OBJECTIVES : In Europe, approval under exceptional circumstances (EC) could be granted to drugs that are unable to provide comprehensive efficacy and safety data due to disease rarity or unethical issues. Therefore, these drugs may reach the market with only limited clinical evidence. This study aims to investigate how the drugs approved under EC are evaluated in terms of actual benefit (AB) and improvement in actual benefit (IAB) by the French health authority (HAS).

METHODS : Drugs granted a European marketing authorization under EC until June 2019 were identified from European Medicines Agency (EMA) website. HAS reports of these drugs were reviewed to extract reimbursement decision and recommendations.

RESULTS : A total of 34 drugs were approved under EC in Europe, among which 6 were withdrawn, and 8 were not assessed by HAS, thus 20 HAS reports were reviewed for analysis. AB was appraised as important for 12 drugs, moderate for 5 drugs, weak for 1 drug and insufficient for 2 drugs. Only 2 drugs received negative recommendations: Kolbam® due to limited patient number (N=13) for efficacy evaluation, and Raxone® with insignificant efficacy versus placebo. Among the 12 drugs rated with important AB, 9 had non-comparative trials, 2 had double-blinded placebo controlled trial, and 1 had before-after study as pivotal studies. IAB was rated as major for 1 drug, important for 3 drugs, moderate for 2 drugs, minor for 5 drugs and no improvement for 1 drug.

CONCLUSIONS : Products approved under EC have high likelihood of reimbursement despite scarce clinical evidence, but the incremental added benefit is challenging. In France, single arm trial does not seem an obstacle for reimbursement of drugs indicated for rare diseases with no available alternatives.