This site is intended for health professionals only

Orphan drugs: new emerging treatments

Orphan legislation, eagerly awaited by the hundreds of thousands of patients suffering from rare diseases, has been successfully implemented in the EU.

The incentives laid down in the legislation, which came into force in April 2000, aim to assist sponsors in the development of medicinal products for rare diseases and ultimately provide medicinal products to patients in the shortest possible timeframe.

Incentives include a 10-year period of market exclusivity once authorised throughout the EU, protocol assistance in the form of scientific advice from the European Medicines Agency (EMEA), eligibility for Community and Member State initiatives that support research and development of orphan medicinal products, unreserved access to the centralised procedure and the possibility to request fee reductions from the EMEA.

Medicinal products eligible for incentives are identified through the Community procedure for orphan designation. The EMEA is responsible for designation through its Committee for Orphan Medicinal Products (COMP), which is composed of health professionals representing each of the Member States, three patient representatives and three representatives nominated by the EMEA. Amongst its current members are five pharmacists.

A medicinal product will be designated as an orphan medicinal product in the EU based on the following criteria:(1)

  • Rarity of the condition or lack of sufficient return on investment.
  • Absence of satisfactory method(s) of diagnosis, prevention or treatment of the condition in question or if method(s) exist, significant benefit to those affected by the condition.

In this context, “significant benefit” has been defined in legislation as a clinically relevant advantage or a major contribution to patient care.(2)

Achievements to date

As the fifth anniversary of EU orphan legislation approaches, one can conclude that the orphan initiative has been very successful to date. In February 2005 the COMP adopted its 271st positive opinion recommending orphan designation, and more than 250 medicinal products have been officially designated as orphan by the European Commission.

The orphan designations granted to date already cover a wide variety of rare diseases, including genetic diseases and rare cancers, for which there is currently either no treatment or only unsatisfactory treatment options. The distribution of positive COMP opinions on designation by anatomic– therapeutic classification is provided in Figure 1. A Community register, listing all designated orphan medicinal products, is published on the website of the European Commission (see Resources).


The majority of the products designated to date are chemical products. Approximately 20% of the products are biotechnology products. This distribution is expected to change over time as an increasing number of innovative products are presented for orphan designation, including products for gene therapy and human cell therapy.

There are many burdens in the development of medicinal products for rare diseases. In many cases, there is a lack of preclinical models to screen for potential activity. Furthermore, for many rare conditions, it is difficult to recruit sufficient numbers of patients to conduct clinical trials adequately powered to show significant effects. As a result, the trials may be very lengthy, and often only a few patients can be recruited per centre. Protocol assistance is considered a priority by the EMEA, as it is imperative in guiding sponsors of orphan medicinal products towards a successful application for marketing authorisation.

Protocol assistance takes the form of advice, covering all aspects of chemical–pharmaceutical, preclinical and clinical development, or regulatory assistance on the content of the application for marketing authorisation. The EMEA is responsible for the provision of protocol assistance, in consultation with its scientific committee responsible for the evaluation of applications for marketing authorisation, the Committee for Medicinal Products for Human Use (CHMP) and its Scientific Advice Working Party (SAWP). In January 2005, a total of 71 protocol assistance and follow-up requests had been received by the Agency.

Nineteen designated orphan medicinal products have gone on to receive marketing approval in the EU. As a consequence, up to approximately 830,000 patients suffering from these orphan diseases in the Community stand to benefit from the availability of these new treatments. These include:

  • Rare metabolic disorders (hyperammonaemia, Fabry disease, Gaucher disease, mucopolysaccharidosis I and Wilson’s disease).
  • Serious precancerous conditions (high-grade dysplasia in Barrett’s oesophagus and familial adenomatous polyposis).
  • Rare cancers (gastrointestinal stromal tumour, adrenal cortical carcinoma and different leukaemias).
  • Others (patent ductus arteriosus, primary pulmonary arterial hypertension, acromegaly, essential thrombocythaemia and advanced levodopa-responsive Parkinson’s disease with severe motor fluctuations and hyper/dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results).

Of the orphan medicinal products authorised to date, 28% have been authorised on the basis of phase III, double-blind, randomised, placebo-controlled multicentre clinical trials, whereas 44% have been based on phase II studies (two of them double-blind, randomised and placebo-controlled). Compassionate use data and bibliographic data were the basis for successful applications in four cases.

Sixty-one percent of the marketing authorisations were granted under “exceptional circumstances”, which means that at the time of the evaluation it was deemed that the applicant could not reasonably be expected to provide comprehensive evidence on the safety and efficacy of the medicinal product. Further studies will, therefore, be needed to maintain the marketing authorisation, which will be reviewed annually by the Agency.


Five years after the implementation of the orphan regulation in Europe, more than 250 products for orphan conditions have been designated in Europe. Most of them are indicated for cancer or metabolic diseases. So far, 19 products have reached the market and are available for the treatment of rare diseases, which could potentially benefit about 830,000 patients in Europe.

The development of orphan drugs has been performed in the majority of cases with standard methodologies (randomised controlled clinical trials). Most of the positive opinions were adopted under exceptional circumstances. A number of biotechnology products and innovative therapies have been designated, and this tendency is expected to increase in the near future.

The true impact of the orphan initiatives on public health is being revealed progressively, as the number of orphan products reaching the market, and thus available to patients, increases.


Melanie Carr MRPharmS
Scientific Administrator
European Medicines Agency (EMEA), London, UK

Dr Jordi Llinares-Garcia
Scientific Administrator
European Medicines Agency (EMEA), London, UK

The views presented in this article are those of the authors and should not be understood or quoted as being made on behalf of the EMEA and/or its scientific committees.


European Medicines Agency
Community register of medicinal products


  1. Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products. OJ num. L 18 of 22.01.2000
  2. Guideline on the format and content of applications for designation as orphan medicinal products and on the transfer of designations from one sponsor to another. ENTR/6283/00Rev 2.

Be in the know
Subscribe to Hospital Pharmacy Europe newsletter and magazine