The FDA’s Rare Diseases Program: Driving the development of orphan drugs

Written By: Dr. Nicola Davies

Source: thepharmaletter

Rare diseases are characterized by the US Food and Drug Administration (FDA) as those conditions that affect less than 200,000 people in the American population. While 200,000 may seem a large number, it is obviously characteristic of rare diseases to be…well, rare, says Dr Nicola Davies in her regular exclusive contribution to The Pharma Letter.

For example, Cushing syndrome - an endocrine disorder that affects adults 20-50 years of age, has a prevalence rate of 5.9 for every 100,000 people. This small statistic of incidence is just one of the hurdles that pharma companies must face in the development of orphan drugs. Orphan drugs are expensive to develop, design, and market - while providing a low rate of return - making these drugs expensive to produce and distribute. This not only means that the development of orphan drugs can be unattractive to companies, but it also makes access to orphan drugs difficult and expensive for patients who need them the most.

To combat the unavailability of drugs for rare diseases and to encourage the development of orphan drugs, the Center for Drug Evaluation and Research (CDER) - a branch of the FDA - initiated the Rare Diseases Program to work with industry partners to develop orphan drugs.

What does the Rare Diseases Program offer?

The development of orphan drugs faces several challenges. For one, the prevalence of some rare diseases results in a historically low number of data points to determine the disease’s natural history and pathophysiology. Data availability is even lower for rare pediatric conditions. Those who develop orphan drugs, therefore, have to rely on historical or even anecdotal data to develop drugs. This results in increased costs and manpower invested in drugs to be used by very few. In addition, small data sets result in prolonged duration of drug development. This can be detrimental in rare diseases with poor prognosis and a progressive nature.

One of the outcomes to emerge from the recognition of these challenges in orphan drug development is the initiation of the Rare Diseases Program. Despite rare diseases affecting miniscule portions of the population, the FDA still considers them a public health issue and strongly encourages the development of drugs for rare diseases. It supports these efforts by exempting developers from user fees, providing marketing exclusivity on the drug (marketing rights protected by law), and grant supports for drug development. In addition, other branches of government offer tax credits and other incentives.

Due to the many challenges that orphan drug development faces, the FDA has relaxed some of its strict guidelines to encourage development of cures for rare diseases. For example, there are some toxicology study exceptions for orphan drugs that do not exist for common diseases. To this end, the Rare Diseases Program encourages pre-Investigational New Drug (pre-IND) application meetings to discuss rare disease exceptions and facilitate information exchange. In addition, orphan drugs are often eligible for accelerated approval that allows them to be approved with early signs of clinical benefit. Orphan drugs can also qualify for fast track status that allows pharma companies to essentially apply for new drug status so that the drug can be monitored on a rolling review basis as and when trials are completed. 

Has the Program made a difference?

Since 2000, the number of orphan drugs is on the rise. As many as 165 drugs were designated as orphan drugs in 2008 compared to only 69 in 2000. Of these drugs, oncology drugs accounted for about one third of approved orphan drugs between 2000 and 2006. Hematologic conditions and immunologic disorders also saw a near 10% drug approval rate among orphan drugs. These numbers generally indicate that CDER policies on orphan drugs are having a positive impact on the pharma industry. Indeed, the Rare Diseases Program has largely encouraged investment in orphan drug development and is growing to become a valuable resource for the pharma industry.

However, there has also been some criticism of the program. There have been claims that in orphan drug applications, there is considerable reviewer variability and varying degrees of flexibility with approved study designs. In addition, the CDER itself has initiated discussions on the lack of resources it faces and the resulting lack of pre-application meetings and follow-up on agency funded studies. 

The Healthcare Professional’s perspective

Orphan drugs largely improve longevity and quality of life in those living with rare conditions, particularly rare pediatric conditions. In addition, the Rare Diseases Program may also be viewed by physicians as a resource for more information on conditions they don’t encounter regularly. Physicians are now able to offer treatments and alternative treatments to patients with rare conditions. This is largely because of the FDA’s consolidated list of approved orphan drugs. This widely available information enables doctors and other healthcare professionals to point patients in the direction of subsidies for expensive medications.

While health professionals seem to applaud the strides the pharma industry has made in terms of orphan drugs, price remains an issue for them.1 Orphan drug treatments are expensive and may remain out of reach to those who cannot afford it. Despite the high costs, though, the program has provided many incentives for developers to invest in orphan drugs. This is particularly true of pediatric rare diseases, through the priority review voucher (PRV) program, which has supported the development of drugs like elosulfase alfa (Vimizim) for Morquio A Syndrome. In addition, health professionals have pointed out the lax oversight the FDA practices on orphan drug development and the various ways in which developers are abusing the incentives available to them.2

The Rare Diseases Program has obviously jump started a movement towards increased development of orphan drugs. While most of the program’s impact has been positive, it remains necessary to ensure a streamlined review system. This will help developers and healthcare professionals make better medical decisions for their patients.


  1. Tribble, S. and Lupkin, S. (2017). High Prices for Orphan Drugs Strain Families and Insurers.  Kaiser Health News. Retrieved from: [Last accessed 13/03/2017].
  2.  Institute of Medicine (US) Committee on Accelerating Rare Diseases Research and Orphan Product Development; Field M.J., Boat T.F., Rare Diseases and Orphan Products: Accelerating Research and Development. Washington (DC): National Academies Press (US); 2010. 3, Regulatory Framework for Drugs for Rare Diseases. Available from: [Last accessed 13/03/2017].