Yuki Ando

Multiregional Clinical Trials: Japanese Perspective on Drug Development Strategy and Sample Size for Japanese Subjects

Multiregional clinical trials including Japanese subjects are playing a key role in new drug development in Japan. In addition to the consideration of differences in intrinsic and extrinsic ethnic factors, deciding the sample size of Japanese subjects is an important issue when a multiregional clinical trial is intended to be used for Japanese submission. Accumulated experience suggests that there are several points to consider, such as the basic principles described in the guidance document, drug development strategy, trial phase, and disease background. The difficulty of interpreting the results of Japanese trials should also be considered.

Practical issues and lessons learned from multi‐regional clinical trials via case examples: a Japanese perspective

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.

Clinical Development and Trial Design of Biosimilar Products: A Japanese Perspective

In recent years, development of biosimilar products has attracted considerable attention. Because of the structural complexity of biologics, it is difficult to demonstrate that a biosimilar product is identical to the reference product. Therefore, for the development of biosimilar products, we need to adopt an approach that is different from generic product development. In this article, we discuss the guidelines for the development of biosimilar products along with the case examples of biosimilar product development in Japan. In addition, we discuss several issues of clinical trial design for demonstrating biosimilarity to a reference product.

Sample Size Considerations in Clinical Trials when Comparing Two Interventions using Multiple Co-Primary Binary Relative Risk Contrasts.

The effects of interventions are multidimensional. Use of more than one primary endpoint offers an attractive design feature in clinical trials as they capture more complete characterization of the effects of an intervention and provide more informative intervention comparisons. For these reasons, multiple primary endpoints have become a common design feature in many disease areas such as oncology, infectious disease, and cardiovascular disease. More specifically in medical product development, multiple endpoints are used as co-primary to evaluate the effect of the new interventions. Although methodologies to address continuous co-primary endpoints are well-developed, methodologies for binary endpoints are limited. In this article, we describe power and sample size determination for clinical trials with multiple correlated binary endpoints, when relative risks are evaluated as co-primary. We consider a scenario where the objective is to evaluate evidence for superiority of a test intervention compared with a control intervention, for all of the relative risks. We discuss the normal approximation methods for power and sample size calculations and evaluate how the required sample size, power, and Type I error vary as a function of the correlations among the endpoints. Also we discuss a simple, but conservative procedure for appropriate sample size calculation. We then extend the methods allowing for interim monitoring using group-sequential methods. Supplementary materials for this article are available online.

Balancing societal needs and regulatory certainty: the case study of peramivir in Japan.

Regulators must balance societal and medical requirements against the need for certainty about benefit and risk for new medicines. This is described in a case study of the expedited review and approval of peramivir, a novel neuraminidase inhibitor, in Japan in the context of the emergence of new strain of influenza in 2009. The case illustrates the importance of regulatory science and transparency in supporting such decision making.

Adaptive clinical trials for new drug applications in Japan

Adaptive design is regarded as an efficient method for clinical trials in order to increase the success rate of a new drug in development, and recently has been actively discussed among regulatory agencies, industry and academia. Since adaptive design involves interim analyses and is more complex than traditional fixed design, some points such as possibility of introducing statistical and operational bias should be considered when planning and implementing such trials. In this article, we share our perspectives in the consideration of adaptive design clinical trials based on our experiences discussing adaptive design in clinical trial consultation meetings in Japan.

Discussion of “Adaptive and Model-Based Dose-Ranging Trials: Quantitative Evaluation and Recommendations”

Dose-finding is one of the most important steps during the drug development process in all disease areas. Failure to determine the appropriate dose leads to lower success rates of clinical trials in the late phases of development. Use of an adaptive design for dose-finding would help sponsors investigate a broader range of doses efficiently, thereby increasing the success rate of clinical trials and facilitating the clinical drug development process. Although adaptive dose-ranging (ADR) approaches have been widely studied, a clear summarization and discussion of the methods is lacking. This paper summarizes several current methods and is a good reference for biostatisticians/investigators who design ADR trials. An increasing number of clinical trial consultation meetings are being conducted to discuss ADR trials within the Pharmaceuticals and Medical Devices Agency (PMDA). To date, these meetings primarily discuss the necessity and the advantages of such trials. However, the methodology of ADR will be discussed in detail in the near future, making this paper a useful resource. We begin with a brief mention of our experiences and perspectives in reviewing ADR trials based on the PMDA clinical trial consultation meetings (Section 2). In Section 3, there is a description of the simulation results and their findings with respect to the ADR approaches of the paper. In Section 4, we conclude our discussion with some recommendations.