A statistical framework for quantile equivalence clinical trials with application to pharmacokinetic studies that...

Bridging clinical trials are sometimes designed to evaluate whether a proposed dose for use in one population, for example, children, gives similar pharmacokinetic (PK) levels, or has similar effects on a surrogate marker as an established effective dose used in another population, for example, adults. For HIV bridging trials, because of the increased risk of viral resistance to drugs at low PK levels, the goal is often to determine whether the doses used in different populations result in similar percentages of patients with low PK levels. For example, it may be desired to evaluate that a proposed pediatric dose gives approximately 10% of children with PK levels below the 10th percentile of PK levels for the established adult dose. However, the 10th percentile for the adult dose is often imprecisely estimated in studies of relatively small size. Little attention has been given to the statistical framework for such bridging studies. In this article, a formal framework for the design and analysis of quantile-based bridging studies is proposed. The methodology is then developed for normally distributed outcome measures from both frequentist and Bayesian directions. Sample size and other design considerations are discussed.