Sample Size Needed to Demonstrate Bioequivalence for Narrow Therapeutic Index Drugs: Modeling Based Method
PRESENTED TO: BioPharma Services Inc.
PRESENTED BY: Y. DING, J. HE, P. PEQUENO, F. TRABELSI
PURPOSE
Sample Size Needed to Demonstrate Bioequivalence for Narrow Therapeutic Index Drugs: Modeling Based Method – Sample size calculation plays an important role in pharmaceutical research and development as it allows to have adequate statistical power to draw appropriate conclusions. For Highly variable drug (HVD), the reference scaled average bioequivalence (SABE) is now commonly used and deemed helpful for HVD meet the acceptance criteria. For narrow therapeutic index (NTI) drug, the acceptance criteria are tightened by the regulatory agencies as small differences in dose or blood/plasma concentration may impact significantly on efficacy and/or safety.
The sample size for NTI could be very large when we use the traditional approach-including power, intra-subject coefficient variability (ISCV), ratio for formulations and confidence interval 90%-111% as requested by many agencies.
The US Food and Drug Administration (FDA) recently published new draft bioequivalence guidance on the requirement for warfarin formulations, which is considered a NTI drug, and the proposed approach is also the reference SABE where the criteria will be tightened in relationship to the variability of the reference product. In other words, the reference scaling is expected to be down for NTI. How does this new approach impact the sample size estimation?
Our research applied the proposed FDA approach using 4-way, 2-sequence, fully replicated crossover design to simulate data with different sample sizes at different levels of ISCV of 5%, 10%, 15%, 20% and 22% using thousands of simulations. The objective is to assess the most adequate estimation of the sample size which will give sufficient statistical power to demonstrate BE for NTI drugs
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