Harmonization of clinical trial guidelines for assessing the risk of inhibitor development in hemophilia A treatment.

At the present time, the most significant complication of hemophilia therapy is the development of neutralizing antibodies (inhibitors) to factor (F) VIII, which adds greatly to the difficulty and expense of preventing and treating bleeding episodes. Both patient-related and therapy-related variables contribute to the development of inhibitors. The multifactorial nature of inhibitor development and the relatively small numbers of patients that participate in clinical trials make it difficult to accurately assess the risk of inhibitor development. Adding to that challenge is the lack of a uniform standard of design for conducting clinical trials to evaluate the safety of FVIII products. This hinders the comparison of products and is an obstacle to the meta-analysis necessary to make statistically valid assessments of inhibitor risk. This article reviews similarities and differences in clinical trial guidelines of European and US regulatory agencies and discusses the need for their harmonization to facilitate the assessment of FVIII products.