Orphan Designation 

An “orphan designation” is granted by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for a drug/biologic to create financial incentives for developing therapies for rare diseases.  

This article focuses on the FDA orphan designation program in respect to the incentives offered, the prevalence that defines an orphan disease, as well as the procedural process of obtaining the designation. 

Keywords 

ODD, OMPD, orphan, prevalence, rare  

Introduction 

A rare disease is, as implied, a disease that affects a relatively low number of patients in the population. Many (over 6,000) rare diseases have been identified to date, and it is estimated that 3.5% – 5.9% of the worldwide population is affected by these diseases. 72% of rare diseases are genetic, while others result from infections, allergies, and environmental causes. Due to the low prevalence of each disease, medical expertise is rare, and knowledge and effective care are extensively lacking. In the past, drug manufacturers would not invest in therapies for rare diseases as they could not cover the vast costs of drug development and profit from marketing drugs to such small groups of patients. Despite the urgent need for rare disease1 medicines, they came to be known as orphans of health systems, as companies would not develop these medicines, and the patient was often denied proper diagnosis and treatment2 of therapies for orphan diseases.   

In order to encourage the development, the US Food and Drug Administration (FDA)  launched programs to create financial incentives for developing these therapies. An “orphan designation” is granted for a drug/biologic developed to treat an orphan disease.  

Since their inception, orphan designation programs have successfully created incentives for developing orphan drugs. For example, in 1983, the US Congress passed the Orphan Drug Act (ODA) laid down in 21 Code of Federal Regulations (CFR) §3163 to create financial incentives for orphan drug developers. Since 1983, the Act has resulted in the development of more than 250 orphan drugs, which are available to treat a potential patient population of more than 13 million Americans2

Orphan Drug Designation in the US 

To be eligible for Orphan Drug Designation (ODD) granted by the FDA, a drug or biologic product should be intended for the safe and effective treatment, diagnosis, or prevention of rare diseases/disorders. To be defined as a rare disease in the US, the disease should affect fewer than 200,000 people in the US (prevalence is <200,000 persons) or affect more than 200,000 persons but not expected to recover the costs of developing and marketing a treatment drug (drugs that will not be profitable within 7 years following approval by the FDA).  

How to Submit a Request for ODD Designation  

An application4 of ~30 pages is submitted to the Office of Orphan Products Development (OOPD) by a US representative5.  

The basic elements in US FDA orphan designation4 application  

  • Administrative information 
  • Information on the disease or condition: Pathophysiology, etiology, treatment options and prognosis 
  • Scientific rationale that demonstrates the drug’s “promise” to treat, diagnose or prevent the disease/condition, e.g., drug description and mode of action relevant to disease/condition; proof of concept studies, in vitro and in vivo data, clinical studies relevant to drug and disease/condition (if available) 
  • Regulatory status 
  • Determining the population estimate to support that the disease is rare: calculate the number of patients in the US based on established literature references and current US population estimates to show prevalence is < 200,000  

The evaluation process takes a maximum of 90 days from application submission. The application can be submitted on any date.   

The benefits of a US FDA orphan designation 

  • Potential 7-year marketing exclusivity after approval 
  • Exemption from user fees (waiver of NDA/BLA user fees) 
  • Tax credits for qualified clinical testing  

Annual report  

An annual summary of information on the status of orphan drug development should be submitted. These are short documents (~10 pages) submitted between 12 and 14 months from the date of initial designation acceptance annually. The summaries include a review of preclinical and clinical studies performed and planned, a short description of the investigation plan for the coming year, and any anticipated or current problems/difficulties in testing/potential changes that may impact orphan designation.  

Acronyms and abbreviations 

BLA, Biologics License Application; CARs, Cumulative Abnormal Returns; CFR, Code of Federal Regulations; FDA, [US] Food and Drug Administration; NDA, New Drug Application; ODA, Orphan Drug Act; ODD, Orphan Drug Designation; OMPD, Orphan Medicinal Product Designation; OOPD, Office of Orphan Products Development;  

References 

(1) EURORDIS Rare Diseases Europe. What is a rare disease? www.eurordis.org/information-support/what-is-a-rare-disease/ (accessed). 

 
(2) US FDA. Orphan Products: Hope for People With Rare Diseases. 2018. https://www.fda.gov/drugs/information-consumers-and-patients-drugs/orphan-products-hope-people-rare-diseases (accessed). 

(3) US FDA. 21 CFR §316. 2023. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=316 (accessed. 

4) US FDA. Recommended Tips for Creating an Orphan Drug Designation Application. 2018. https://www.fda.gov/media/111762/download (accessed. 

(5) ADRES Ltd. Guiding you through regulatory processes. https://adres.co.il/regulatory-affairs/ (accessed). 

About the authors 

Liron Gibbs-Bar, PhD, is an associate senior regulatory and scientific consultant at ADRES and ADRES EU. She has more than eight years of experience in regulatory affairs, including regulatory strategy, briefing packages, and clinical trial applications writing, as well as interactions with regulatory authorities.  
Dr. Gibbs-Bar has a PhD in developmental biology from the Weizmann Institute of Science. She can be reached at liron@adres.bio 

About the authors

Rivka Zaibel
President and Founder @ ADRES International Biotech Consultation and Execution

Rivka Zaibel brings over 36 years of expertise in the biopharmaceutical and biotechnology industries, including 20 years dedicated to regulatory and quality management of drugs, biologics, medical devices, and combination products. She has extensive experience leading multidisciplinary projects and managing both internal and external activities across the development lifecycle, from lead compound identification through CMC, preclinical and clinical development, to product registration. Staying at the forefront of regulatory standards in both the US and Europe, Rivka has engaged in numerous meetings with regulatory authorities to advance projects development. Additionally, she mentors initiatives such as SPARK, Biodesign, and EIT, and serves as a lecturer in the Master’s program for Development and Regulation of medical technologies at Tel Aviv University. 

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Liron Gibbs-Bar, PhD
Associate senior regulatory and scientific consultant at ADRES and ADRES EU

Liron Gibbs-Bar, PhD, is an associate senior regulatory and scientific consultant at ADRES and ADRES EU. She has more than eight years of experience in regulatory affairs, including regulatory strategy, briefing packages, and clinical trial applications writing, as well as interactions with regulatory authorities.  
Dr. Gibbs-Bar has a PhD in developmental biology from the Weizmann Institute of Science. She can be reached at liron@adres.bio 

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