Major flaws found in fast-tracking of some drugs in the US

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A study has exposed major flaws in the fast-tracking of some drugs available to the US public without any stringent clinical evidence of their benefits.

Researchers from the London School of Economics and Political Science (LSE) and the US say that many US patients with serious illnesses are being treated by drugs which have questionable data. The findings relate to drugs given 'accelerated approval' by the US Food and Drug Administration (FDA) without any strong clinical evaluation.

The study assessed 37 new drugs given accelerated approval by the FDA between 2000 and 2013.

Drugs eligible for accelerated approval are assessed as "reasonably likely" to provide clinical benefits but the bar for their market entry is far lower than those receiving regular approval, according to Dr Huseyin Naci, an LSE health policy researcher.

Naci said: "FDA's accelerated approval pathway allows potentially promising drugs to receive marketing authorisation on the basis of surrogate measures that are easy to obtain, rather than clinically meaningful outcomes. The evidence ultimately accrued on these drugs has major flaws and is inadequate to address the information needs of patients and doctors."

The study is the first in the world to systematically evaluate more than 7,000 clinical studies conducted on drugs receiving accelerated approval by the FDA.

Naci said the shortcomings were as a result of the FDA introducing more flexibility to its evidence standards over the past three decades.

The key findings reported by Naci and his colleagues from the University of Pennsylvania and Stanford University included: randomised trials – the gold standard of evaluating clinical effectiveness – constituted only a small minority of existing evidence; one-third of randomised trials were in therapeutic areas outside of FDA approval and less than half evaluated the therapeutic benefit of these drugs, but used them instead as common backbone treatments; drugs receiving accelerated approval were often tested concurrently in different therapeutic areas; and for most drugs no substantial time lag was apparent between the average start date of trials evaluating their effectiveness and their use as background therapy.

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 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.
Findings: 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.
Conclusions: 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.

Huseyin Naci, Olivier J Wouters, Radhika Gupta, John PA Ioannidis

London School of Economics material The Millbank Quarterly abstract

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