A Bayesian approach based on discounting factor for consistency assessment in multi-regional clinical trial.

Multi-regional clinical trial (MRCT) has become an increasing trend for its supporting simultaneous global drug development. After MRCT, consistency assessment needs to be conducted to evaluate regional efficacy. The weighted Z-test approach is a common consistency assessment approach in which the weighting parameter W does not have a good practical significance; the discounting factor approach improved from the weighted Z-test approach by converting the estimation of W in original weighted Z-test approach to the estimation of discounting factor D. However, the discounting factor approach is an approach of frequency statistics, in which D was fixed as a certain value; the variation of D was not considered, which may lead to un-reasonable results. In this paper, we proposed a Bayesian approach based on D to evaluate the treatment effect for the target region in MRCT, in which the variation of D was considered. Specifically, we first took D random instead of fixed as a certain value and specified a beta distribution for it. According to the results of simulation, we further adjusted the Bayesian approach. The application of the proposed approach was illustrated by Markov Chain Monte Carlo simulation.

Bayes shrinkage estimator for consistency assessment of treatment effects in multi-regional clinical trials.

The primary objective of a multi-regional clinical trial is to investigate the overall efficacy of the drug across regions and evaluate the possibility of applying the overall trial result to some specific region. A challenge arises when there is not enough regional sample size. We focus on the problem of evaluating applicability of a drug to a specific region of interest under the criterion of preserving a certain proportion of the overall treatment effect in the region. We propose a variant of James-Stein shrinkage estimator in the empirical Bayes context for the region-specific treatment effect. The estimator has the features of accommodating the between-region variation and finiteness correction of bias. We also propose a truncated version of the proposed shrinkage estimator to further protect risk in the presence of extreme value of regional treatment effect. Based on the proposed estimator, we provide the consistency assessment criterion and sample size calculation for the region of interest. Simulations are conducted to demonstrate the performance of the proposed estimators in comparison with some existing methods. A hypothetical example is presented to illustrate the application of the proposed method.

Identification of Drug Characteristics for Implementing Multiregional Clinical Trials Including Japan.

PURPOSE: Multiregional clinical trials (MRCT) are a standard strategy used to improve global drug approval efficiency and the feasibility of clinical trials. Japan is the world's third largest drug market with a unique health care system, making it a key inclusion as an operational region for MRCT (MRCT-JP) for global drug development. We aimed to identify the factors required for efficient drug development by comprehensively reviewing the clinical trials of drugs approved in Japan to identify the factors associated with whether or not MRCT-JP is implemented. METHODS: We surveyed the review reports and summaries of application data published by the Pharmaceuticals and Medical Devices Agency. We identified drugs for which the clinical trial data package included MRCT-JP and selected the same number of drugs for which the clinical trial data package did not include MRCT-JP from the most recent survey period for comparison. We also examined other publication information, in addition to the review reports, as necessary. The influence of each explanatory variable was analyzed by logistic regression analysis, with whether or not MRCT-JP was implemented as the explanatory variable. Statistical significance was set at 5%. FINDINGS: In the survey period up to September 2017, 165 drugs developed with MRCT-JP were approved for manufacture and sale in Japan. "Respiratory system," "inhalation," "biological drug," and "under review" evaluation status for the United States, European Union, and other areas, "approved" evaluation status for the United States, "new ingredients," "priority review," "non-Japanese firm," and "Top 1-10" and "Top 11-20" drug sales rankings for pharmaceutical companies were identified as potential factors leading to the implementation of MRCT-JP. In contrast, "general anti-infectives for systemic use," "various," "external," "chemical compound," "unsubmitted" evaluation status for both the United States and European Union, and "Top 51+" drug sales rankings were potential factors for not implementing MRCT-JP. IMPLICATIONS: Therapeutic classification and agent type, in addition to capital type and United States and European Union evaluation status suggested by a previous study, were associated with implementing MRCT-JP. It is important to determine the best way to utilize MRCT-JP to maximize the value of products. Our findings were based on successful cases and may therefore be helpful for designing clinical development plans. Appropriate use of MRCT-JP will improve productivity in the pharmaceutical industry.