Using four decades of FDA orphan drug designations to describe trends in rare disease drug development: substantial growth seen in development of drugs for rare oncologic, neurologic, and pediatric-onset diseases

Abstract

Background Orphan drug designations are a useful proxy to investigate trends in rare disease drug development. Drug developers must receive a designation before they are eligible for the economic incentives of the Orphan Drug Act in the United States. We created a database of all orphan drugs designated between 1983 and 2019 that included numerous drug characteristics, including therapeutic area. In addition, we constructed a “broad disease” categorization of designations as an alternative to therapeutic area, based on disease etiology and age of onset rather than organ system. By looking at the pattern of orphan drug designations over the past four decades, this analysis studied the impact of the evolving rare disease drug development landscape and considers the future of rare disease therapies over the coming decades. Results Between 1983 and 2019, a total of 5099 drugs and biologics received orphan drug designation. Designations more than doubled between the 1980s and 1990s, almost doubled between the 1990s and 2000s, and almost tripled in number between the 2000s and 2010s. The top three therapeutic areas represented in the orphan drug designations were: oncology (1910, 37%), neurology (674, 13%), and infectious diseases (436, 9%). The broad disease categorization found that the proportion of designations for pediatric-onset diseases has increased in the most recent decade to 27%. Conclusions Analysis of the last four decades of orphan drug designation indicates seismic shifts have occurred in the rare disease drug development space. The number of designations granted more than quadrupled between the 1990s and 2010s. While these substantial increases led to growth in the absolute number of designations within all therapeutic areas (bar one) and broad disease categories, the relative proportions have seen considerable change over time. In the most recent decade, there have been notable increases in the proportion of drugs in oncology, pediatric-onset diseases, and neurologic disorders. The dramatic rise in overall orphan designations over the past four decades suggests we may continue to see an upward trajectory in designations leading to an increased number of approvals for drugs and biologics designed specifically for diagnosing, preventing, and treating rare diseases in the coming decades.

FDA Orphan Designations, Approvals, and Regulatory Review Time since the Enactment of the Orphan Drug Act (1983)

“…We found a signi cant reduction in the time lag between orphan drug designation and approval following the implementation of the FDA's Orphan Drug Designation Modernization Plan in 2017. The Plan aimed to streamline the orphan drug application review process, address all pending orphan designation requests, and review all orphan drug approval requests within a 90-day window (17). Hence, our ndings suggest that the Plan's goal of expediting FDA orphan drug approval review time was achieved.…”

“…We classi ed the orphan drug designations according to the type of products (chemical entity or biological product), indication (prevention, treatment, or diagnosis), number of active ingredients (single or xed-dose combinations), and sponsored country of incorporation (US or non-US). Then, we classi ed the orphan designations by general category of therapeutic area (17), including oncology, infectious diseases, excluding HIV, genetic disorders, poisoning and toxic effects, and other therapeutic areas. Also, we classi ed orphan designation for HIV and related comorbidities as a separate category from infectious diseases since economic incentives and FDA expedited approval pathways were implemented to improve accessibility to new drugs, speci cally HIV/AIDS (10)(11)(12).…”

“…Some studies evaluated trends in approvals of orphan new molecular entities (NMEs) (16), secondary indications, and new formulations (15). A recent study assessed trends in orphan drug designation by therapeutic class (17). Yet, no studies have examined the reasons behind those FDA orphan designations..…”

Challenges and opportunities for improving access to approved neonatal drugs and devices

“…The Orphan Drug Act of 1983 gave the FDA authority to use federal subsidies and grant protection against generic competition. Advocacy for drug reform has facilitated processes at FDA to expedite the review of treatments for serious conditions and thereby fill unmet medical needs [ 25 ]. This includes both financial incentives (delaying generic competition) and specific designations including “fast track, breakthrough therapy, and accelerated approval pathways” that allow surrogate measures of effectiveness while waiting for more definitive research [ 26 ].…”

Identification of ER/SR resident proteins as biomarkers for ER/SR calcium depletion in skeletal muscle cells

“…There is an incentivized need to expedite orphan drug development and drug repurposing for the therapeutic intervention of rare diseases [ 21 ]. Henderson and colleagues recently screened 9,501 compounds approved by U.S. and numerous international regulatory agencies and characterized several for their anti-exodosis properties [ 10 ].…”