Orphan drugs

The Regulation of Orphan Drugs came into force in the EU in April 2000 [Regulation (EC) No. 141/2000]. Pursuant to the Regulation, the European Medicines Agency grants orphan drug designations upon application for preparations that will be developed into drugs for treating rare diseases. The applications are assessed by the Committee for Orphan Medicinal Products (COMP).

The COMP consists of a chairperson, a representative from each of the 28 EU Member States, three representatives of patient associations, three representatives recommended by EMA, one representative from Norway and one from Iceland. When making decisions, 2/3 of members eligible to vote must be present. 

Preconditions for obtaining an orphan drug designation is that the incidence of the disease treated with the drug does not exceed 5 out of 10,000 EU citizens, the disease is life-threatening or chronically disabling and there is no good therapy available. When applying for an orphan drug designation, the applicant must present acceptable calculation for the incidence of the disease (<5/10,000/year). Moreover, the applicant must present appropriate justification for using the drug for the suggested therapeutic indication. If pharmacotherapy already exists for the disease, the new candidate must represent a significant improvement to efficacy, tolerability or usability characteristics.

The applications are processed in the COMP meetings. Each application is appointed an assessor and an EMA coordinator. During the first processing round, the application is processed in writing. If the application is approved, the approval is provided in writing. If the application raises questions to which the applicant should answer, the applicant can be requested to submit their answers in writing, or attend the next COMP meeting for a hearing. After the hearing, a decision is made on the approval / rejection of the application. The applicant may also cancel their application during the process.    

Drugs with an orphan drug designation are offered scientific and administrative advice and reduced fees for marketing authorisation and other pharmacovigilance operations. After the marketing authorisation is granted, the drug is protected for 10 years against generic products for treating the rare disease. Moreover, orphan drugs receive national support.

Investigations aiming for a marketing authorisation for an orphan drug encounter problems associated with small research subject populations. In many rare diseases, the number of patients in Europe or in the world is so small that it is almost impossible to obtain hundreds of patients for an investigation. Furthermore, carrying out clinical trials that comply with good clinical practice might be difficult when the trial is carried out in several centres that treat only a few patients. The EMA has created guideline presenting possible approaches for obtaining reliable information in clinical trials with small populations (Guideline on clinical trials in small populations CHMP/EWP/83561/2005)

Detailed knowledge of the disease mechanism and the pharmacological properties of the drug molecule help in the planning of clinical trials. In orphan drug development, the importance of preclinical pharmacodynamic studies conducted in animals and cell or tissue models might be very high, since such studies can help in the planning of the dose and route of administration for humans. This enables clinical studies on patients to be planned in a way that they answer a specific question.

The granting of a marketing authorisation for orphan drugs follows the same principles as in other medicines. The problems of engaging patients to participate in the studies will be taken into account as well as possible. The assessment of the reliability of evidence uses the following hierarchy, presented here in descending order of reliability: meta-analyses of high-quality controlled clinical studies, individual randomised and controlled clinical studies, meta-analyses of  observational studies, individual observational studies, published case report series, individual case reports and expert opinions.

The marketing authorisation applications for orphan drug are always assessed using the centralised procedure. The assessors are experts representing the medicines agencies of different European countries.

Often, an orphan drug is granted a conditional marketing authorisation, because the drug is considered to be highly necessary on medical grounds (it responds to an unmet medical need), but there is too little research information to grant an ordinary marketing authorisation. In such a case, the marketing authorisation holder is informed of what kind of information on the efficacy and safety of the drug they must submit in the future to maintain the marketing authorisation. A conditional marketing authorisation is usually updated once a year, and the accumulated research information is assessed during the update process.

In the future, the development of drugs will be increasingly aligned towards individual pharmacotherapies based on known connections between a patient’s biological characteristics, such as genetics, and the expected response (or adverse effects) before the pharmacotherapy is even started. The treatment of rare diseases already follows this approach fairly closely.

Over 100 marketing authorisations have been granted to orphan drugs. Many rare diseases can also be found in the Finnish population, which is why it is important to make orphan drugs available to Finnish patients.