Statistics Forum: Thomas Jaki and Lisa Hampson

Thomas Jaki and Lisa Hampson

Thursday 05 December 2013, 1200-1230
A54, Postgraduate Statistics Centre Lecture Theatre

Designing multi-arm multi-stage clinical trials with a safety and an efficacy endpoint

Multi-arm clinical trials that compare several active treatments to a common control have been proposed as an efficient means of making an informed decision about which of several treatments should be evaluated further in a confirmatory study. Additional efficiency is gained by including interim analyses and in particular seamless Phase II/III designs have been the focus of recent research. Common to recent work is the constraint that selection and formal testing should be based on a single efficacy endpoint, despite the fact that in practice, safety considerations will often play a central role in determining selection decisions.

In this talk we develop a multi-arm, multi-stage design for a trial with an efficacy and safety endpoint. The design extends group-sequential ideas and considers the situation where a minimal safety requirement is to be fulfilled and the treatment yielding the best combined safety and efficacy trade-off satisfying this constraint is selected for further testing. The treatment with the best trade-off is selected at the first interim analysis while the whole trial is allowed to comprise of J analyses.

We show that the design controls the family-wise error rate in the strong sense and illustrate the method through an example and simulation. We find that the design is robust to miss-specification of the correlation between the endpoints and requires a similar number of subjects to a trial based on efficacy alone.