Gliead asked FDA to rescind the orphan drug designation for coronavirus treatment remdesivir it just received 48 hours earlier - Why?

Last Monday, Gilead received the orphan drug designation from US FDA for remdesivir to treat Covid-19. Two days later on Wednesday, we saw the news that Gilead asked FDA to rescind its orphan drug designation - it was really an unusual step taken by a company in 37-year history since Orphan Drug Act was enacted in 1983.

A drug with orphan designation will give many benefits to the drug developer.

• Exemption from PDUFA (Prescription Drug User Fee Act) marketing application fee (FY 2020: $2.94+ million)
• 7 years of exclusivity in the U.S.
• Tax credits related to clinical trial expenses
• Orphan products grants program
• Submission of a pediatric assessment per PREA is not required
• FDA assistance in clinical trial design

After Gilead received the orphan drug designation, it immediately drew a lot of critics. The company was criticized by lawmakers and patient advocates after receiving the orphan designation for the experimental antiviral drug, saying it was taking advantage of the rapidly accelerating health crisis.

"It's embarrassing to take something that's potentially the most widespread disease in the history of the pharmaceutical industry and claim it's a rare disease."

“This is an unconscionable abuse of a programme designed to incentivise research and development of treatments for rare diseases.”

“Calling COVID-19 a rare disease mocks people’s suffering and exploits a loophole in the law to profiteer off a deadly pandemic,”

Gilead had maintained that at the time that it had filed for the orphan designation, the coronavirus outbreak was nowhere near the level of severity it is at now. It also contended that it had sought the orphan status to expedite approval for the drug, in particular for a required paediatric study plan.

According to the Orphan Drug Act approved in 1983, the orphan drug designation was for drug development in rare disease or condition where the rare disease or condition means: 

(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 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.

Determining orphan drug designation based on the # of patients is usually good for ultra-rare diseases and for diseases with genetic disorders. However, it can be problematic when it comes to diseases with a dynamic feature in the number count (the Covid-19 pandemic is a great example):

• Defining and counting rare diseases is not straightforward.
• Difficulties in obtaining definitive diagnoses contribute
• Limitations in systems for reporting and tracking orphan disease diagnoses.
• Countries have adopted different definitions of a rare disease
• Researchers are continuously identifying new diseases or disease variants.

The epidemiology of rare diseases—including the determination of prevalence (the number of people affected at any one time), incidence (the number of new cases in a given year), and patterns of disease (e.g., age distribution) in the population—is inexact.

A rare disease may become a prevalent disease

• Some conditions that initially are classified as rare eventually outgrow that categorization. Covid-19 infection is a good example of this. Even though the # of confirmed cases is still below the 200,000 mark, very soon, the threshold of 200,000 cased will be crossed. Another example is HIV/AIDS. When AIDS emerged in the United States, it fit the legislative definition of a rare disease—affecting fewer than 200,000 individuals. As the infection spread, as diagnostic capabilities and data collection systems improved, and as researchers developed effective treatments that reduced mortality without curing the disease, the total number of individuals with AIDS grew to nearly 470,000 by 2007 and the number of individuals with HIV infection exceeded 1.1 million (CDC, 2009c). 
• If effective but not curative treatment can turn a rare disease into a common one,

A prevalent disease may become a rare disease

Effective prevention can, conversely, turn a common condition into a rare disease. This is the case with many once common childhood infections such as mumps and measles. Public health officials are concerned, however, that factors such as the development of drug-resistant infectious agents and the opposition of some parents to childhood vaccinations could reverse the situation for some now rare diseases. The former concern—drug resistance—is partly a significant scientific challenge (i.e., developing new anti-infectives) and partly a public health and clinical practice challenge (i.e., discouraging overuse of antibiotics). Preventing negative health consequences from anti-vaccination sentiment involves public health expertise, social science research, clinician communication skills, and public policy responses.

• Post-polio syndrome
• Precision Medicine – genetic biomarkers further divide the disease into subgroups

For the Covid-19 situation, if we purely base the orphan designation on the # of patients, it will meet the criteria in the beginning, then not meet the criteria, and meet the criteria again. In any way, obtaining an orphan drug designation for remdesivir in treating Covid-19 patients is indeed unethical.