Letting post-marketing bridge the evidence gap: the case of orphan drugs

Developing medicines for rare diseases is difficult. Small target populations limit the potential to recover investments in research and development, and even when medicines get to clinical trials, there may be too few patients to support adequately sized trials. Trials for these drugs often also have other shortcomings—for example, the use of placebo as control, surrogate endpoints instead of hard clinical outcomes, or an inadequate length of follow-up. As a result, orphan drugs—those intended for rare diseases (box 1)1—are not only few but often have insufficient evidence of efficacy and safety at the time of approval.2

Regulation introduced in Europe in 2000 aimed to encourage research and development into orphan drugs.1 The regulation did not substantially improve the evidence underlying their approval2 3 4 but allowed regulators to grant marketing authorisation trusting that post-marketing research would bridge the gap of knowledge on their safety and effectiveness. To check whether those expectations are being met and the missing data provided, we examined the evidence generated in the 10 years after marketing …