Abstract
BackgroundInformation 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.MethodsThis 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.ResultsAmongst 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 RelevanceIn 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.
Highlights
In the United States (US), orphan drug designation refers to a special status granted by the Food and Drug Administration (FDA) to drugs that are indicated for a disease that affects 200,000 or fewer persons in the US or drugs with no reasonable expectation that sales will offset the costs of development and marketing [1]
Characteristics of FDA‐approved orphan drugs We identified 214 drugs with orphan drug designation approved by the US FDA between 1 January 1999 and 31 December 2018
Summary of findings This study provides an overview of orphan drug safety through the first, most comprehensive longitudinal analysis of the FDA database on orphan drugs
Summary
In the United States (US), orphan drug designation refers to a special status granted by the Food and Drug Administration (FDA) to drugs that are indicated for a disease that affects 200,000 or fewer persons in the US or drugs with no reasonable expectation that sales will offset the costs of development and marketing [1]. Evidence of orphan drug safety collectively remains scarce and inconsistent while heterogeneity across studies renders the synthesis of results infeasible. Other orphan drug safety studies may have included all novel therapeutics with limited insight on the regulatory environment of orphan drugs. This presents challenges for patients with rare diseases and clinicians in understanding the process behind orphan drug approval, many of whom may already be deterred by the inherent uncertainty of disease progression, and overestimate the risks alongside newly approved orphan drugs. 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
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