BRUSSELS, Belgium - The details of the EU's new orphan drug rules have been finalized, and drug firms can now apply to the European Agency for the Evaluation of Medicinal Products in London to benefit from the new system for promoting development of drugs for rare diseases.

The new system, which is intended particularly to boost development in the biotechnology sector, "opens up new treatment opportunities for patients," the European Commission said when it announced the new rules.

In theory, the incentives, including up to 10 years of market exclusivity and the possibility for fee exemptions for marketing authorization, have been in force since January, when the regulation came into effect. But in practice, these measures could not be implemented until the commission set up the Committee for Orphan Medicinal Products (COMP), and adopted the necessary definitions and criteria.

So far, 31 companies have expressed interest in applying, the commission said. And at its first meeting, in April, the new COMP committee calculated that during 2000, the EU will spend $2 million on aid to the applicant companies, in terms of protocol assistance, waiving of marketing authorization fees, and preauthorization inspections. It predicts that 11 applications will be approved in 2000, 14 in 2001, 20 in 2002 and 22 in 2003. The commission said that orphan drug applications could benefit patients not only in Europe, but also in developing countries, since diseases such as malaria or sleeping sickness also would be eligible.

The detailed rules say how the criteria for designation of a medicinal product as an orphan medicinal product should be implemented, when the authorities are establishing disease prevalence, likely return on investment for drug sponsors, and whether satisfactory alternative methods of diagnosis, prevention and treatment already exist. They also define concepts such as "similar medicinal product" and "clinical superiority," used in the regulation to decide eligibility.

Applications must include authoritative references to demonstrate that the disease or condition for which the medicinal product would be administered affects not more than five in 10,000 people in the EU. The submission also must include data on all costs that the sponsor has incurred in the course of developing the medicinal product, details of any grants, tax incentives or other cost recovery provisions received, and a statement of all development costs that the sponsor expects to incur after the submission of the application, as well as details of all production and marketing costs already incurred or expected during the first 10 years of marketing. An estimate and justification for the expected revenues from sales of the medicinal product in the EU during the first 10 years after authorization also will be required.

Orphan status will not be granted if a "similar medicinal product" exists - defined by the new rules as a medicinal product containing a similar active substance or substances as contained in a currently authorized orphan medicinal product, and which is intended for the same therapeutic indication. The limitations here are explicitly listed by the commission.

So, for instance, there must be major differences in amino acid sequences for proteinaceous substances for them to be considered dissimilar; products would be classed as similar if monoclonal antibodies bind to the same target epitope; and polynucleotide substances (including gene transfer and antisense substances) consisting of two or more distinct nucleotides would be considered similar if the difference in the nucleotide sequence of the purine and pyrimidine bases or their derivatives was not major. For antisense substances, the addition or deletion of one or more nucleotides not significantly affecting the kinetics of hybridization to the target normally would not be considered enough to make them dissimilar; and for gene transfer substances, unless the differences in the sequence were significant, the substances normally would be considered similar. Nor would products quality if the differences in structure related only to modifications to the ribose or deoxyribose sugar backbone or to the replacement of the backbone by synthetic analogues, or differences in the vector or transfer system. Closely related complex partly definable substances (such as two related viral vaccines, or two related cell therapy products) would not qualify, either.