Problems Persist in Orphan Drug Market

Study finds more consistency is needed to ensure the safety, efficacy, and fair pricing of orphan drugs.

A recent review of orphan drugs found that the quality of clinical evidence for these medications is inconsistent and there is no clear mechanism for setting prices.

In a research article published in BMJ Open, investigators concluded that “a more robust, transparent and standard mechanism for determining annual costs is imperative” for orphan drugs.

What is an Orphan Drug?

An orphan drug is a therapeutic agent designed to manage an orphan disease, a medical condition with low prevalence. In the United States, that low prevalence is defined as affecting 1 of 1500 individuals. In Europe, orphan diseases are defined to affect 5 of 10,000 people. Also in Europe, authors noted, an ultra-orphan designation is used for conditions affecting less than 1 of 50,000 individuals.

Bringing Orphan Drugs to Market

Authors explained that because low patient volumes discourage commercial investment in research and development (R&D), drug regulatory authorities offer incentives for pharmaceutical companies to develop and manufacture orphan drugs. In the United States, the orphan market enjoys 7-year exclusive licensing, faster assessment procedures, and tax incentives. In Europe, orphan drugs receive 10-year exclusive licensing, fee reductions, and drug agency assistance with scientific evidence.

Researchers conducted a literature review that suggested that current evaluation and approval processes in place in Europe and the United States were not adequately or consistently assessing the clinical and cost-effectiveness of orphan drugs.

So, the objective of their study was to: (1) evaluate the efficacy and safety of all orphan drugs approved in Europe; (2) determine the annual cost of each orphan drug; (3) compare the costs of branded orphan drugs and their generic equivalents; and (4) explore any correlation between disease prevalence and annual cost.


This study searched the EMA database and found 74 orphan drugs authorized for market up to April 2014. For each drug, information on its efficacy, safety, and annual costs was gathered via electronic searches in PubMed, EMBASE, and Google Scholar. Two reviewers independently extracted data and evaluated the level and quality of evidence for each orphan drug on the market.

Levels of evidence were ranked according to the University of Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence criteria. This standard considers levels of evidence for therapy/prevention/aetiology/harm, prognosis, diagnosis, differential diagnosis, and economic and decision analyses.

Quality of evidence was assessed using the criteria and system established by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) standard.

Quality of Orphan Drugs in Question

Of 74 orphan drugs, 25 (33.8%) had OCEBM level 1 evidence, 35 (47.3%) were level 2, and 14 (18.9%) were level 3. None of the 74 orphan drugs on the market showed evidence of high overall quality.

Fifty-four of 74 approved orphan drugs (73%) demonstrated moderate quality of evidence according to GRADE criteria, 16 (21.6%) rated low quality of evidence, and 4 (5.4%) had a very low quality of evidence.

Eighty-five percent of orphan drugs demonstrated significant clinical effects, but 86.5% were associated with serious adverse events.

In a subset of orphan drugs used to treat cancer, 96.6% (n = 28) had evidence of serious adverse events. For the cancer subset, bone marrow suppression (58.6%) was the most common adverse event, followed by hepatotoxicity (20.7%).

Annual costs varied widely, from £726 to £378,000. No measurable relationship was found between effiacy, safety, and cost.

The study found a significant inverse relationship between disease prevalence and annual drug cost (P = .01), largely due to the influence of ultra-orphan diseases.

Looking at the 10 orphan drugs for which a generic alternative is available, the branded products were 1.4 to 82,000 times more expensive than the generic.

Implications for the Orphan Drug Market

Authors concluded that there is inconsistency in the quality of evidence of approved orphan drugs and no clear mechanism for determining their prices.

Some of their recommendations to improve available information were to prioritize and update reviews for orphan drugs, institute a review group to fill knowledge gaps, conduct further industry-funded trials, report suspected adverse events, monitor their clinical use, and study the relationship between R&D costs and orphan drug prices.