PRO44 IMPACT OF PIVOTAL STUDY DESIGN ON WORLDWIDE ORPHAN DRUG REGULATORY LABELING AND MARKET ACCESS

Abstract

Global regulatory authorities established the orphan drug designation to incentivize development of new drugs for rare and underserved diseases with high unmet need. As a measure of success of the designation, orphan drug sales currently represent more than 15% of overall global drug sales and is growing rapidly relative to non-orphan drugs. Incentives associated with orphan designation include routine allowance of novel/ non-randomized pivotal study designs using real-world evidence (RWE), accelerated regulatory review, increased likelihood of regulatory approval, and greater pricing latitude. We evaluated how orphan drug pivotal study design impacts regulatory labeling, health technology assessment (HTA), and market access, globally. We reviewed global regulatory documents, trial data, HTAs, and payer coverage policies for drugs with orphan designations that were approved in both the United States and Europe from 2014–2018. We identified and evaluated >50 orphan drugs matching the criteria, including 40% for oncology indications, and 30% for genetic disorders. While the majority of drug labeling was consistent with, or broader than, the patient population included in pivotal studies, HTAs/ payer policies often restricted reimbursement to a narrower population. Furthermore, where HTAs/ payer policies initially (or ultimately) rejected, restricted eligible patients vs. regulatory labeling, or limited access to special arrangements (e.g., Cancer Drugs Fund in the United Kingdom), trial design was often cited; a lack of sufficient comparator data, study duration, and/or relevant patient inclusion was commonly referenced. Recent examples highlighted include avelumab, axicabtagene ciloleucel, burosumab, cenegermin, cerliponase alfa, daratumumab, inotersen, inotuzumab ozogamicin, ixazomib, letermovir, midostaurin, nintedanib, niraparib, nusinersen, patisiran, venetoclax, among others. While regulators commonly grant orphan drugs approval based non-randomized trial designs, with smaller sample sizes and narrower populations represented, drug developers must plan to avoid common evidence gaps that lead to delayed, suboptimal reimbursement, and/or outright access denial. Improved strategic use of RWE is also recommended.