Sample Size Needed to Demonstrate BE for Narrow Therapeutic Drugs

PURPOSE

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 The US Food and Drug Administration (FDA) recently published new draft guidance on the requirement for warfarin formulations, which is considered a NTI drug, and the proposed approach is also the reference SABE where the criteria will be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.

Table 1 – Summary of Simulated Data Using Fully Replicated Design

Table 3. The Estimated Sample Size for Two-way Crossover Design Using Traditional Approach

CONCLUSION

Our simulations showed that SABE approach as proposed by FDA for NTI appears to be more flexible when assessing the sample size for BE demonstration.
1. The passing rate increases as the ISCV decreases in each of three sample size groups.
2. Total of 24 sample size showed there were more than 90% passing rates when ISCV is equal or less than 15% with strong power.
3. For simulations data which was met BE criteria, if the Ratio of Geometric Means is within 90%-111%, the BE passing rate is above 90% for different levels of ISCV.
4. Sample size of N=24 may be appropriate if ISCV is less than or equal to 15% in a fully replicate design to be well powered.
5. The sample size estimated using this reference SABE in the fully replicated design seems less conservative as compared to the other tightened approach of 90% CI falling within 90% to 111%.

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