Abstract

Biosimilar products are a relative newcomer in the pharmaceutical industry. It was only in 2006 that the first biosimilar product, Omnitrope[textregistered] (somatropin), a human growth hormone produced by Sandoz was approved by the European Medicine Agency, followed later the same year by the US Food & Drug Administration, and in 2009 by Pharmaceuticals and Medical Devices Agency in Japan. The clinical component of a biosimilar development borrows extensively from traditional drug development. However, when it comes to clinical study designs, this may not always be applicable. This article investigates Type I error violations that occur when blinded sample size reviews are applied in equivalence testing as used in biosimilar drug development. We give a derivation which explains why such violations are more pronounced in equivalence testing than in the case of superiority testing. In addition, the amount of Type I error inflation is quantified by simulation as well as by some theoretical considerations. Nonnegligible Type I error violations arise when blinded interim reassessments of sample sizes are performed particularly if sample sizes are small, but within the range of what is practically relevant.

摘要

生物仿制药在制药行业是一个相对较新的名词。直到2006年，山德士生产的第一种生物仿制药产品Omnitrope [stexttroped]（生长激素）才被欧洲医学署批准，同年下半年又获得美国食品药品监督管理局的批准，并于2009年获得批准。由日本制药和医疗器械局提供。生物仿制药开发的临床组成部分大量借鉴了传统药物开发的经验。但是，当涉及临床研究设计时，这可能并不总是适用。本文研究了在生物仿制药开发中使用的等效试验中进行盲法样本量审查时发生的I类错误违规行为。我们给出一个推论，该推论解释了为什么在等效性测试中比在优越性测试中更明显地违反此类违规行为。此外，I类错误膨胀的数量可以通过仿真以及一些理论上的考虑进行量化。当对样本量进行盲目中期重新评估时，尤其是在样本量较小但在实际相关范围内的情况下，会发生不可忽略的I型错误违规。