Challenges of defining reliable clinical surrogate end points in haemophilia trials: a critical review

The success of a treatment in haemophilia patients experiencing a bleeding episode is very difficult to define. A variety of efficacy assessment tools have been developed in an effort to better assess when haemostasis has been achieved. These assessment tools are particularly important for the evaluation of the efficacy of therapeutic agents whose mechanism of action is based on pharmacological activity in haemostasis rather than upon the principle of 'replacement therapy'. This review focuses on a number of efficacy measures, summarizing their methodology and discussing their validity. In addition, future developments and requirements in order to evaluate the effectiveness of haemostatic treatment are discussed. The majority of end points used for evaluation of haemostasis relate to the relief of symptoms arising from bleeds. The results of this review highlight that several efficacy end points are frequently combined in order to provide a more comprehensive assessment of efficacy. Key limitations of current methodology are the subjectivity of assessment by either the patient or clinician, and the incomparability of results between trials.