Faiz Kermani
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Rare diseases represent an important area of unmet medical need (Table 1). Globally, it is estimated that 5000–8000 distinct rare diseases exist, with approximately 30 million people in the EU and
25 million people in the US suffering from such conditions.1–3 Most diseases are assessed by their impact on society as a whole and little attention is paid to rare diseases because of
their low prevalence. Officially, rare diseases are defined as those affecting fewer than five in 10000 people in the EU and
fewer than 200000 people in the US.3 These disorders pose serious difficulties for sufferers and their families.
Patients often face long delays in getting an accurate diagnosis because many rare diseases are poorly characterized and doctors
may not be familiar with them. Even after an appropriate diagnosis, patients often have few treatment options and usually
have to wait years in the hope that a drug will be developed and approved for their specific condition. In the meantime, they
are forced to seek expensive alternatives; however, they may experience problems with reimbursement.
Table 1: Challenges concerning rare disease management.
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Many pharmaceutical and biotech companies have been reluctant to engage in expensive research for rare diseases without assurance
of a return on their investment. To be considered profitable, a treatment must be applicable to a certain number of patients
during a certain number of years of commercial exclusivity. Progress has also been held back by the paucity of research on
rare diseases and availability of scientific data.
Nevertheless, there have been improvements in the regulatory environment and thanks to the continuing efforts of patient organizations
to raise publicity, rare diseases now represent a growing area for research. The unmet medical need has also been officially
recognized, leading to the introduction of orphan drug legislation in the US, Australia, Singapore, Japan and finally in the
EU in April 2000. Other countries such as Canada, New Zealand, South Korea and India have appropriate legislation under consideration.
Orphan medicinal products are those intended for the diagnosis, prevention and treatment of a disease so rare that developing
these products through conventional legislation would mean they would never be sufficiently profitable for companies.Orphan drug legislation in the US and Europe
In 1983, thanks largely to the lobbying efforts of patients, the US government introduced the Orphan Drug Act. This act contains
incentives for the pharma industry to develop products for rare diseases and contained provisions to allow patients with a
rare disease better access to treatments. The main incentives to industry are a 7year period of marketing exclusivity (which
some industry observers have likened to a type of patent) and tax benefits on clinical trials between the date of orphan drug
legislation and new drug application (NDA). The act has been further refined through Congressional amendments in 1984, 1985,
1988 and 2007.
To handle regulatory matters in this field, the FDA set up the Office of Orphan Products Development.4 To date, more than 1700 drugs and biologics have been designated as orphan drugs in the US, with more than 300 achieving
marketing approval. In the decade prior to 1983, fewer than 10 orphan products were brought to market, showing that modest
regulatory incentives can have a large effect on drug development.5
In the US, the National Organization for Rare Disorders (NORD) lobbies on behalf of patients with rare disorders and was established
in 1983 by patients and families who worked together to get the Orphan Drug Act passed. It holds annual meetings where thought
leaders from government, academia, the patient community and industry meet to help establish an agenda for action related
to the R&D of orphan products on a national and international basis.5
Following the work of the French government in 1995 to convince the European Council of Health Ministers to vote in a resolution
to develop orphan medicinal products legislation, a number of European countries began to pay closer attention to the issue
of orphan drugs. One of the major lobbying groups for specific European orphan drug legislation is the European Organization
for Rare Disorders (EURORDIS),6 a coalition of 340 rare disease organizations in 38 countries — 29 of which are EU member states. Besides hoping to see
legal framework in place for orphan drugs, EURORDIS aims to obtain better co-operation between national patient organizations
and to campaign for patients to receive reimbursements for their treatments.
In December 1999, the European Parliament and the Council adopted regulation (EC) No. 141/2000 on Orphan Drugs. The time lag
for orphan drug legislation in Europe was partly because of the makeup of the EU, where healthcare responsibilities are shared
between member state bodies. Nevertheless, as in the US, the adoption of orphan drug legislation had a noticeable impact on
EU drug development. EURORDIS figures show that, since 2000, 560 drugs and biologics have been designated as orphan drugs,
and 52 have achieved marketing approval.
The EMEA and its Committee for Orphan Medicinal Products (COMP) have facilitated implementation of the orphan drug legislation.
The COMP is composed of one representative per member state, three EMEA representatives and three members to represent patients'
organizations. The EMEA provides extensive support to the COMP through its secretariat by validating applications, providing
summary reports of orphan applications and supporting meetings of COMP. For a medicinal product to receive designation as
an orphan medicinal product in the EU, it is required to comply with criteria outlined in Article 3 of Regulation (EC) No.141/2000.
In the EU, the incentives to industry are slightly different to those of the US in that market exclusivity is for a 10 year
period after the grant of a marketing authorization. This period of market exclusivity is subject to certain restrictions
and can be reduced to 6 years if at the end of the fifth year the criteria outlined in Article 3 are no longer met; for example,
if the product is shown to be sufficiently profitable to no longer justify market exclusivity.
