Drug for Treating Rare Diseases: Orphan Drug, Orphan Disease, Orphan Subset

Section 526(a) of the Federal Food, Drug and Cosmetic Act (FD&C Act) defines a ‘‘rare disease or condition’’ as following:

any disease or condition which (A) affects less than 200,000 persons in the United States, or (B) affects more than 200,000 in the United States and for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from sales in the United States of such drug. Determinations under the preceding sentence with respect to any drug shall be made on the basis of the facts and circumstances as of the date the request for designation of the drug under this subsection is made.

In “Ophan drug act final rule” issued on June 12, 2013, Orphan Drug Regulations further clarified the term “ophan subject”

‘‘orphan subset’’ of persons with a particular disease or condition that otherwise affects 200,000 or more persons in the United States (‘‘non-rare disease or condition’’), for the purpose of designating a drug for use in that subset.

Regulations provided the incentives for sponsors to develop the drugs for orphan diseases. The incentives includes:

• Seven-year marketing exclusivity to the first sponsor obtaining FDA approval of a designated drug
• Tax credit equal to 50% of clinical investigation expenses
• Exemption/Waiver of PDUFA application (filing) fees
• Assistance in the drug development process
• Orphan Products Grant funding

However, in order to obtain the approval, the clinical trials are still needed to demonstrate the efficacy and safety. The requirements specified in FDA guidance “Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products” will still be met.

A debatable question is whether or not there should be less requirement for orphan drug development studies:

• Should one single pivotal study be sufficient for approval?
• Should the surrogate endpoint or biomarkers be used?
• Should there be different requirement for the size of so called ‘safety database’?
• Should alternative clinical trial design or different statistical approaches be used? 
• Should there be different drug approval pathways for orphan diseases? 

Given that the size of the patient population may vary in great deal depending on the type of orphan disease (orphan versus ultra orphan), it is not possible for the regulators to have an one set of rules that could apply to all orphan disease. The general desire from the sponsor side or patient advocate groups is to have less requirements for drug development in orphan disease.

The National Organization for Rare Disorders (NORD), is a unique federation of voluntary health organizations dedicated to helping people with rare "orphan" diseases and assisting the organizations that serve them. NORD is committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and service.

Everylife Foundation for Rare Diseases is an organization dedicated to accelerating biotech innovation for rare disease treatments through science-driven public policy. They have organized a series of rare disease workshops to facilitate the process and help guide improvements in the development process for rare disease treatments. The most recent workshop is on “Accelerated Approval for Rare Disease Treatments”. All presentation slides are posted for free. 

Additional references:

• FDA/CDER Small Business Chronicles - Orphan Drugs

• FDA: Designating an Orphan Product: Drugs and Biologics
• FDA Basics Videos: Time Cote on Orphan Drugs
• Hughes et al “Drugs for exceptionally rare diseases: do they deserve special status for funding?”
• Regulatory Framework for Drugs for Rare Diseases
• Orphanet Journal of Rare Diseases