Abstract
Abstract
Background
Information about the specific regulatory environment of orphan drugs is scarce and inconsistent. Uncertainties surrounding the postmarketing long-term safety of orphan drugs remain. This study aimed to evaluate the labelling changes of orphan drugs and to identify postmarketing safety-associated approval factors.
Methods
This retrospective cohort study includes all drugs with orphan drug designation approved by the Center for Drug Evaluation and Research of the US Food and Drug Administration between 1999 and 2018. Main outcomes are safety-related labelling changes up to 31 December 2019. We defined any safety-related labelling changes as postmarketing safety events (PMSE). Safety-related withdrawals, suspensions, and boxed warnings were further categorised as severe postmarketing safety events (SPSE). Outcome measurements include frequencies of PMSE, SPSE, and association between approval factors and the occurrence of safety events.
Results
Amongst the 214 drugs identified with orphan drug designation (25.7% biologics), 83.6% were approved through at least one expedited programme, and 29.4% were approved with boxed warnings. During a median follow-up of 6.74 years since approval, 69.2% and 14.5% of the analysed orphan drugs had PMSE and SPSE, respectively. Safety-related withdrawal (0%, 0/214), suspended marketing (0.46%, 1/214) and new boxed warnings are uncommon (3.7%, 8/214). The safety-related labelling changes were more frequent in the drugs approved with boxed warnings [Incidence rate ratio (IRR): 1.95 (1.02–3.73)] and approved for long-term use [IRR: 2.76 (1.52–5.00)].
Conclusions and Relevance
In this long-term postmarketing analysis, approximately 70% of FDA-approved orphan drugs had safety-related labelling changes although severe safety events were rare. While maintaining early access to orphan drugs, the drug regulatory body has taken timely regulatory action with postmarketing surveillance to ensure patient safety.
Funder
lks faculty of medicine, university of hong kong
department of medicine, university of hong kong
Publisher
Springer Science and Business Media LLC
Subject
Pharmacology (medical),Genetics (clinical),General Medicine
Reference28 articles.
1. US Food and Drug Administration (FDA). Title 21 food and drugs. Chapter I food and drug administration department of health and human services. Subchapter D drugs for human use. Part 316 orphan drugs. United States: Federal Register; 2020. https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=718f6fcbc20f2755bd1f5a980eb5eecd&mc=true&n=sp21.5.316.c&r=SUBPART&ty=HTML#se21.5.316_121.
2. Fonseca DA, Amaral I, Pinto AC, Cotrim MD. Orphan drugs: major development challenges at the clinical stage. Drug Discov Today. 2019;24(3):867–72.
3. Food and Drug Administration. Fast track, breakthrough therapy, accelerated approval, priority review, United States: Food and Drug Administration; 2018. https://www.fda.gov/patients/learn-about-drug-and-device-approvals/fast-track-breakthrough-therapy-accelerated-approval-priority-review.
4. Kepplinger EE. FDA’s expedited approval mechanisms for new drug products. Biotechnol Law Rep. 2015;34(1):15–37.
5. Zhang AD, Puthumana J, Downing NS, Shah ND, Krumholz HM, Ross JS. Assessment of clinical trials supporting US food and drug administration approval of novel therapeutic agents, 1995–2017. JAMA Netw Open. 2020;3(4):e203284.
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