Access to orphan drugs despite poor quality of clinical evidence

center dot The clinical evidence level of orphan medicines in European market authorization submissions is low: few randomized controlled trials, short treatment follow-up, rarely hard clinical endpoints. center dot The success rate at centralized market authorization is lower for orphan drugs (62.9%) than for non-orphan medicines (70.7%). center dot The burden of disease of rare diseases is high, affecting the lives of at least 30 million patients in the European Union (EU). WHAT THIS STUDY ADDS center dot As opposed to market authorization, orphan drugs gain reimbursement more easily than non-orphan innovative drugs. center dot Lower quality of evidence of clinical efficacy and safety, more uncertainty on cost-effectiveness and higher product prices are accepted for orphan drugs. center dot There is a need for collaboration between the European Commission, competent for market authorization, and the EU member states, competent for reimbursement, in assessing the therapeutic risks and benefits of orphan drugs, to reduce the evidence gap post marketing. AIM We analysed the Belgian reimbursement decisions of orphan drugs as compared with those of innovative drugs for more common but equally severe diseases, with special emphasis on the quality of clinical evidence. METHODS Using the National Health Insurance Agency administrative database, we evaluated all submitted orphan drug files between 2002 and 2007. A quality analysis of the clinical evidence in the orphan reimbursement files was performed. The evaluation reports of the French 'Haute Autorite de Sante', including the five-point scale parameter 'Service Medical Rendu (SMR), were examined to compare disease severity. Chi-squared tests (at P < 0.05 significance level) were used to compare the outcome of the reimbursement decisions between orphan and non-orphan innovative medicines. RESULTS Twenty-five files of orphan drugs and 117 files of non-orphan drugs were evaluated. Twenty-two of 25 (88%) submissions of orphan drugs were granted reimbursement as opposed to 74 of the 117 (63%) non-orphan innovative medicines (P = 0.02). Only 52% of the 25 orphan drug files included a randomized controlled trial as opposed to 84% in a random control sample of 25 non-orphan innovative submissions (P < 0.01). The duration of drug exposure was in most cases far too short in relation to the natural history of the disease. CONCLUSIONS Orphan drug designation predicts reimbursement despite poor quality of clinical evidence. The evidence gap at market authorization should be reduced by post-marketing programmes, in which the centralized regulatory and the local reimbursement authorities collaborate in an efficient way across the European Union member states.