Challenges and opportunities for orphan drug development and commercialization: US and EU perspective

By Poonam Balani

Although the patient numbers suffering from individual orphan diseases is comparatively low, an estimated 350 million people worldwide suffer from orphan diseases. The US introduced the Orphan Drug Act in 1983, followed by a similar legislation in Japan in 1993 and in the EU in 2000. The orphan drug designations have increased exponentially and are expected to have worldwide sales of over $176 billion by the end of 2020[1]. This previously overlooked market, which was deemed economically non-viable by the big pharmaceutical companies, now attracts large investments due to changes in the regulatory support in the form of fast-track reviews, reduced costs of development and tax incentives Orphan drugs also enjoy a significant competitive advantage in being first to market[2] as they are priced high and enjoy a high market share. The high consumption of orphan drugs also tends to offset the smaller patient pool available for treatment. The US FDA data shows that 9 of the 22 new medications (41%) approved in 2016, are orphan drugs[3]. In 2016, a total of 349 orphan drug designations were granted by the FDA and 209 by the EMA[4].

Orphan Drug Designation

For orphan drug designation in the US, the sponsors have to demonstrate that the treatment population is fewer than 200,000. It is possible to apply for the orphan designation of a drug for the same use in the EU and the US using a common application form (FORM FDA 3671). The application is reviewed by the Office of Orphan Products Development (OOPD) before designation approval, denial or a request for additional information.

In order to qualify for an orphan drug designation for the EU, the drug ‘must be intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 people in the EU’[5] and it should be unlikely to be marketed without incentives. Additionally, there should be no prior satisfactory method of diagnosis, prevention or treatment authorized in the EU for the condition. If so, the product should offer significant benefit to the patients affected by the condition. The Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) is responsible the orphan drug designation process.

The Challenges

The pharmaceutical development for a rare disease faces several challenges due to poor understanding of the disease progression, heterogeneous patient populations with variable phenotypes, and lack of clinical trial data. One of the most challenging factors in designing clinical trials for orphan drugs is the setting up investigative sites, as most large clinical trial centers have little or no prior experience in orphan diseases. Additionally, an estimated 50-75% of patients with rare diseases are children, and patient recruitment/management is a challenge with the younger demographic[6].

Orphan Drug Development in the US: Grant Programs and Accelerated Development

The FDA has several dedicated programs and schemes to promote orphan drug development and research. These include: Orphan Drug Designation program; The Rare Pediatric Disease Priority Review Voucher Program; The Humanitarian Use Device (HUD) Program for Medical Devices, which is intended to benefit patients in the treatment or diagnosis of a disease or condition affecting no more than 8,000 individuals in the US per year[7]. Three extramural grant programs are intended to provide funding for orphan drug development and research. Other incentives for development of drugs for orphan diseases include tax credits (up to 50% of the clinical trial and development costs); a 7 year period of market exclusivity to the product, and scientific guidance and advice for protocol preparation.[8] Several regulatory tools such as the fast track approval, breakthrough designation and accelerated approval pathway reduce approval times and can be requested independently of each other and help in limiting the scope of a preapproval clinical development required.

EU Landscape for Orphan Drug Development

The EU does not provide any tax credits for clinical trial costs and reductions in regulatory fees favor small and medium enterprises. Tax credits may be provided by individual member states. The EU grants a 10 year market exclusivity and guidance and protocol assistance while promoting research on rare diseases through framework programs. Accelerated approval is granted via Priority Medicines (PRIME) Program; centralized procedure; conditional approval; and approval under exceptional circumstances and accelerated assessment.

 Harmonization Efforts in the US and the EU for Approval of Orphan Drugs

The approval criterion for orphan drugs is no different than other drugs. However, the FDA applies the principle of flexibility in its approval standards to new therapies for rare disorders. While orphan drugs may be reviewed via fast-track scheme, regulatory approval may be accompanied with laborious Risk Evaluation and Mitigation Strategies (REMS) requirements, resulting in delays in approval. Although the US and the EU agreed to utilize a common application process for orphan drugs in 2007, both agencies maintain separate approval processes. Regulatory agencies have varied opinions on the interpretation of acceptable risks and benefits, disease burden, affected populations, and associated economic costs. Regulatory agencies also tend to be stringent with respect to GMP inspections. For example, the FDA conducts its own audits and does not accept GMP certifications from other regulatory agencies.

Addressing the differences and expanding the similarities can improve the alignment in the regulatory requirements in the US and the EU, and is expected to result in greater cooperation in the orphan drug development and approval process.


[1] The Orphan Drug Report 2015. Available at

[2] file:///D:/WORK/2017/pharma%20and%20regulatory%20affairs/The_Science_of_Hope_the_need_the_challanges_and_three_proven_strategies_for_successful_orphan_drug_development.pdf








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