Opinion

Policy Implications of the Designation VIEWPOINT for Remdesivir to Treat COVID-19

Kao-Ping Chua, MD, On March 23, 2020, the US Food and Drug Administra- Remdesivir and the Orphan Drug Act PhD tion (FDA) granted Gilead Science an orphan drug des- Although it can be argued that the FDA could have cho- Susan B. Meister Child ignation for remdesivir to treat coronavirus disease 2019 sen not to grant orphan drug designation for remdesi- Health Evaluation and (COVID-19), even though this status is usually reserved vir to treat COVID-19, our view is that the agency had little Research Center, 1 Department of for drugs that treat rare diseases. In explaining its de- ability to deny Gilead’s application. Under the Orphan Pediatrics, University cision, the agency stated that at the time of Gilead’s ap- Drug Act, FDA must evaluate applications for designa- of Michigan Medical plication for designation, there were sufficiently few tion based on information at the time of application.6 Gi- School, Ann Arbor. confirmed cases of COVID-19 in the United States that lead has stated that it sought designation in early March remdesivir met criteria for designation under the Or- 2020.3 As of March 15, 2020, there were 2918 con- Rena M. Conti, PhD 1 7 Questrom School of phan Drug Act of 1983. firmed US cases of COVID-19, so COVID-19 was a “rare” Business, Institute for The FDA’s decision sparked immediate criticism.1 A disease at the time of application. Health System group of 51 advocacy organizations wrote a letter to the The FDA also would have had little ability to revoke Innovation and Policy, Department of chief executive officer of Gilead calling the designation the orphan drug designation for remdesivir had Gilead 2 Markets, Public Policy, an “unconscionable abuse” of orphan drug policy. Per- not asked the agency to do so. The FDA regulations and Law, Boston haps due to the intense public backlash, Gilead asked the wouldhavepreventedtheagencyfromrevokingthedes- University, Boston, FDA to revoke the orphan drug designation just 2 days ignation solely because the prevalence of COVID-19 grew Massachusetts. after it was granted.3 beyond 200 000 cases.6 The FDA could have revoked In our view, the orphan drug designation for the designation if it had concluded that remdesivir remdesivir was inconsistent with the purpose of the had not been eligible for designation at the time of Orphan Drug Act. This designation also highlights a application6;for example if the agency later deter- loophole in orphan drug policy that could be used mined that the prevalence of COVID-19 exceeded again. 200 000 cases in early March 2020 due to wide- spread undertesting. However, given the small number The Orphan Drug Act of confirmed cases and limited testing capacity in early The provides incentives for the March, such a retrospective determination would have development of drugs to treat rare diseases. Sponsors been difficult to justify.7 can receive these incentives if a drug meets 1 of the 2 criteria for orphan drug designation.4 Typically, as was Federal Legislation to Close the Loophole the case for remdesivir, the FDA grants a designation The FDA’s limited ability to deny orphan drug designa- because the drug would treat a disease affecting fewer tion for a drug that treats a rapidly spreading disease, than 200 000 people in the US.4 In unusual circum- coupled with its limited ability to revoke this designation stances, the agency grants a designation for drugs that once the disease is no longer rare, creates a loophole would treat a common disease after the sponsor dem- that drug sponsors could use again. To close this loop- onstrates that the likely sales would be insufficient to hole, Congress could amend the Orphan Drug Act so recoup development and marketing costs.4,5 Once a that the FDA can revoke an orphan drug designation designation is granted, sponsors receive a 25% federal granted based on disease prevalence if the number of tax credit for the costs of clinical testing and are also affected people in the US later exceeds 200 000. Alter- eligible to apply for FDA grants to further defray these natively, Congress could limit or terminate orphan drug costs.6 If an orphan-designated drug receives FDA exclusivity once the product was deemed sufficiently approval for an orphan indication, the Orphan Drug profitable, following the approach of a policy in the Act provides sponsors with a 7-year period of “orphan European Union.8 For sponsors considering applying for drug exclusivity” during which competitors are barred an orphan drug designation to treat a disease that may from marketing the same drug to treat the same soon become widespread, the prospect of a short-lived disease.4 designation or exclusivity period might decrease the The purpose of these incentives is to promote the motivation to apply. Corresponding development of drugs for rare diseases that otherwise Author: Kao-Ping may not be brought to market because of their limited Implications for Orphan Drug Policy Chua, MD, PhD, Department of sales potential. COVID-19, however, is not a rare dis- The orphan drug designation for remdesivir adds to Pediatrics, University of ease in the US. As of April 3, 2020—just 11 days after the prior concerns about the exploitation of loopholes in Michigan, 300 N Ingalls FDA granted remdesivir the designation—the number of the Orphan Drug Act. For example, adalimumab (Hu- St, SPC 5456, Rm 6E18, confirmed US cases of COVID-19 surpassed 200 000.7 mira; AbbVie), a tumor necrosis factor blocking agent, Ann Arbor, MI 48109-5456 (chuak@ Clearly,the orphan drug designation for remdesivir was was the top-selling prescription drug in the US with med.umich.edu). inconsistent with the purpose of the Orphan Drug Act. $13.7 billion in sales in 2018. Despite these block-

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buster sales and the fact that adalimumab is most often used for this designation to Sublocade even though Subutex had $285 mil- non-rare diseases such as rheumatoid arthritis, psoriasis, Crohn lion in sales between 2002 and 2011.5 In 2019, however, the FDA disease, and ulcerative colitis, AbbVie has obtained 7 orphan indi- revoked the designation for Subutex after concluding that Reckitt- cations from the FDA, each of which entitled the sponsor to Benckiser’s 1994 cost-recovery analysis was based on unreason- orphan drug benefits. Of the 7 orphan indications, 6 are for differ- able assumptions. For example, the analysis assumed that Subu- ent age-based subpopulations of patients with juvenile idiopathic tex would only be in prescribed in methadone outpatient arthritis, uveitis, or hidradenitis suppurativa.9 On the basis of this treatment programs—the only settings in which buprenorphine and other examples, drug sponsors have been criticized for pur- could be prescribed in 1994—even though it was likely at the time suing a strategy of partitioning diseases by patient age or disease that restrictions on buprenorphine prescribing would be loosened subtype to create populations that are artificially rare.10 owing to the drug’s safety, allowing it to be used in additional A second example is extended-release buprenorphine injec- settings.5 tion (Sublocade; Indivior). In 2017, the FDA approved this drug to treat opioid use disorder under a 1994 orphan drug designation Conclusions for buprenorphine sublingual tablets (Subutex) granted to Indiv- The examples of remdesivir and Sublocade illustrate how drug spon- ior’s parent company, Reckitt-Benckiser. The 2017 approval for sors have taken advantage of policy loopholes to obtain orphan drug Sublocade potentially would have entitled Indivior to a 7-year benefits for drugs that address public health crises, such as the opi- period of orphan drug exclusivity during which other buprenor- oid epidemic and the COVID-19 pandemic. Opioid use disorder and phine products could not have been marketed. The FDA granted COVID-19 are not rare diseases. Congress and the FDA should en- the designation based on Reckitt-Benckiser’s argument that sales sure that the benefits of the Orphan Drug Act are only used in a man- would be insufficient to recoup development costs, and extended ner consistent with their purpose.

ARTICLE INFORMATION 20, 2020. https://www.citizen.org/news/gilead- CFRSearch.cfm?CFRPart=316&showFR=1& Published Online: August 17, 2020. must-relinquish-monopoly-on-potential- subpartNode=21:5.0.1.1.6.3 doi:10.1001/jamainternmed.2020.2759 coronavirus-treatment/ 7. Johns Hopkins University and Medicine. Conflict of Interest Disclosures: None reported. 3. Gilead Sciences. Gilead Sciences Statement on Coronavirus Resource Center. Accessed May 12, Request to Rescind Remdesivir Orphan Drug 2020. https://coronavirus.jhu.edu/map.html Funding/Support: Dr Chua is supported by a career Designation. Accessed April 20, 2020. https:// 8. Bagley N, Berger M, Chandra A, Garthwaite C, development award from the National Institute on www.gilead.com/news-and-press/company- Drug Abuse (grant number 1K08DA048110-01). Stern A. The orphan drug act at 30. In: Lerner J, statements/gilead-sciences-statement-on-request- Stern S, eds. Innovation Policy and the Economy, Dr Conti is supported by a grant from the American to-rescind-remdesivir-orphan-drug-designation Cancer Society. 2018, Volume 19 (National Bureau of Economic 4. Food and Drug Administration. Orphan Drug Act Research Innovation Policy and the Economy). Role of the Funder/Sponsor: The funders had no - Relevant Excerpts, 2018. Accessed May 12, 2020. Chicago, IL: University of Chicago Press; 2019. role in the creation of this article; collection, https://www.fda.gov/industry/designating- management, analysis, and interpretation of the 9. Food and Drug Administration. Orphan drug orphan-product-drugs-and-biological-products/ designations and approvals. Accessed April 1, 2020. data; preparation, review, or approval of the orphan-drug-act-relevant-excerpts manuscript; and decision to submit the manuscript https://www.accessdata.fda.gov/scripts/ for publication. 5. Chua KP, Conti RM. Revocation of Orphan Drug opdlisting/oopd/index.cfm Designation for Extended-Release Buprenorphine 10. Daniel MG, Pawlik TM, Fader AN, Esnaola NF, REFERENCES Injection: Implications and Next Steps. Health Makary MA. The orphan drug act: restoring the Affairs Blog. March 5, 2020. 1. Lupkin S. FDA Grants Experimental Coronavirus mission to rare diseases. Am J Clin Oncol. 2016;39 Drug Benefits for Treatments. 6. Electronic Code of Federal Regulations. Part 316: (2):210-213. doi:10.1097/COC.0000000000000251 National Public Radio. March 24, 2020. Orphan Drugs. Accessed May 12, 2020. https:// www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ 2. Public Citizen. Gilead Must Relinquish Monopoly on Potential Coronavirus Treatment. Accessed April

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