For the first time in 13 years, the European Commission has published guidance on how to interpret and apply articles of the Orphan Drug Regulation. The guidance was published in the form of a Notice, and in less than one week the European Medicines Agency had incorporated several aspects of the Notice into its post-orphan medicinal product designation procedures guidance. The Notice clarifies key concepts and provides greater predictability for sponsors, specifically on criteria for designation as an orphan drug, procedure for designation, and European Union (EU) marketing authorization.

The incentives available to sponsors of orphan products are well established, and include protocol assistance, access to the centralized procedure, reduced fees, research grants, and 10 years of marketing exclusivity.  And although orphan drugs do not automatically qualify for the accelerated assessment procedure (which is 150 rather than 210 days, exclusive of clock stops), they may qualify if the Committee for Medicinal Products for Human Use (CHMP) determines that they meet a major public health need. The benefits of orphan drug designation are clear; however, certain aspects of the orphan designation and subsequent marketing authorization process are not spelled out in the Regulation, so sponsors will benefit from the additional guidance provided in the recent Notice.

In the Notice, the Commission acknowledges the growing prominence of personalized medicine and the ensuing stratification of patient populations, but cautions that “subsetting” of conditions is only acceptable when it can be scientifically justified that the product will not be of value to the larger population. The guidance states that the characteristics used to define the orphan indication “should be essential for the product to carry out its action.

The Commission provides greater clarity on the “significant benefit” concept, crucial to the EU Orphan Regulation, by offering additional context for the phrases “clinically relevant advantage” and “major contribution to patient care”. A claim of clinically relevant advantage should be based on clinical evidence of improved efficacy or the safety/tolerability profile for the entire population affected by the condition or a particular subset. A major contribution to clinical care should reflect ease of self-administration or improved adherence to treatment, provided difficulties adhering to the existing treatment are documented and data show a better clinical outcome, including quality of life, with the new treatment form. The bar for a major contribution to clinical care is set high for new pharmaceutical forms, given that if an orphan marketing authorization is granted, the entry of generics for the initial form may be prevented because the generics and orphan product would be considered similar products. The Commission recognizes that, at the time of orphan designation, justification for significant benefit is likely to be based on assumptions; therefore, it recommends that sponsors seek protocol assistance, including guidance on how to demonstrate significant benefit during clinical development.

When a sponsor submits a marketing authorization, they must also submit a report on the maintenance of the orphan designation. This report is reviewed by the Committee for Orphan Medicinal Products (COMP) in parallel to the review of the Marketing Authorisation Application by the CHMP. In the situation where two products for the same condition are developed in a similar time frame, the Commission Notice explains that the second sponsor is expected to provide evidence of significant benefit if notification of marketing authorization of the first product has been published in the Official Journal of the European Union by the time of the COMP evaluation. However, the Notice also states that the evidence may be based on indirect comparison due to the recent development of both products.

The clarity provided on the items described above, along with the additional procedural details and the more complete definition of an existing “satisfactory method of diagnosis, prevention or treatment” that are included in the Commission Notice should serve to increase sponsors’ confidence in their orphan drug development strategies. In the next few months additional clarity for orphan drug development is expected when the Commission provides an update on its proposed changes to the Regulation that defines “similar active substance.” Included in the proposed changes are definitions for “principal molecular structural features” and an update of the examples for biological products to account for technological advancements.