Intended for healthcare professionals


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

BMJ 2016; 353 doi: (Published 22 June 2016) Cite this as: BMJ 2016;353:i2978
  1. Roberta Joppi, researcher1 2,
  2. Chiara Gerardi, researcher1,
  3. Vittorio Bertele’, researcher1,
  4. Silvio Garattini, director1
  1. 1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
  2. 2Pharmaceutical Department, Local Health Unit of Verona, Via Salvo D’Acquisto 7, 37122 Verona, Italy
  1. Correspondence to: R Joppi roberta.joppi{at}

Post-approval studies seldom cover the deficit of knowledge about orphan drugs, find Roberta Joppi and colleagues

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

Box 1: Definition of “orphan medicinal product”

European regulation No 141/2000 says that a medicinal product shall be designated as an orphan medicinal product if its sponsor can establish:

a) that it is intended for the diagnosis, prevention, or treatment of a life threatening or chronically debilitating condition that affects ≤5 in 10 000 persons in the EU when the application is made or for which marketing is unlikely to generate sufficient return on investment without incentives

b) And that no satisfactory method of diagnosis, prevention, or treatment of the condition has been authorised in the EU or, if such method exists, that the medicinal product will be of significant benefit to those affected by the condition

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 …

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