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Orphan drugs legislation: what are the implications?

Before the development of orphan drugs legislation, it was not attractive to pharmaceutical companies to invest in the development or clinical trials of compounds for the treatment of rare disorders, because of the limited market for such products. European Union (EU) orphan drugs legislation was adopted in 1999 by the European Parliament.

This was late in comparison with the USA, where legislation has been in place since 1983. Since that time, more than 1,000 drugs have been granted orphan designations and more than 200 products given marketing authorisation. Thus, after significant delay, the legislation finally gives us a chance to catch up.

The committee responsible for orphan drugs designations, the Committee for Orphan Medicinal Products (COMP), was set up in 2000. The European Organisation for Rare Diseases (EURORDIS, Table 1) has two seats on this committee, so patient representatives are involved in the designation process. Patient organisations contribute by sourcing experts with specialist knowledge of these rare diseases, to better understand whether the disease in question meets the criteria set out in legislation to qualify as a rare disease.


Criteria for inclusion

In order for a disease to qualify for orphan drug designation, it must have an incidence of five people in every 10,000 or less, and it must be life-threatening or very debilitating, causing serious disability or having a profound affect on a person’s quality of life.

Most of these diseases are of genetic origin, with many being caused by inborn errors in metabolism, and sometimes developing later in life, such as the neurological disorder Huntington’s disease. So far, there has been little access to treatment for these conditions. Therefore, the development of new drugs for these disorders and the investigation of existing products for new indications will be of significant benefit.

Orphan drugs

So far, about 250 protocols (for new products or new indications) have been submitted, among which 159 have obtained orphan drug designation. Of these   159 drugs, only 12 have proceeded all the way to receiving marketing authorisation to date (Table 2), including products for Fabry disease, Gaucher disease and some rare cancers.


It is quite striking that about one-third of the products that have been designated are aimed at rare cancers. A full list of designations is available on the European Agency for the Evaluation of Medicinal Products (EMEA) website.


The most important incentive to pharmaceutical companies developing orphan products is 10-year exclusivity, which is accorded to the product when it receives marketing authorisation. This gives the company a strong guarantee that they will see a return on investment when the drug reaches that point.

Other incentives include provision of protocol assistance – this is important, as it can be difficult to produce the same level of documentation for these products as for a blockbuster product. Orphan drugs can be tested only in a very limited patient population, so it is difficult to perform good clinical trials, and it is useful to receive assistance from EMEA with this issue.

Fees are waived for such protocol assistance, and part of the registration fees are also waived at the time of marketing authorisation.

Safety implications

As mentioned, clinical trials can be carried out only to a limited extent, as the disease solely affects a small number of people. It is therefore vital that any adverse effects are registered afterwards. However, there is currently no European-wide surveillance system for the collection of postmarketing data on orphan drugs.

Discussions to establish effective systems for post- marketing surveillance are ongoing.

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Working groups have been established by COMP, comprising representatives from patient groups, academia and industry, with experts from COMP ensuring that there is a high degree of transparency and understanding of the issues at stake. One of the initial tasks has been to find experts who can establish whether diseases meet the criteria set out in the legislation, and whether the product would be of significant clinical benefit to that group of patients.

Raising awareness

It is interesting to see how the whole arena of orphan drugs is evolving.

Although EURORDIS is just 6.5 years old, it comprises more than 200 member organisations that have an important role within EU Member States in ensuring better knowledge and raising awareness among the medical and pharmaceutical communities of rare conditions and the potential benefits that could be drawn from orphan drugs legislation.

It is important that we get more epidemiological and clinical data on rare diseases, to give us a better picture of the diseases and their treatment, and raising awareness is vital to achieve this.

Implications for pharmacists

Companies such as Orphan Europe (a company that has headquarters in Paris and subsidiaries in Germany, Spain, Italy, Poland and the UK) develop orphan products from discovery to preclinical and clinical development stages, and also provide expert knowledge on regulatory and marketing issues in different European countries.

As practice for prescription of drugs and pricing and reimbursement systems vary between European countries, such companies help establish tailormade marketing profiles for each drug. In addition, pre-approval distribution in agreement with the regulatory systems of the country where the drug will be marketed can sometimes be obtained.

Ongoing developments

Establishing this kind of regulation must be done simultaneously with a number of other initiatives, such as continued programmes of basic research and major European research programmes, as more than 5,000 rare disorders are involved, most of which have no known treatment so far.

Thus, it is vital that research is stimulated, and also that national governments ensure that provision is made in European legislation and in research programmes for rare disorders. For example, research can be stimulated by linking together different biobanks in different European countries, thus improving access to the tissues stored in such places, over mutual websites.

We are just at the beginning of exploring opportunities for breakthroughs in a number of rare diseases, and such initiatives will be of benefit for research into these diseases. As research is closely linked to biotechnology, biotech companies should also have an important role in the development of this area of research. There should be increasing interest in some of these diseases in the coming few years, as they comprise an important area of R&D.

To ensure that patients get treatment as quickly as possible, the EMEA investigates the availability of drugs from the USA in Europe. Most drugs are available in Europe, but it is important to ensure that treatment options are not omitted; other regions of the world, such as Australia, should also be included in the investigation.

Orphan drugs are managed through centralised procedures, so it is important to investigate the availability of the products following authorisation. Some significant variations in delays have been experienced in different EU Member States, and this issue should be followed closely.

Significant variability in pricing also needs to be monitored carefully, to ensure that these variations are as limited as possible.


Terkel Andersen
Paris, France


Orphan Europe

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