for ethnic sensitivity analysis. Depending on the stage of development, ethnic sensitivity analysis can be conducted using in vitro or literature data, other Asian clinical data, or Chinese clinical data.

Delays in the introduction to the Japanese market of drug-eluting stents (DES) developed overseas (i.e., "device lag") decreased sharply between 2004 and 2012. The reduction accompanied a shift in clinical development from a succession pattern (initial product development and approval overseas followed by eventual entrance into the Japanese market) to parallel development (employing multiregional clinical trials (MRCTs)). Although resource-intensive in the short-term, MRCTs are proving to be an effective tool in simultaneous global product development. Creative study designs and the absence of significant ethnic differences in Japanese subjects regarding DES safety and efficacy and the pharmacokinetic behavior of their coating drugs propel this process. More general factors such as medical need and industry incentivization also encourage this shift. Physicians' preference for DES over other percutaneous coronary interventions, the expanding global DES market, and streamlined development and approval prospects each motivate industry to continue investing in DES product development. The efforts of various stakeholders were also integral to overcoming practical obstacles, and contributions by 'Harmonization by Doing' and a premarket collaboration initiative between the USA and Japan were particularly effective. Today, USA/Japan regulatory cooperation is routine, and Japan is now integrated into global medical device development. MRCTs including Japanese subjects, sites, and investigators are now commonplace.

ABSTRACTIn recent years, multi-regional clinical trials (MRCT) that conduct clinical trials simultaneously in Asian Pacific region, Europe, and the United States have become very popular for global pharmaceutical development. The main purpose of multi-regional clinical trials is to shorten the time for pharmaceutical development and regulatory submission, and approval around the world. In practice, however, clinical results observed from some regions (sub-population) may not be consistent with the results from other regions and/or all regions combined (entire population). The inconsistency observed may be due to ethnic differences in different regions, differences in medical practice, time points of assessment, or by random chance due to small sample size for the region. Some regional regulatory agencies require consistency evaluation between local country results and overall results. However, the challenge is there is no detailed guidance on the definition of ‘consistency’ and methodology to evaluate it. Therefore, the questions are: how to evaluate consistency and what statistical methods are appropriate to be used for consistency evaluation? In this article, several statistical tests for consistency (similarity) between clinical results observed from a specific sub-population and the entire population are proposed. These methods are compared through extensive simulation. As most published articles discussed consistency evaluation for superiority situations, we have discussed consistency evaluation for non-inferiority situation in this article through a simulated example concerning consistency in some countries. Recommendations of the statistical methods to be used for consistency evaluation are given. Other aspects that should be considered for consistency evaluation are also provided.

Editor's Note: In this Meeting Report, Tetsuomi Takano provides an excellent summary of 2 related tutorial sessions held at the DIA 6th Annual Conference in Japan for Asian New Drug Development (KFC Hall, Tokyo, Japan, April 27, 2012). The sessions focused on best practices for development regulatory affairs and clinical development related to multiregional clinical trials (MRCTs) in China, Korea and Taiwan. I am grateful to Mr Takano for this contribution to the journal, and I am sure readers will find it both interesting and educational. J. Rick Turner, Outgoing Editor-in-Chief .

To accelerate the drug development process and shorten approval time, the design of multiregional clinical trials (MRCTs) incorporates subjects from many countries/regions around the world under the same protocol. After showing the overall efficacy of a drug in all global regions, one can also simultaneously evaluate the possibility of applying the overall trial results to all regions and subsequently support drug registration in each of them. In this paper, we focus on a specific region and establish a statistical criterion to assess the consistency between the specific region and overall results in an MRCT. More specifically, we treat each region in an MRCT as an independent clinical trial, and each perhaps has different treatment effect. We then construct the empirical prior information for the treatment effect for the specific region on the basis of all of the observed data from other regions. We will conclude similarity between the specific region and all regions if the posterior probability of deriving a positive treatment effect in the specific region is large, say 80%. Numerical examples illustrate applications of the proposed approach in different scenarios.

The multi-regional clinical trials (MRCTs) being administered in different regions of the world now play a major role in providing evidence for the efficacy and safety of new drugs amidst the simultaneous global development and worldwide registration of such drugs, in support of the expeditious availability of medical products to patients. However, such trials present considerable challenges as far as quality, design, implementation, analysis, and interpretation are concerned. In this article, we share our observations and lessons learned from the design, implementation, analysis, and interpretation of some MRCTs with case examples. Current Japanese regulatory guidance on MRCTs is introduced along with some suggestions for design, implementation, and interpretation.

Globalized drug development studies, such as multiregional clinical trials (MRCTs), have attracted much attention due to their ability to expedite drug development and shorten the time lag of drug release. While observing the overall effect of a new drug, the region-specific effects to support drug registration in constituent regions can also be evaluated. Several challenges arise in conducting MRCTs, such as the heterogeneity in the variability of the primary endpoint across regions. However, most of the existing statistical methods assume a common variability, which may not be valid in practice due to differences across regions (eg, diversities in ethnicity or disparities in medical culture/practice). We present a statistical method for the design and evaluation of MRCTs to consider the heterogeneous variability across regions. We assessed the overall sample size requirement and addressed the region-specific sample size determination to establish the consistency of treatment effects between the specific region and the entire group. We demonstrate the proposed approach with numerical examples.

Insights in the application of research-grade diagnostic kits for biomarker assessments in support of clinical drug development: Bioanalysis of circulating concentrations of soluble receptor activator of nuclear factor κB ligand

Letter: The Internet of Medical Things (IoMT): A New Frontier in the Digital Age for Rare Disease Clinical Trials and Global Drug Development.

Globalization of oncology drug development has accelerated the adoption of multiregional clinical trials (MRCTs) as pivotal evidence for regulatory approvals in major markets, including Japan. While MRCTs enhance efficiency and generalizability, they introduce challenges related to inter-ethnic variability and data extrapolation. Japan's regulatory framework, guided by pharmaceuticals medical devices agency (PMDA) principles and the "Guideline for Clinical Evaluation Methods of Anticancer Drugs," emphasizes patient efficacy, safety and relevance, historically requiring local data to supplement global findings. This review analyzed the approvals of oncology drugs in Japan over 5 years, focusing on the role of Japanese subgroup data and overall survival (OS) outcomes in pivotal trials. Among 165 approvals for oncology drugs, OS in pivotal trials was set as a sole primary endpoint in 9.1% (15/165) and as co-primary/dual primary endpoints in 10.3% (17/165); alternative endpoints such as progression-free survival were accepted when OS was impractical. In 7.9% (13/165) of all approvals, Japanese subpopulation results diverged from trends of overall population (hazard ratio [HR] > 1 in Japanese subpopulation), and 4.2% (7/165) of the approvals involved trials in which the primary endpoint of OS (including a sole, co-primary or dual primary endpoint) was not achieved. The PMDA decisions reflected holistic evaluation, considering trial design integrity, secondary endpoints, and qualitative consistency rather than rigid HR thresholds. Differences in efficacy in Japanese subgroup rarely impacted labeling, underscoring reliance on global evidence with local scientific considerations. These findings highlight the PMDA's pragmatic approach to endpoint flexibility and extrapolation, reinforcing the importance of early regulatory engagement and strategic alignment in MRCT design for oncology drug development in Japan.

Chapter 7 describes regulatory progress in drug development using multi-regional clinical trial (MRCT) data in Japan in the last decades. Japan has utilized MRCT data even before the issue of the ICH E17 guideline, and such experiences have been reflected in the key principles of the ICH E17 guideline and current practice in Japan. The chapter discusses the challenges and impacts of the ICH E17 guideline implementation in Japan, including the past experiences in reviewing MRCT data for drug approval.

BackgroundRare diseases have been increasingly recognized as unmet medical and health needs worldwide; a growing demand for the development of orphan drugs emerges subsequently. Therefore, it is of great interest for both the Chinese regulatory agency and pharmaceutical companies to keep tract on the clinical development of orphan drugs in China.Objective and methodThis study aims to reveal the current situation and trend of the clinical development of orphan drugs in China, based on the data collected from the Chinese official platform, dating from January 1, 2013 to December 31, 2021.ResultsA total of 331 clinical trials for orphan drugs were extracted from the platform, covering 31 rare diseases and 124 drugs. Increases were seen in the annual number of clinical trials and drugs being tested, with a sharp increase after 2018. About the disease types of the 331 trials, Parkinson disease (young-onset, early-onset) (86, 26%), hemophilia (70, 21%), homozygote hypercholesterolemia (60, 18%) were the most common. Furthermore, it was also observed that the largest number of clinical trial units for rare disease in east China (90, 41%) and the smallest number located in northwest China (18, 6%) and northeast China (18, 6%).ConclusionsThe growth trends illustrate the progress in clinical trial and drug development of rare diseases from 2013 to 2021. However, promoting orphan drugs development still is an important issue in China; at the same time, further efforts should be made for meet the unmet needs of disease types and balance the uneven distribution of medical resources for clinical trial on rare diseases.