There are many common diseases that affect millions of people across the world. On the other hand, there are so-called rare conditions that affect a small number of people. According to the National Institutes of Health (NIH), a rare disease is defined as a condition that affects fewer than 200,000 individuals or fewer in the US. (1) This definition was created by U.S. Congress in the Orphan Drug Act of 1983.(2)  Although rare diseases affect small numbers of patients by definition, they are estimated to collectively affect ~350 million patients globally,(3) more than double the number of patients affected by AIDS and cancer combined.    

There may be as many as 7,000 rare diseases and the total number of Americans living with a rare disease is estimated at between 25-30 million.(4) These conditions can threaten a person’s life and limit their well-being, 50% of the people affected by rare diseases are children. (5) There are many different causes of rare diseases. Based on the NIH report (1), the majority are thought to be genetic, directly caused by changes in genes or chromosomes. In some cases, genetic changes that cause disease are passed from one generation to the next. In other cases, they occur randomly in a person who is the first in a family to be diagnosed. Many rare diseases, including infections, some rare cancers, and some autoimmune diseases, are not inherited. While scientists are learning more each year, the exact cause of many rare diseases is still unknown.

Many rare diseases do not have effective treatment. This situation is due to several factors, such as challenges in recruitment, low patient numbers, complex causes and limited understanding of pathology and progression, lack of established endpoints, late phase compound failures, and difficulty doing clinical trials. (6)

All drug launches are complex, launches of orphan drug for rare disease is particularly so. The development of orphan drugs has been financially incentivized through U.S. Orphan Drug Act. that treat rare conditions, as it often involves a more expensive and difficult process. The Act states that companies and drug developers can request their product to be designated as an Orphan Drug. This will be granted by the Food and Drug Administration (FDA) if the drug meets a specific set of criteria. The characteristics in detail can be consulted at  21 CFR Part 316 (The Code of Federal Regulations) and here is a rundown of what is needed:

• The drug is meant to treat a rare condition;

• There is documentation that adequately supports the fact that the intended condition is indeed rare and is experienced by no more than 200 thousand people in the U.S. ;

• There is a scientific rationale that means that the drug is plausible as a treatment for the rare condition.(7-8)

Since the Orphan Drug Act was signed into law in 1983, the FDA has approved hundreds of drugs for rare diseases, but most rare diseases do not have FDA-approved treatments. Specifically, FDA sees significant progress in the development of treatments for rare diseases, the agency approved 32 novel drugs and biologics with orphan drug designation in 2020.

Why is it useful to apply for and receive orphan drug designation? There are significant benefits for the drug manufacturer and developer. There are benefits, such as tax credits of 50% off the clinical drug testing cost awarded upon approval, Waiver of the Prescription Drug User Fee (which is around $3 million at the moment, so it represents a significant expense when trying to launch a new drug product), up to 7 years of market exclusivity, and access to the Orphan Product Grants Program that helps fund research and product development for rare conditions. These are significant benefits that can do a lot of good for promoting and introducing a product meant for rare diseases into a market that sorely needs them. (7)

Orphan drug designation in the United States may be obtained through the office of Orphan Products Development of the FDA. When filing for Orphan Drug Designation, the process must be initiated by someone who is defined as a sponsor, which can be a person, a bio pharmaceuticals company, an organization, an academic institution, etc. The sponsor is generally the commercial manufacturer of the drug or the one responsible for doing the clinical trials.

The sponsor has to submit a form and a request that includes a statement of what they are seeking and for which condition the drug works, the contact information and a brief description of the drug as a product, the description of the rare disease, the description of the drug that identifies the active ingredient and other chemical characteristics, a discussion of the scientific rationale, and the information from the studies and clinical experience. The sponsor also needs to prove that the condition only affects a specific subset of people, that it is truly a rare condition. The designation can be given for the use of an unapproved drug or a drug that is approved but used in a different way. The word sponsor is used throughout the regulations. The most recent version of the requirements can be found on the Electronic Code of Federal Regulations website. (9)

Normally, it takes about 90 days for FDA to review the request. It can be either granted or denied. If there is missing documentation, FDA might send a letter requesting it. The request may be denied for various reasons, such as that the condition is not rare, that the drug is not sufficiently tested or there is no sufficient rationale to think it would be helpful, if the statement omits information or has false information, or if the drug or the condition are not known sufficiently well. FDA also has the right to revoke this status after it was granted if there is untrue information or if the drug had not been eligible at the time for the status.(8)

Currently, the easiest way to apply is through the designated portal at https://edm.fda.gov/wps/portal/Home. During the COVID-19 pandemic, it also became possible to submit via email, but sponsors are strongly encouraged to create a secure email account before doing so. The portal is easy to use and offers a history of all submissions as well.(10)

Noteworthy, the National Center for Advancing Translational Sciences (NCATS) has launched the Rare Diseases Registry Program (RaDaR) website to provide the rare diseases community with easily accessible guidance on how to set up and maintain high-quality registries. The registry is a collection of information about patients, usually focused around a specific diagnosis or condition. The goal is to enable rare disease patient organizations to better promote and support patient-focused research.(11)

Therefore, the orphan drug market is an important part of the pharmaceutical industry overall. Patients have a growing need for treatment for conditions that are rare, and companies receive a lot of benefits in releasing a drug that can be used for a rare disease, making a positive impact on its earnings and also on a social and humanitarian level. 

References

1 https://www.nih.gov/about-nih/what-we-do/nih-turning-discovery-into-health/rare-diseases

2 https://www.fda.gov/media/99546/download

3 Global Genes. (2019) https://globalgenes.org/rare-facts/

4 https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases. 

5 Global Genes. https://globalgenes.org/rare-disaese-facts-statistics);

6 https://www.fda.gov/patients/rare-diseases-fda

7 Electronic Code of Federal Regulations. (2021). Subpart C—Designation of an Orphan Drug. Retrieved from https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=718f6fcbc20f2755bd1f5a980eb5eecd&mc=true&n=sp21.5.316.c&r=SUBPART&ty=HTML#se21.5.316_123

8 FDA. (2021). Designating an Orphan Product: Drugs and Biological Products. Retrieved from https://www.fda.gov/industry/developing-products-rare-diseases-conditions/designating-orphan-product-drugs-and-biological-products

9 https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=718f6fcbc20f2755bd1f5a980eb5eecd&mc=true&n=sp21.5.316.c&r=SUBPART&ty=HTML#se21.5.316_121.

10 Advances in experimental medicine and biology,  (2017) 1031, 641–648. 

11 https://registries.ncats.nih.gov/

About the Author

Lin Zhang, M.D., senior director of a health care industry company in the United States. With the experience in clinical medicine, biotechnology, health industry and other fields, he is responsible for the research and development of plant medicine, functional food and health products. He was a clinician and worked for the National Cancer Institute, FDA and the National Cancer Center of Japan for many years.