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The effectiveness safety and costs of orphan drugs an evidence based review

Project title

The effectiveness, safety and costs of orphan drugs: an evidence-based review.

Project reference


Final report date

23 October 2015

Project start date

01 April 2014

Project end date

30 September 2014

Project duration

6 months

Project keywords

orphan drugs; rare diseases; evidence; cost effectiveness, safety review.

Lead investigator(s)

Dr Igho Onakpoya, Research Fellow, Evidence Synthesis Nuffield Department of Primary Care Health Sciences, University of Oxford

NIHR School Collaborators
  • Dr Elizabeth Spencer, Epidemiologist : Nuffield Department of Primary Care Health Sciences University of Oxford
  • Professor Carl Heneghan; Professor of Evidence Based Medicine, Nuffield Department of Primary Care Health Sciences University of Oxford
  • Professor Matthew Thompson: Professor Department of Family Medicine University of Washington, USA

Project objectives

The objective of this review was to critically appraise and evaluate the evidence on the clinical usefulness of orphan drugs presently being use in patient management, make cost comparisons of branded orphan drugs versus their generic or unlicensed equivalents, as well as determine whether the prevalence of orphan diseases have any relationships with the costs of drugs used in their management.

Changes to project objectives

No changes from proposal

Brief summary


We searched the EMA database to identify orphan drugs granted marketing authorization up till April, 2014. Electronic searches were also conducted in PubMed, Embase, and Google Scholar to assess data on effectiveness, safety and annual costs. Orphan drugs granted marketing authorisation up until 30th April, 2014 were identified. Drugs which have been designated with “orphan status”, but have not received EMA marketing authorisation were excluded. The quality and strength of the overall body of evidence for each orphan drug was then evaluated using a checklist adapted from the GRADE criteria Two reviewers independently evaluated the levels and quality of evidence and extracted data.


We identified 74 orphan drugs, with 54 (73%) demonstrating moderate quality of evidence. 85% showed significant clinical effects, but serious adverse events were reported in 86.5%. Their annual costs were between £726 and £378,000. There was a significant inverse relationship between disease prevalence and annual costs (p = 0.01); this was largely due to the influence of the ultra-orphan diseases. We could not determine whether the balance between effectiveness and safety influenced annual costs. For 10 drugs where generic alternatives were available, the branded drugs were 1.4 to 82,000 times more expensive.


The available evidence suggests that there is inconsistency in the quality of evidence of approved orphan drugs, and there is no clear mechanism for determining their prices. In some cases far cheaper generic agents appear to be available. A more robust, transparent and standard mechanism for determining annual costs is imperative

Plain English summary

Orphan drugs are medicinal products used for the treatment of patients with rare diseases, which are medical conditions affecting about 1 in 2,000 persons. Because the number of individuals with rare diseases is low, drug companies are reluctant in making investments into research for development of medicines which can treat such conditions. Drug regulatory authorities have therefore provided incentives to encourage drug manufacturers to develop novel drugs to treat orphan diseases.

Orphan drugs are important in primary care as many patients with orphan disease are managed in these settings. Over the last two decades, several orphan drugs have been approved for use in Europe and the USA, but the effectiveness of some has not been clearly shown, and information about their safety is lacking. Furthermore, this group of drugs are quite expensive. Therefore, the purpose of this study is to examine the effectiveness and safety of orphan drugs and determine if the rarity of orphan diseases bears any relationship with their high costs.

We searched the website of the European Medicines Agency (EMA) to identify orphan drugs that have been approved for use up till April 2014. In total, we identified 74 drugs; 54 had modest level of evidence, and 63 showed evidence of positive benefits for their approved treatments. However, 64 had evidence of harmful effects. The yearly cost associated with the use of the drugs per patient was between £726 and £378,000. The less common an orphan drug, the more expensive the yearly costs; however, this finding was due to the very rare orphan drugs. We could not determine whether the balance between positive benefits and harmful effects were considered when setting the prices of the drugs. For 10 drugs where non-proprietary brands were available, the branded drugs were 1.4 to 82,000 times as costly.

In conclusion, there is no consistent evidence showing that the EMA-approved orphan drugs are effective or safe for use, and it is difficult to tell how the prices of the drugs at set. In some cases, the non-branded versions of orphan drugs are far cheaper. A clearer method for setting the prices of these drugs is therefore warranted.


Published articles

Onakpoya IJ, Spencer EA, Thompson MJ, Heneghan CJ. Effectiveness, safety and costs of orphan drugs: an evidence-based review. BMJ Open. 2015 Jun 24;5(6):e007199:

Public involvement

This was a review of the literature, and did not involve participant involvement.


The article has already been cited once, and I have received correspondence emails from other researchers commending us for the work; indeed we have been invited to collaborate with an HTA group in Italy in the light of this. Further, we have had communications from some of the drug manufacturers who have tried to give reasons why the prices are high, and have also been provided with the current annual costs of some of the drugs.

We plan to conduct a series of systematic reviews of several orphan drugs for which there are currently no reviews, as well as update the reviews for those drugs with more recent published trial results. We expect that the results of these reviews will shed more light on whether the huge amounts the NHS pays for these drugs provides good value for money.

This project was funded by the National Institute for Health Research School for Primary Care Research (project number 234)

Department of Health Disclaimer

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR School for Primary Care Research, NIHR, NHS or the Department of Health.