Intended for healthcare professionals


The problem of orphan drugs

BMJ 2010; 341 doi: (Published 17 November 2010) Cite this as: BMJ 2010;341:c6456
  1. Robin E Ferner, professor1,
  2. Dyfrig A Hughes, professor2
  1. 1West Midlands Centre for Adverse Drug Reactions, City Hospital, Birmingham B18 7QH, UK
  2. 2Centre for Economics and Policy in Health, Institute of Medical and Social Care Research, Bangor University, Bangor, UK
  1. r.e.ferner{at}

Incentives to make orphan drugs should be proportionate to their benefits

Amifampridine (3,4-diaminopyridine phosphate) is approved for Lambert-Eaton syndrome under laws designed to encourage manufacturers to develop drugs for life threatening or chronically debilitating rare disorders—“orphan diseases.”1 2 It costs up to £44 200 (€52 000; $71 300) per patient each year (doi:10.1136/bmj.c6466). When bought from chemical suppliers, the equivalent dose of 3,4-diaminopyridine base costs £280. The clinical evaluation of the product relies on published literature that refers mainly to clinical experience with the free base form of 3,4-diaminopyridine.3 The European Union legislation under which it is licensed allows medicines to be designated “orphan drugs” during development, receive financial benefits before approval, and have several years free from competition if granted a marketing authorisation (licence).

The intention of orphan drug legislation in the United States and Europe—put bluntly—is to make the development of drugs for orphan diseases profitable. The unintended consequence is exploitation of the rules for profit. Like tax avoidance, this is legal, but not necessarily desirable.

The regulations can be exploited in different ways. Drugs can be licensed successively for several orphan disorders4: imatinib is indicated for seven separate rare malignancies. Medicines already marketed can be licensed for an orphan disease and remarketed: it costs £160 a year to treat a patient with sickle cell disease using 500 mg capsules of hydroxycarbamide (hydroxyurea) licensed for chronic myeloid leukaemia, but it costs £14 900 a year using 1 g tablets of hydroxycarbamide licensed as an orphan drug for sickle cell disease. Oral ibuprofen for analgesia costs £0.08 per gram, but intravenous ibuprofen for patent ductus arteriosus costs £6575 per gram. This is tens or hundreds of times more than the cost of producing sterile ibuprofen solution for intravenous injection in an NHS facility. Diclofenac, which does not have orphan status, costs £0.11 per gram in tablet form and £4.80 per gram as an injection.

There is virtue in a drug having a marketing authorisation because it assures pharmaceutical quality and pharmacovigilance, and it places liability for harm on the holder of the marketing authorisation. However, the regulations are less stringent for orphan drugs, and in many cases, including that of amifampridine, applicants for a licence do not need to conduct prelicensing clinical trials but can rely on pre-existing data that often come from publicly funded research.

Prescribing expensive licensed drugs when cheaper and effective alternatives exist inflates the costs of care, and—because resources are finite—other patients suffer. In the United Kingdom, doctors are discouraged from prescribing unlicensed drugs. The General Medical Council (GMC) requires them to “be satisfied that an alternative, licensed medicine would not meet the patient’s needs.”5 The Medicines and Healthcare Products Regulatory Agency states that “all medicines must have a marketing authorisation unless exempt.”6The Royal Pharmaceutical Society discourages the manufacture of unlicensed medicinal products (“specials”) when licensed products exist.7 Doctors are consequently reluctant to prescribe, and pharmacists to supply, products that are cheap and effective. This is the case even for non-orphan drugs. For example, nifedipine licensed for treatment of hypertension is an effective oral tocolytic and costs just over £1 per patient, but the licensed intravenous tocolytic, atosiban, costing 400 times as much, is often used instead.

The costs of drugs in the United Kingdom fall on the NHS. But in the US, where many patients have to pay, most chose unlicensed bevacizumab for age related macular degeneration ($75 per dose) rather than ranibizumab ($2000 per dose).8

The utilitarian view values health gain for common and rare diseases equally.9 The current incentives to licence drugs for rare diseases in effect put more value on health improvement in rare diseases than in common ones.1 Waxman argued that such a strategy was necessary to overcome the financial disincentives to developing treatments for rare disorders that exist in a free market. There is presumed public support for this view, although a recent study failed to find evidence for it.10 The incentives are now too generous.11 The drug industry should be encouraged to make innovative drugs for rare diseases but accept value based pricing when it arrives in the next Pharmaceutical Price Regulation Scheme.12 Repackaged, rebranded, or recycled drugs merit little reward. The NHS could, and should, make and distribute “specials” for rare diseases, as the Agence Générale des Equipements et Produits de Santé does in Paris. And in the interest of all patients, the GMC should allow doctors to prescribe a drug that meets the individual patient’s needs but is not licensed for the specific indication, even if a licensed medicine exists for the same indication.


Cite this as: BMJ 2010;341:c6456


  • Analysis, doi:10.1136/bmj.c6471
  • Feature, doi:10.1136/bmj.c6459
  • Observation, doi:10.1136/bmj.c6466
  • Competing interests: Both authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; DAH was a member of advisory boards (Pfizer, AstraZeneca, and Bristol-Meyers-Squibb) and a consultant to Pfizer in the previous three years; REF is a member of the pharmacovigilance expert advisory group of the Medicines and Healthcare Products Regulatory Agency (MHRA) and NHS member of the appeal panel of the National Institute for Health and Clinical Excellence.

  • Provenance and peer review: Commissioned; externally peer reviewed.


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