Group sequential designs for pragmatic clinical trials with early outcomes: methods and guidance for planning and implementation.

Background: Group sequential designs are one of the most widely used methodologies for adaptive design in randomized clinical trials. In settings where early outcomes are available, they offer large gains in efficiency compared to a fixed design. However, such designs are underused and used predominantly in therapeutic areas where there is expertise and experience in implementation. One barrier to their greater use is the requirement to undertake simulation studies at the planning stage that require considerable knowledge, coding experience and additional costs. Based on some modest assumptions about the likely patterns of recruitment and the covariance structure of the outcomes, some simple analytic expressions are presented that negate the need to undertake simulations.

Methods: A model for longitudinal outcomes with an assumed approximate multivariate normal distribution and three contrasting simple recruitment models are described, based on fixed, increasing and decreasing rates. For assumed uniform and exponential correlation models, analytic expressions for the variance of the treatment effect and the effects of the early outcomes on reducing this variance at the primary outcome time-point are presented. Expressions for the minimum and maximum values show how the correlations and timing of the early outcomes affect design efficiency.

Results: Simulations showed how patterns of information accrual varied between correlation and recruitment models, and consequentially to some general guidance for planning a trial. Using a previously reported group sequential trial as an exemplar, it is shown how the analytic expressions given here could have been used as a quick and flexible planning tool, avoiding the need for extensive simulation studies based on individual participant data.

Conclusions: The analytic expressions described can be routinely used at the planning stage of a putative trial, based on some modest assumptions about the likely number of outcomes and when they might occur and the expected recruitment patterns. Numerical simulations showed that these models behaved sensibly and allowed a range of design options to be explored in a way that would have been difficult and time-consuming if the previously described method of simulating individual trial participant data had been used.