Methodology to validate surrogate endpoints in clinical trials: which level of evidence is fit for purpose?

Abstract

Finding and validating surrogates endpoints in clinical trials is critical to the development of many new therapies. It enables to decide whether trial results can be read out earlier, and/or to infer results on clinically-significant endpoints in cases where appropriate trials for these results are not ethically feasible and/or too long. First, we will discuss the reasons behind the growing need for surrogates identification and validation and how it translated into recent guidelines in Germany and the UK. This topic will be addressed in the context of surrogacy for overall survival for different types of cancers and infections. Recent examples of regulatory acceptance and rejections will be analyzed. Second, we will present methodologies used for surrogate validation – their purpose and limitations. The methodologies will be illustrated with specific examples that evaluate two survival endpoints conducted with software newly-developed for this purpose. Finally, we will discuss the context in which surrogates have more potential to be accepted – the types of disease, the type of submission and type of intervention that lead to best results. An audience composed of clinicians, modelers, statisticians, members of industry and regulatory bodies will be expected to share their experiences and views on the use of surrogates for decision-making. We will facilitate the discussion to bring out cases of need for surrogates at launch or for reimbursement, cases of regulatory acceptance of surrogates, different ways to validate the surrogates, and recent experience with NICE & G-BA on surrogate use and validation.