In 2001, after fewer than three months of review, the Food and Drug Administration (FDA) marked an important moment in the treatment of cancer. That year the FDA granted accelerated approval to imatinib mesylate (Gleevec) for the treatment of patients with chronic myelogenous leukemia who were in blast crisis or had progressed to an advanced stage of disease that was no longer addressable by interferon. The approval was by no means routine at the time. The three trials serving as the basis for the decision were all single-arm studies that evaluated cytogenetic and hematologic response rates – measures that stood in for more traditional primary endpoints, such as overall survival (OS). Offering access so early in a drug’s development was a gamble. Patients and the healthcare system would bear the costs and consequences if the drug didn’t work or proved to have unacceptable side effects. But the possible upside was also enormous. The prognosis at these stages of disease was dire, and patients would otherwise be forced to wait months or years for additional evidence on imatinib to accrue. By 2003, it was clear that the gamble had paid off. The FDA granted full approval on follow-up studies that showed a 90.8% survival rate after two years of treatment. The victory was more than scientific - patients who had received imatinib before its full approval benefitted from the early availability of a treatment that quickly became the standard of care. But if the success of imatinib stands as one bookend of the experience with the accelerated approval pathway (AAP), the other end might find its exemplar in eteplirsen (Exondys 51). The FDA granted authorization to Sarepta Therapeutics in 2016 to market this treatment as the first for Duchenne Muscular Dystrophy (DMD). The excitement in the patient community was palpable, but the approval came despite sharp and unusually public internal disagreement within the FDA over whether the drug had met the bar for demonstrating reasonable likelihood of clinical benefit. Following its approval, some private payers deemed the evidence inadequate for coverage and balked at paying for eteplirsen, although coverage denials were routinely overturned on appeal. The annual cost of the drug in real-world practice rose to over $1 million per patient, and the drug quickly became a source of blockbuster revenue for Sarepta. 3 To many, the capstone of this saga has been the drug maker’s failure to follow through on its post-marketing evidence requirement. As part of the accelerated approval of eteplirsen, the FDA required Sarepta to conduct studies to characterize the treatment’s effects by 2018 and to confirm benefits of treatment by 2021. The company launched no studies until late in 2019 and, at the time of this paper, more than four years after eteplirsen’s accelerated approval, no additional evidence of the drug’s efficacy or safety has been made publicly available. The FDA, for its part, has taken no action against Sarepta and, in fact, granted accelerate approvals to its second and third DMD drugs in 2019 and 2021, respectively. This paper aims to create a clearer understanding of both the opportunities and the challenges inherent to the AAP. We also present an analysis of potential reform options and their possible consequences as policymakers re-examine how best to strengthen the pathway within the broader landscape of an innovative US health care system.
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