Many of the small pharma companies that VRS supports are developing drugs for rare diseases and conditions.  Development of orphan drug (or biologic) products is important to the medical community.  “Many diseases appear early in life, and a total of 30 percent of children with orphan diseases die before the age of five.  Global estimates put the number of different diseases between 5000 and 7000, with an average of five new conditions discovered every week.  Unfortunately, in total, only 5 percent of orphan diseases have FDA approved treatment (

Challenges in Orphan Drug Development

As with most drug development, there are many challenges along the way.  However, orphan drug development has a unique and very difficult set of challenges.  These challenges include:

  • Small population size.
    • Limited sample size;
    • Difficulty enrolling studies, and
    • The same patients often enroll in multiple studies.
  • Highly heterogeneous group of disorders (and often high phenotypic diversity within the individual disorders).
  • No prior pathways to follow.
    • Clinical endpoints unclear.
  • Diseases are poorly understood.
    • Are you treating the disease or treating the symptoms
    • If treating symptoms, what impact does it have on the quality of life for the patient?

While in the past many sponsors have been reluctant to develop drugs for rare diseases and conditions, many large size and small specialty pharma companies are now investing in orphan drug development programs.  Why the change?  Sponsors are realizing the substantial revenue and significant competitive advantage that is acquired through incentives provided by FDA.  For example, Rituxan®, for its use as an orphan drug and for extended usage for other types of cancer and rheumatoid arthritis (Genentech), generated $8.678 billion in sales in 2014[i].

Main Incentives for Orphan Drug Development

  • Grants;
  • FDA fee waivers;
  • Tax incentives;
  • Marketing exclusivity, and
  • Shorter development time and higher rates of approval.
money pill

The Orphan Products Grants Program provides grants for clinical studies on safety and/or effectiveness that will either result in, or substantially contribute to, market approval of these products.  Additionally, FDA has announced funding $2 million in research grants for natural history studies in rare diseases.  “The goal of the program is to help characterize the natural history of rare diseases, identify subpopulations, and develop and/or validate clinical outcome measures, biomarkers and companion diagnostics.”[i]

Natural History studies are often used in orphan indications and are not the same as patient registries.  While a patient registry is an organized system that uses observational study methods to collect uniform data (clinical and other) to evaluate specified outcomes for a particular disease, or condition, a natural history study is intended to be specific and to describe a disease.

A natural history study will[ii]:

  • Track the course of a disease over time, and
  • Identify demographic, genetic, environmental and other variables that correlate with disease and outcomes in the absence of treatment.


“Not understanding how a rare disease progresses is often a major obstacle in the development of life‑saving medical products.  Information about a disease’s natural history can aid in clinical trial design, identify study end points and lead to faster, better trials – hopefully leading to new and effective diagnostics and treatments.” said Gayatri Rao, M.D., J.D., director of the FDA’s Office of Orphan Products Development, within the Office of Special Medical Programs.

Grant applications are due October 14, 2016 and funding for grantees is expected in March 2017.  For more information on federal grants, please refer to the Orphan Products Natural History Grants Program.