Naci, Huseyin 
ORCID: 0000-0002-7192-5751, Wouters, Olivier J. ORCID: 0000-0002-2514-476X, Gupta, Radhika and Ioannidis, John P. A.
(2017)
Timing and characteristics of cumulative evidence available on novel therapeutic agents receiving Food and Drug Administration accelerated approval.
The Milbank Quarterly, 95 (2).
261 - 290.
ISSN 0887-378X
Abstract
Context: Therapeutic agents treating serious conditions are eligible for Food and Drug Administration (FDA) accelerated approval. The clinical evidence accrued on agents receiving accelerated approval has not been systematically evaluated. Our objective was to assess the timing and characteristics of available studies. Methods: We first identified clinical studies of novel therapeutic agents receiving accelerated approval. We then (1) categorized those studies as randomized or non-randomized; (2) explored whether or not they evaluated the FDA-approved indications; and (3) documented the available treatment comparisons. We also meta-analyzed the difference in start times between randomized studies that (1) did or did not evaluate approved indications and (2) were or were not designed to evaluate the agent’s effectiveness. Findings: In total, 37 novel therapeutic agents received accelerated approval between 2000 and 2013. Our search identified 7,757 studies including 1,258,315 participants. Only one third of identified studies were randomized controlled trials. Of 1,631 randomized trials with advanced recruitment status, 906 were conducted in therapeutic areas for which agents received initial accelerated approval, 202 were in supplemental indications, and 523 were outside approved indications. Only 411/906 (45.4%) trials were designed to test the effectiveness of agents that received accelerated approval (“evaluation” trials); others used these agents as common background treatment in both arms (“background” trials). There was no detectable lag between average start times of trials conducted within and outside initially approved indications. “Evaluation” trials started on average 1.52 years, (95% CI: 0.87 to 2.17) earlier than “background” trials. Conclusions: Cumulative evidence on agents with accelerated approvals has major limitations. Most clinical studies including these agents are small and non-randomized, and about a third are conducted in unapproved areas, typically concurrently with those conducted in approved areas. Most randomized trials including these therapeutic agents are not designed to evaluate directly their clinical benefits but incorporate them as standard treatment.
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