Parents for Orphans

May 1, 2002

Applied Clinical Trials

A new guideline details basic requirements for submitting a successful application for a proposed orphan drug in the European Union.

Just two years after the new European Union legislation on orphan drugs came into effect, the 100th recommendation of designation of an orphan drug has emerged from the EU scientific body responsible for this new branch of medicines promotion in Europe. The three latest applications to win this statusat the late March meeting of the EUs committee for orphan medicinal productsare treatments for emphysema secondary to congenital alpha-1 antitrypsin deficiency, glioma, and esophageal cancer. The scientific recommendations are also largely going on to receive formal designations of orphan product status from the European Commissionwhich is empowered under the EU procedure to give the final yes or no.

As of the end of March, 169 applications had been submitted, and 101 positive scientific recommendations had been made by the committee. Of these, 98 had already been formally approved by the Commission. The committee has reached only five negative opinions on applications. Of these, two applications were withdrawn, and three were appealed (one appeal resulted in a definitive negative opinion, one in a definitive positive opinion, and the third is still in the appeal process). Altogether, 43 of the applications submitted have been withdrawn over the two years. But the mechanism is still highly attractivethe committee has already received notifications of intent to file applications for another 47 treatments. The mechanism seems, therefore, to be earning its place.

Alongside the operation of the procedure, continuous refinements are being brought to it to improve its functioning. Further information, in the form of summarized committee opinions, is now routinely published on treatments after the formal Commission decision to designate them as orphans. The committee recently revised its guideline on the format and content of applications for designation as orphan products. And it adopted new guidance in the form of points to consider on the calculation and reporting of the prevalence of a condition for orphan designation.

The guideline
The revised guideline (available at 628300en.pdf) clarifies some of the basic requirements for a successful application, supplementing the terms set out in the EU regulation of January 2000. It provides advice on how to compile the documents that sponsors should provide in an application for orphan medicinal product designation. When regulators have gained experience with the procedure, the guideline will be updated to include more detailed explanations and examples. It also provides advice to sponsors that wish to transfer the designation of an orphan medicinal product and/or to change the name or address of a sponsorin essence, to transfer the orphan designation to another sponsorwhich requires detailed documentation of the original designation and of the intended recipient.

It adds some new definitions. For example, condition is defined as any deviation(s) from the normal structure or function of the body, as manifested by a characteristic set of signs and symptoms (typically a recognized distinct disease or a syndrome). The guideline explains that the word condition is used in the regulation to ensure that the regulation applies also to treatments for conditions which are not classical diseases, in particular genetic disorders. It defines orphan condition as the condition as defined above that meets the criteria defined in the regulation. An orphan indication is the proposed indication for the purpose of orphan designation. This specifies if the medicinal product which is the subject of the designation application is intended for diagnosis, prevention or treatment of the orphan condition. And it defines therapeutic indication as the proposed indication for the marketing authorization, based on the sponsors expectations at the time of the designation application. The granted therapeutic indication at the time of marketing authorization will be the result of the assessment of the quality, safety and efficacy data submitted with the marketing application and may be different to the one proposed at the time of designation application.

The guideline makes clear that an application for designation as an orphan medicinal product must be made before any application for marketing authorization is made for that indication: a previous application in any EU member state (whether successful or not) renders a product ineligible for orphan designation for that indication. To apply for more than one indication for the same product, separate applications should be submitted for each orphan indication. In this regard, treatment and prevention of the same condition are considered as two separate indications and should be the subject of two separate applications for orphan designation.

The active substance should be declared by its recommended international nonproprietary name (INN; also called generic name), accompanied by its salt or hydrate form if relevant (and if the recommended INN is not available the proposed INN should be provided). The sponsor should submit details of the proposed orphan indication for which designation is being sought (and this may be broader than the proposed therapeutic indication).

A contract research organization can be the sponsor of an orphan medicinal product as long as it is established in the EU. In all cases, names and addresses of manufacturers and sites of manufacture of the active substances and of the medicinal product (if available) should be provided.

Details of conditions
Details of the condition that the medicinal product is intended to diagnose, prevent, or treat should be provided, including a clear description of the disease or condition in question and its causes and symptoms. The sponsor should submit details of the proposed orphan indication for which designation is applied. This should define the target condition or disease distinguishing between treatment, primary prevention, secondary prevention, and diagnostic indications. The orphan indication may comprise a broader population than the population defined by the proposed therapeutic indication, and should be the population on which the prevalence is estimated. The indication applied for may be modified during the designation process.

A section covering medical plausibility should be completed for all applications, with details of the rationale for the use of the medicinal product in the proposed orphan indication. And where applications refer to a subset of a particular condition, a justification of the medical plausibility for restricting use should be submitted, along with methods or criteria used to delineate this population subset.

The characteristics defining a distinct condition should determine a group of patients in whom development of a medicinal product is plausible, based on the pathogenesis of the condition and pharmacodynamic evidence and assumptions. Recognized distinct medical entities would generally be considered as valid conditions. Such entities would generally be defined in terms of their specific characteristicsfor example, pathophysiological, histopathological, and clinical characteristics. Degrees of severity or stages of a disease would generally not be considered distinct conditions. The fact that a subset of patients exists in whom the medicinal product is expected to show a favorable benefit/risk profile (as defined in the proposed therapeutic indication) would generally be insufficient to define a distinct condition.

Sponsors will have to present convincing arguments to justify the medical plausibility of any proposed subset and the rationale for excluding the larger population. A subset of a disease which, when considered as a whole, has a prevalence greater than 5 in 10,000, could be considered a valid condition if patients in that subset present distinct and unique evaluable characteristics with a plausible link to the condition, and if these characteristics are essential for the medicinal product to carry out its action. In particular, the pathophysiological characteristics associated with this subset should be closely linked to the pharmacological action of the medicinal product in such a way that the absence of these characteristics will render the product ineffective in the rest of the population.

Patients may be affected by more than one condition. Generally the intersection of two (or more) concomitant conditions would not be considered as a valid condition. It could be acceptable, however, if an intersection resulted in a certain new evaluable characteristic essential for the pharmacological effect and the medical outcome. Exceptionally, the need for a particular treatment modality (regardless of underlying diseases) can be considered as a valid criterion to define a distinct condition.A statement justifying the life-threatening or chronically debilitating nature of the condition, or the seriously debilitating or serious and chronic nature of the condition, should be provided, supported by scientific or medical references.

Information on the prevalence of the condition or disease in the EU should be supported by documentation that includes a comprehensive review of authoritative references to demonstrate that the disease or condition for which the medicinal product would be administered affects no more than 5 in 10,000 persons in the EU. The guideline calls for a clear explanation of how estimated prevalence was calculated, indicating the methods and results for identifying source data and documentation and calculating the prevalence. Studies should be summarized in tabular form and include all relevant information such as definition and size of study population, case definition.

If no up-to-date references are available, the sponsor should provide a clear basis for the assumption that the disease or condition will meet the orphan criteria. They should describe the methods and results for identifying databases of rare diseases. Information from relevant databases in the EU should be provided, if available. Where an existing database refers to the prevalence of the disease or condition in one member state, an explanation as to why it is plausible to extrapolate this data to other member states should be provided, taking into account possible ethnic and/or cultural differences. In the absence of EU databases, reference may be made to third-country databases, provided the extrapolation to the EU population is made.

Where a disease or condition has been considered within the framework of other EU actions on rare diseases (such as financially supported to improve information on rare diseases, or in the context of EU research projects), this information should be provided.

Where applications are based on the argument that without incentives, it is unlikely that the marketing of the medicinal product in the EU would generate sufficient return to justify the necessary investment, sufficient documentation should be provided, including data on all costs incurred or expected to be incurred in the course of development and marketingincluding preclinical and clinical studies, formulation studies, stability studies, literature searches, meetings with regulatory authorities, costs of supplying the medicinal product, and preparation of the application for designation.

The documentation must indicate the number of studies or investigations performed in each case, with details of duration and timing, the number of patients or animals, and the amount of staff time involved. It should also include details on any grants, tax incentives, or other cost recovery provisions received either within the EU or in other countries. An estimate and justification is also required for the expected revenues from sales of the medicinal product in the EU during the first 10 years after authorization.

Justification is needed as to why the existing methods of treatment are not considered satisfactory or for the assumption that the new medicinal product seeking designation will be of significant benefit to those affected by the condition. This may be based on clinical information, scientific literature, or the results of comparative studies, whether of a definitive or preliminary nature.

Points to consider
The new documentation on points to consider on the calculation and reporting of the prevalence of a condition for orphan designation sets out in more detail the justifications required from the applicant. No matter how rare a condition actually is, it is not sufficient to state that it is obviously rare and the prevalence is far below the 5 in 10,000 limit, says the committee, which also states, Where all available data show conclusively that the population prevalence lies well-below the threshold, the fulfillment of the prevalence criterion will be a relatively simple task. In less clear situations, careful weighing of the evidence from available sources and formal numerical combinations of available data may be necessary to establish that the population prevalence lies below the threshold.

But it goes on to recognize that in some very rare diseases or conditions obtaining relevant morbidity data to demonstrate that the prevalence meets the orphan criterion may be the most difficult task.

It is no mean feat that so many successful applications have been made already through the new system, even in the absence of this more detailed guidance. The hope must be, now that more of the administrative preparation is clearer, that even more orphans will at last find a parent to care for them.