Gilead's Request To Revoke Remdesivir Orphan Designation Reflects Pandemic Pressures
Executive Summary
Two days after US FDA granted remdesivir orphan status for treatment of COVID-19, Gilead told the agency it is unnecessary. EMA says it would not grant orphan drug designation to a COVID-19 treatment.
In a surprising reversal, Gilead Sciences Inc. announced on 25 March that it has asked the US Food and Drug Administration to rescind the orphan drug designation for remdesivir for treatment of COVID-19, which the agency granted two days earlier. By the end of the day, the agency had processed the request and withdrawn the designation.
Several groups had issued calls for the FDA to revoke the designation after it became public, arguing that the number of people in the US infected with COVID-19 would soon surpass the 200,000 limit for being deemed an orphan disease. (Also see "Orphan Drug Designation For Remdesivir Is 'Consistent' With Precedent, Former FDA Lawyer Says" - Pink Sheet, 24 Mar, 2020.)
EURODIS-Rare Diseases Europe, an alliance of over 900 rare disease patient organizations, issued a statement urging the European Union not to follow FDA in granting orphan designation to COVID-19 treatments.
Asked about the issue, a spokesperson for the European Medicines Agency said EMA had not received an application for treatment of COVID-19 from any sponsor. "COVID-19 is a global pandemic and given the acceleration of cases of infections in the EU and worldwide, the threshold of infections can be expected to soon be beyond what would qualify as a rare disease," the spokesperson said.
The company seems to have taken the criticism to heart. It noted that it had requested the designation in early March. The number of individuals in the US infected with COVID-19 has increased exponentially since then, now totaling more than 50,000 cases.
"Gilead is confident that it can maintain an expedited timeline in seeking regulatory review of remdesivir, without orphan drug designation," Gilead said in a statement. "Recent engagement with regulatory agencies has demonstrated that submissions and review relating to remdesivir for the treatment of COVID-19 are being expedited."
Designation Provides Clinical Trial Benefits
Dan Orr, former FDA regulatory counsel and a partner at Womble Bond Dickinson, said the optics were bad, but Gilead didn't do anything wrong.
"The company may have been trying to get the orphan drug designation not for the exclusivity, but for the tax advantages," Orr said. "It's disappointing that in the rush to judgment against Gilead, the company's critics have likely made it more difficult to test whether remdesivir is a safe and effective treatment for COVID-19 and may have delayed getting it to the patients who need it."
Orr said that orphan drug designation offers a lot of flexibility in clinical studies, such as flexible endpoints and alternative study designs. He noted that it is not possible to run a conventional trial during a pandemic and many ongoing trials are being suspended.
Gilead said, "Among the benefits of orphan drug designation, this status results in a waiver of the requirement to provide a pediatric study plan prior to the submission of a New Drug Application – a process that can take up to 210 days to review."
But when FDA requires a pediatric study plan, the agency usually likes to have it before the beginning of Phase III, a stage that remdesivir is already well beyond at this point. And given that kids seem to fall victim to COVID-19 less often while the need for treatment of adults is critical, at least a partial waiver seems likely if a satisfactory plan cannot be finalized in time.
On 26 February, Gilead announced the initiation of two Phase III trials of remdesivir for COVID-19, which are to enroll approximately 1,000 patients at medical centers primarily in Asian countries, as well as other countries with high numbers of diagnosed cases.
The National Institute of Allergy and Infectious Diseases is running a Phase II adaptive trial of remdesivir, which will initially compare remdesivir to placebo. Once a therapy is shown to be efficacious it is to become the control arm for new candidates. (Also see "COVID-19 Study Of Gilead’s Remdesivir Using Ebola-Style Adaptive Platform Trial" - Pink Sheet, 17 Mar, 2020.)
Revocation Of Orphan Status Is Rare
It is rare for an orphan drug designation to be revoked. Last year, the agency rescinded the orphan drug designation for Indivior PLC's opioid use disorder drug Sublocade (buprenorphine extended-release), saying it had relied on unreasonable assumptions regarding total market size and failed to consider information about other dosage formulations. (Also see "US FDA Revokes Orphan Drug Designation For Indivior’s Sublocade" - Pink Sheet, 11 Nov, 2019.)
Hyman, Phelps & McNamara noted in a 2016 blog post that FDA had revoked the orphan drug designation for Altus Pharmaceuticals Inc.'s TheraCLEC-Total pancreatic enzyme product for treatment of exocrine pancreatic insufficiency because the drug could be used in a larger population of HIV/AIDS patients. And in 2016, the agency revoked the designations for four products for the treatment of hypertension in pediatric patients: Carmel Biosciences Inc.'s valsartan oral solution, both BioRamo LLC's and Silvergate Pharmaceuticals Inc.'s lisinopril oral solution, and Silvergate's enalapril maleate.
In response to questions, FDA said that a sponsor may voluntarily withdraw an orphan drug designation request or an orphan drug designation at any time after the request is submitted or granted by submitting a written request for withdrawal to FDA.
The agency said that there have been 744 orphan designated drugs that have not been approved and had their designation withdrawn by the sponsor. There have been four orphan designated drugs that were approved and had their designation withdrawn by the sponsor.
Francesca Bruce contributed to this article.