The peculiarity of a rare disease is by definition a rarity in the human population and means a lack of knowledge by the scientific community and a lack of big investments, but over the past few years, this has began to change.

The classification of a rare disease is slightly different in Europe and the U.S. The European Union considers diseases to be rare when they affect less than five per 10 000 persons, while FDA defines a rare disease as a disease which affects fewer than 200,000 Americans a year.

So, despite having a small number of patients affected with an individual rare disease, rare diseases are, collectively, a large public health problem. There are approximately 7000 diseases that are currently categorized as rare. Such diseases are often affecting pediatric patients, frequently progressive, disabling and life threatening. The specificities of rare diseases, a limited number of patients and a lack of relevant knowledge and expertise, has led to special paths for clinical development being created, as well as cooperation to ensure that scarce knowledge can be shared and resources combined as efficiently as possible, in order to tackle rare diseases effectively across different countries.

In the US, the Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD) mission is to advance the evaluation and development of products (drugs, biologics, devices, or medical foods) that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions and the OOPD provides incentives for sponsors to develop products for rare diseases. Moreover the Orphan Drug Designation program provides orphan status to drugs and biologics intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug.

Thanks to this special path and dedicated office in 2014, FDA announced their highest number to date of new requests for orphan drug designation. They received over 440 requests while just seven years ago, requests were less than half of that. FDA designated and approved more orphan drugs in 2014 than they had in previous years – nearly 300 drugs were designated and 48 were approved, including both novel and repurposed drugs.

In Europe, the European Medicines Agency (EMA) has created special paths and offices to support clinical development in rare diseases. Indeed an orphan designation allows a pharmaceutical company to benefit from incentives from the European Union to develop a medicine for a rare disease, such as reduced fees and protection from competition once the medicine is placed on the market. Applications for orphan designation are examined by the Committee for Orphan Medicinal Products (COMP), which adopts an opinion that is forwarded to the European Commission.

The European Commission then decides whether to grant an orphan designation for the medicine in question. Designated orphan medicines are assessed centrally on a European level by the Agency’s Committee for Medicinal Products for Human Use (CHMP), rather than in each Member State separately. Once they have received an orphan designation, drugs can also apply for a special grant to support the clinical development. Moreover the EMA and the Heads of Medicines Agencies (HMA) have launched a public consultation on the European Union (EU) Medicines Agencies Network Strategy for 2020. One of the focuses of this strategy is to improve the clinical development investment for rare diseases.

Finally the International Rare Diseases Research Consortium (IRDiRC) was the joint idea of the European Commission and the National Institutes of Health (NIH) in the US. It brings together a cross-section of everyone involved in rare diseases, from patients to researchers to biopharmaceutical industry representatives. ‘The consortium’s members have set themselves two ambitious goals for 2020 — to develop 200 new therapies for rare diseases and to find the means to diagnose most of them.

Since 2009, when the global research community started to apply modern genomics to rare disease research, scientists’ ability to identify the causative genes of diseases has increased exponentially. The genes of some 3500-4000 diseases are still unknown, but five to 10 of these new genes are found almost every week. Medical research is being transformed and new genomics technologies will simplify the diagnostic process, and thus reduce the period of diagnostic delay.

Clinical development in the rare disease space is still a challenge mostly due to the really low number of affected patients, lack of clinical sites and misdiagnosis. To develop a drug in rare diseases requires a deep knowledge of the disease and a good network of experts. An added value is surely represented by the patient association where often the vast majority of knowledge of the disease and medical expertise stays. Their dedication and hope to improve medical care is an enormous treasure that can support clinical development. Awareness of the diseases must be also a post approval commitment, as well as educational strategies as an integrated part of the full development program, to spread out the clinical knowledge and support the medical and patient communities. In addition, approaches to clinical studies using adaptive statistical design, and regulatory special paths where only a limited population is required to be exposed to the drug before conditional approval for sure will help and improve time for a new molecule to become a drug for rare diseases.

To conclude, despite the challenges, the rare disease space represents an opportunity to improve medical care and to invest in new potential drug development. In the last decade applications for orphan drug designation and approval for rare disease indication has constantly improved. This really represents a unique opportunity to develop a drug in an unmet medical setting and both US and European regulators are encouraging investment in orphan drugs and are offering support from their side to investments in this area. Also many small and big biopharmaceutical industries are dedicating more and more of their resources to invest in the clinical development for rare diseases.