Surrogate endpoints and non-inferiority trials in chronic viral hepatitis.

The Authors comment on paper by Garattini S, Bertelè V. Ethics in clinical research. J Hepatol 2009;51:792–797 and particularly on their statement that ‘‘Quality of life, morbidity and mortality should always be the primary hard end-points for evaluating new drugs”. The authors believe that this rule should be applied with caution in the field of chronic viral hepatitis because of the slow progression of this disease and the availability of surrogate virological end-points. In fact a trial, comparing the effects of different drugs in the setting of HBV-related or HCV-related chronic hepatitis with survival as end-point, would be considered poorly ethical. Indeed, it would take several decades to demonstrate the superiority of one drug over another, and patients would be deprived of the best treatment strategy for a prolonged period. Obviously, toxicity and adverse events must be carefully monitored in trials with a surrogate endpoint. Moreover, the authors think that availability of multiple non-inferior drugs would give the physician a better opportunity to ‘‘customize” treatment for individual patients. Lastly, new non-inferior drugs with lower costs than previous drugs would be welcome. In non-inferior trials, it is important that the margin of noninferiority is based on clinical grounds. In fact, using a wide margin of non-inferiority, a clearly inferior treatment would be considered non-inferior. In other words, a wide non-inferiority margin does not allow us to translate into the clinical setting what is ‘‘non-inferior” from a statistical point of view.