Abstract
In order to fulfill the requirement of a new drug application, a sponsor needs to conduct randomized clinical trials to demonstrate that the test treatment is effective. With placebo control in the clinical trial, efficacy of the test treatment is demonstrated by showing that the test treatment is statistically and clinically superior to placebo. Clinical trials designed with the objective to demonstrate the test treatment is noninferior or equivalent to the active control treatment have long history been applied in drug development for generic and some specific products. On the other hand, due to the ethical concern of exposing patients to placebo when there are proven therapeutic methods available, many of the clinical trials can only be designed with approved active control treatment. Because of the lack of placebo exposure in the current clinical trial, neither sponsor nor the regulatory reviewer can assess whether the test treatment is superior to placebo directly. When the concept of noninferiority and equivalence of bioequivalence trials is applied to this type of trials, it leads to the complication and indirectness to the efficacy assessment of the test treatment (superior to placebo). This chapter discusses the fundamental concepts of noninferiority and equivalence testing applied in generic and some specific drug products and how they be extended in the application for the interpretation for “test treatment is superior to placebo” assessment. We will discuss also why it makes the drug efficacy evaluation so complicated with such an application. Limitations and strength of evidence of using noninferiority or equivalence testing for efficacy evaluation will also be discussed.
This chapter does not represent the official position of the Food and Drug Administration.
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Acknowledgements
The authors want to acknowledge the contributions of many coauthors involved in the many collaborative works and the colleagues provided important information and examples gathered from their review experiences. This article is the fruit of all the collaborative works. The materials presented in this article are also part of the materials that the authors used in the preparation of a short course offered at the Applied Statistics Symposium in 2006, Korea Food and Drug Administration, and joint Statistical Meeting in 2009. The second International Pharmaceutical statistics Workshop sponsored by China East Normal University in 2012. For that we want to thank International Chinese Statistic Association, Korea Food and Drug Administration, China East normal University, and American Statistical Association for sponsoring the short courses. Last but certainly not the least, the contributions of two editors of the book and the referees of the manuscript should be acknowledged. Without their careful reading, comment, and questions, the manuscript would not be as complete and readable.
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Tsong, Y., Zhang, J. (2012). Active-Controlled Clinical Trials. In: Tang, W., Tu, X. (eds) Modern Clinical Trial Analysis. Applied Bioinformatics and Biostatistics in Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4322-3_7
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DOI: https://doi.org/10.1007/978-1-4614-4322-3_7
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