The Orphan Regulation is central to the EU’s strategy of promoting innovation that meets the needs of patients suffering from rare diseases. To qualify for orphan designation and thereby benefit from the framework of the Orphan Regulation, a medicine must meet a number of criteria:

• it must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating;
• the prevalence of the condition in the EU must not be more than 5 in 10,000, OR  it must be unlikely that without incentives marketing of the medicine would generate sufficient returns to justify the investment needed for its development;
• no satisfactory method of diagnosis, prevention or treatment of the condition concerned can be authorised, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition.

Pharmaceutical companies investing in R&D for orphan medicines have to prove at two distinct points in time (at the time of application for orphan designation and at the time of marketing authorisation) that the medicine fulfils the strict requirements for obtaining an orphan designation.

Once a product has been approved for a specific indication, any new, additional indication or extension of the existing orphan indication, requires a separate assessment by the EMA and marketing authorisation decision by the European Commission (following the same strict criteria). 

It is not a simple or quick process and in fact, only a few – around 11% – medicines have more than one orphan indication or treat a larger number of (rare disease) patients.¹

The EU Orphan Regulation² provides protocol assistance, reduced fees for regulatory activities, additional incentives for SMEs, and 10 years of market exclusivity. During that period, the European Medicines Agency (EMA) and the Member States shall not accept another application for an MA for a similar product. It is also worth noting that this exclusivity is not absolute as medicines showing clinical superiority can be approved and marketed during the 10-year period. As a result, there can be multiple treatment options for some rare diseases.

The introduction of the EU Orphan Regulation, along with scientific advances, led to a wave of new treatment options for rare disease patients. Since the adoption of the Orphan Medicinal Products regulation in 2000, more than 160 OMPs had been approved by the European Medicines Agency EMA by 2018.

Despite the considerable success so far, there is still high unmet medical need in rare diseases: only 5% of rare diseases are estimated to have an approved treatment and much work remains to be done. Maintaining the right regulatory, scientific and economic environment for orphan medicine development is therefore imperative if the public health challenge of rare diseases is to be met in future.

The Paediatric Regulation was adopted in 2007 to facilitate the development and availability of high-quality medicines suitable for children. The Regulation has contributed to make paediatric research an integral part of general medicines development, introducing obligations on pharmaceutical companies to research and develop their products in children as well as adults.

When a company completes a Paediatric Investigation Plan (PIP), the rewards can take two alternative forms:

• A 6-month extension to the supplementary protection certificate (SPC), which protects the product  OR
• When the product which is the subject of the completed PIP is an orphan medicinal product, the 10 years of market exclusivity provided by the Orphan Regulation can be extended by a further 2 years.

Rewards are intended to support the industry by helping to offset the additional costs of conducting paediatric research. They are only available when a company has successfully completed its paediatric research as required by the EMA and updated the product labelling to reflect the results.³

The Regulation also provides for incentives for companies to develop off-patent compounds for paediatric indications, through the concept of Paediatric use marketing authorisations (PUMAs).⁴ A PUMA will only cover the paediatric indication(s) and will benefit from a separate 8+2 year period of data and market protection.

Rewards can be valuable but are far from certain to be achieved for all products for which PIPs are completed. According to the 2015 EMA report to the EC, out of the 113 PIPs completed, only 33 products had benefited from the 6-month SPC extension and 3 products obtained the 2-year orphan market exclusivity extension. Until July 2018; only 3 PUMAs have been authorized.

In the period 2007-2016, over 260 new medicines for use by children (new marketing authorisations and new indications) were authorised. Prior to the Regulation, 50% of medicines had not been tested and developed for children. In the past decade, the proportion of paediatric clinical trials has increased by 50% (from 8.25% to 12.4% of all trials conducted in the EU).⁵