European Orphan’s Drug Regulation – Regulatory Week

May 6, 2013 | By Márcio Barra


Regulatory week starts today! What is regulatory week you ask? This week, from April 6 to April 10, a new article, each one regarding a different topic on the European Regulatory affairs themes, will be published every day! So please stay tuned, enjoy, and if you like, please share and comment!

The first one is about the European Orphan’s Drug Regulation.

Soliris, from Alexion, an Orphan drug for the rare condition paroxysmal nocturnal hemoglobinuria (PNH)

An Orphan drug is a drug for a life threatening or chronically debilitating condition, whose prevalence in the EU is not more than 5 in 10,000. This threshold changes from a country to another. In the USA its 7.5 per 10,000 and in Japan it’s 4 per 10,000. The other EU prerequisites for a drug to be called orphan is that no other method of treatment for the given condition exists, or, if it already exists, then the orphan drug must be of significant benefit to the patient (1).It is estimated that between 6000 to 8000 different rare diseases affect up to 6% of the entire EU population. Consequently, diseases that may be rare individually affect a significant proportion of the population when considered as a whole (2).

There are two primary pieces of orphan drug legislation in the EU. The founding legislation is Regulation (EC) No 141/2000 of the European Parliament and the Council of 16 December 1999 on orphan medicinal products. This regulation acts as the main regulatory framework for orphan drugs in Europe, stating the definitions, the criteria for designating a drug as an orphan drug, procedures, provision of protocol assistance, access to centralized procedure without further justification for Community marketing authorization, and the incentives (3).It also established the   Committee for Orphan Medicinal Products (COMP)(3) .

The second is Regulation (EC) No 847/2000, which lays down implementing instructions for Regulation (EC) No 141/2000 , and sets out the definitions of “similar medicinal product” and “clinical superiority” (4). There is also the European Commission Communication 2003/C 178/02, providing some more information on the EC’s interpretation on issues regarding the implementation of the orphan designation and provisions for market exclusivity (5).

To promote the development of orphan medicinal products, the legislation brought incentives to motivate sponsors. These include market exclusivity for 10 years, protocol assistance and reduction of the fees for application and inspection. From 1 February 2009, the applicable fee reductions are a 100% reduction for protocol assistance and follow-up advice, 100% reduction for preauthorization inspections, 50% reduction for new applications for marketing authorization to applicants other than Small and Medium Enterprises (SME), 100% reduction for new applications for marketing authorization only to SMEs and 100% reduction only to SMEs for post authorization activities including annual fees in the first year after granting a marketing authorization. (3, 6)

Regarding market exclusivity, no Member State may accept another MA application for the same therapeutic indication in respect to a similar medicinal product. By similar medicinal product, Regulation (EC) No 847/2000 means a medicinal product containing a similar active substance(s) – that is, a molecule with the same main structural molecular features and mechanism of action – as the one in a currently authorized orphan medicinal product, and that is intended for the same therapeutic indication. However, this market exclusivity for an orphan drug can be lost if the marketing authorization holder of the original molecule can’t meet the demand, if the similar medicinal product proves itself to be clinically superior, if any of the three designation criteria are no longer met, or if, after 5 years, a Member States shows that the orphan medicinal product is excessively profitable (3, 6).

The regulation, as said before, created the Committee for Orphan Medicinal Products, and outlined its functions(3). They are:

  1.  Examine applications for the designation of a medicinal product as an orphan medicinal product. An orphan designation request can be presented to COMP at any stage of development. The evaluation procedure can take up to 90 days;
  2. Advise the European Commission on the establishment and development of policies on orphan medicinal products for the European Union;
  3. Assist the EC in communicating and sharing information with external entities and patient support groups about orphan drugs;
  4. Assist the EC in creating guidelines

Now, it’s important to highlight one aspect: the COMP is responsible for reviewing applications from people or companies seeking orphan-medicinal-product designation. It does not, however, participate in the drug authorization procedure. That task remains the responsibility of the CHMP, even for orphan drugs. The CHMP plays a role in the assessment of the safety, efficacy and quality of an orphan medicinal product. The COMP may only participate in the process by evaluating the application, to confirm if the criteria for orphan designation are met before a medicinal product is granted marketing authorization and starts benefiting from market exclusivity. Moreover, since the approval process goes through the CHMP, understandably the authorization of an orphan drug product can only be through the centralized procedure (6, 7).

The legislation proved itself to be a major boost to the orphan drug market in Europe. Since an orphan drug is the only available option to treat a given disease, these drugs are considered to be of high value, and thus high prices are given to them by the sponsors. The drug Soliris for example, from Alexion, was the world’s most expensive drug, costing more than $409,000 per year, (for treating paroxysymal nocturnal hemoglobinuria (8)), until Glybera’s approval by EMA, a gene therapy priced at more than €1m per patient (9). While extremely expensive, the reasoning is that without these drugs, the costs of caring for people with rare diseases like this can run into the millions, much more than the cost of the orphan drug(8).

The high price, plus the incentives provided by Regulation (EC) No 141/2000, has made orphan drugs a very attractive market for pharmaceutical companies, with approximately 40 approved orphan drugs up to 2012, generating over $200 million each in yearly sales(10). Unless some major change occurs to the regulation in the future, Orphan drugs are here to stay.

1 comment
  1. 1. EMA. Orphan designation. [cited 2013 07-02-2013]; Available from:
    2. D T, F C, C F. Rare diseases and orphan drugs. Annali dell’Istituto superiore di sanità. 2011.
    3. REGULATION (EC) No 141/2000 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 December 1999 on orphan medicinal products, (1999).
    4. Comission E. COMMISSION REGULATION (EC) No 847/2000of 27 April 2000 laying down the provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product and definitions of the concepts ‘similar medicinal product’ and‘clinical superiority’. Official Journal of the European Communities. 2000.
    5. Communication from the Commission on Regulation (EC) No 141/2000 of the European Parliament and of the Council on orphan medicinal products (2003/C 178/02), (2003).
    6. The Textbook of Pharmaceutical Medicine. 6th edition ed. Griffin JP, editor: Wiley – blackwell; 2009.
    7. Llinares J. Orphan designation Key concepts and evaluation criteria. SME workshop 20112011.
    8. Herper M. Inside The Pricing Of A $300,000-A-Year Drug. Forbes2013 [cited 2013 07-02-2013]; Available from:
    9. Jack A. Gene therapy wins Europe approval. Financial Times2012 [cited 2013 02-05-2013]; Available from:
    10. H E, J L. European incentives for orphan medicinal products. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2008.

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