The Milbank Quarterly June 2017  Volume 95, Issue 2 Pages 213–446

The Milbank Quarterly
A Multidisciplinary Journal of Population Health and Health Policy
June 2017  Volume 95, Issue 2  Pages 213–446

“America First”: Prospects for Global Health (pages 224–228)
Version of Record online: 6 JUN 2017 | DOI: 10.1111/1468-0009.12254

Original Investigations
Timing and Characteristics of Cumulative Evidence Available on Novel Therapeutic Agents Receiving Food and Drug Administration Accelerated Approval (pages 261–290)
Version of Record online: 6 JUN 2017 | DOI: 10.1111/1468-0009.12261
Policy Points:
:: Randomized trials—the gold standard of evaluating effectiveness—constitute a small minority of existing evidence on agents given accelerated approval. One-third of randomized trials are in therapeutic areas outside of FDA approval and less than half evaluate the therapeutic benefits of these agents but use them instead as common backbone treatments.
:: Agents receiving accelerated approval are often tested concurrently in several therapeutic areas.
:: For most agents, no substantial time lag is apparent between the average start dates of randomized trials evaluating their effectiveness and those using them as part of background therapies.
:: There appears to be a tendency for therapeutic agents receiving accelerated approval to quickly become an integral component of standard treatment, despite potential shortcomings in their evidence base.
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.
We first identified clinical studies of novel therapeutic agents receiving accelerated approval. We then (1) categorized those studies as randomized or nonrandomized, (2) explored whether 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.
In total, 37 novel therapeutic agents received accelerated approval between 2000 and 2013. Our search of identified 7,757 studies, which included 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 out of 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.
Cumulative evidence on agents with accelerated approvals has major limitations. Most clinical studies including these agents are small and nonrandomized, 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 directly evaluate their clinical benefits but to incorporate them as standard treatment.