A Bayesian approach to pilot-pivotal trials for bioequivalence assessment

Background:
To demonstrate bioequivalence between two drug formulations, a pilot trial is often conducted prior to a pivotal trial to assess feasibility and gain preliminary information about the treatment effect. Due to the limited sample size, it is not recommended to perform significance tests at the conventional 5% level using pilot data to determine if a pivotal trial should take place. Whilst some authors suggest to relax the significance level, a Bayesian framework provides an alternative for informing the decision-making. Moreover, a Bayesian approach also readily permits possible incorporation of pilot data in priors for the parameters that underpin the pivotal trial.

Methods:
We consider two-sequence, two-period crossover designs that compare test (T) and reference (R) treatments. We propose a robust Bayesian hierarchical model, embedded with a scaling factor, to elicit a Go/No-Go decision using predictive probabilities. Following a Go decision, the final analysis to formally establish bioequivalence can leverage both the pilot and pivotal trial data jointly. A simulation study is performed to evaluate trial operating characteristics.

Results:
Compared with conventional procedures, our proposed method improves the decision-making to correctly allocate a Go decision in scenarios of bioequivalence. By choosing an appropriate threshold, the probability of correctly (incorrectly) making a No-Go (Go) decision can be ensured at a desired target level. Using both pilot and pivotal trial data in the final analysis can result in a higher chance of declaring bioequivalence. The false positive rate can be maintained in situations when T and R are not bioequivalent.

Conclusions:
The proposed methodology is novel and effective in different stages of bioequivalence assessment. It can greatly enhance the decision-making process in bioequivalence trials, particularly in situations with a small sample size.