Considerations on Observing Consistent Results of Treatment Effects in Multiregional Trials
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Considerations on Observing Consistent Results of Treatment Effects in Multiregional Trials
Jungo Sawa Schering Plough K K . Tokvo. japan
Akihiro Iwata Schering Plough K K . Tokyo. Japan
Yoshie Onishi Sanofi-Aventis K K , Japan
We evaluate the probability of observing consistent results and the relationships between the required sample size and the effect size for a confirmatory multiregional trial. Three methods are evaluated, including two methods (methods 1 and 2) already proposed by the Ministry of Health, Labor and Welfare in 2007 and a new method proposed to confirm the ratio of one region to the other regions of the true treatment effect in a multiregional trial. We discuss method 1 and a new method with a survival endpoint and method 2 with a normal endpoint using numeric equations
Key Words Probability of observing consistent results; Log hazard ratio: Multiregional trial: Sample size: One region
Correspondence Address jungo Sawa, Kobe Pharmaceutical University. 4 - 1 9 - I , Moloyamakitamachi. Higashinada. Kobe. Japan. 658-8588 (email: kyomu @kobepharma-u. ac.ip).
INTRODUCTION A report by Glickman ( 1 ) indicates the importance of evaluating the outcome in the population in proportion to the potential uses of the products after approval. In Japan, “Basic Principles on Global Clinical Trials” was issued by the Ministry of Health, Labor and Welfare (MHLW) in 2007 ( 2 ) .In the guidance, participating in multiregional trials is recommended to resolve the “drug lag” in Japan. In addition, the sixth Q&A section particularly describes the importance of the consistency of results between the entire study population and the Japanese population to extrapolate the overall results into one region (ie, Japan). Therefore, the number of Japanese patients needed in the study should be carefully planned as well as the interpretation of the results. Meanwhile, minimizing the sample size in one region in a multiregional trial is an important issue in light of the cost and time involved. The guidance provides two examples of methods of choosing the number of Japanese subjects in multiregional studies. Li et al. (3)examine the probability of observing negative subgroup results and the interpretation of the results. Kawai et al. investigate (4) the minimal sample size for the smallest region with high probabilities of observing
and simulations. We show that the probability of observing consistent results is not related to the effect size and the conditional probability is slightly superior to the unconditional one in both method I and the new method. We conclude that the probability of observing consistent results with the new method decreases according to the increase of the number of regions in method I previously proposed. Nonetheless, the slight difference between the new method and method I was observed in a small proportion of patients, which is less than 20%.
consistent results focusing on method 2 in the guidance. Quan et al. (5) examine the number of patients required in the study with v
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