Type I Error Inflation of Blinded Sample Size Re-Estimation in Equivalence Testing

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.