Methodological approaches for generating robust evidence from trials in rare diseases

Generating scientific evidence from clinical trials for the treatment of rare diseases is associated with particular challenges. Standard clinical trial methodology is hardly ever appropriate in the rare disease setting, so innovative approaches need to be developed, evaluated and established. Among the various innovative methodologies introduced two approaches are discussed in more detail: the influence of randomised treatment allocation and the integration of external control information, both with respect to the level of evidence. The evaluation of the impact of randomised treatment allocation is guided by a structured approach which can be used to inform the design in the planning phase of a trial and select an appropriate randomisation procedure. Moreover, after the conduct of the trial the magnitude of actual bias can be estimated, and both a bias-adjusted treatment effect and a bias-adjusted test can be derived to put the level of reachable evidence into context. Adding external control data to randomised clinical trials appears charming with respect to small numbers of available patients but raises the question of how this can be achieved without compromising on the quality of evidence. One approach that seems promising in this respect is to check after a determined proportion of the total sample size whether the addition of external control data appears justified without compromising the pre-specified level of evidence. New approaches need to be accepted by all stakeholders. Their strengths and weaknesses in terms of reachable evidence need to be evaluated and presented in a such a way that they are comprehensible for patients, clinicians, industry, regulatory and HTA bodies.