FDA to Allow Single Pivotal Trial for Drug Approval in Policy Shift

The US Food and Drug Administration will allow sponsors to file for drug approval with just one pivotal trial instead of two, marking a significant change in regulatory standards. A paper published in the New England Journal of Medicine by Dr. Vinay Prasad, director of the Center for Biologics Evaluation and Research, and Dr. Marty Makary, chief of the FDA, confirmed the change in FDA standards.

While US law has been in place since 1997 stating that approval can be based on a single adequate and well‑controlled study when supported by confirmatory evidence, the FDA's standard has been a reliance on two pivotal trials. Under the new guidance, the single pivotal trial will still need to be combined with confirmatory evidence, and the approval process will put a stronger focus on controls, endpoints, effect size, and statistical protocols.

The paper says the move will "substantially reduce costs for sponsors" and "speed drugs to market." Estimates suggest that the cost of a single pivotal study may range from $30 million to $150 million. Makary and Prasad add that as a result of reducing capital costs for drug developers, it should reduce "justification of lofty and rising drug prices for everyday Americans."

Prasad and Makary acknowledge that this guidance may be met with criticism that the FDA is "relaxing its standards," but the pair disagree. "First, the FDA has never been perfect, and even with a default requirement of two trials, the FDA has approved numerous products that were later found to have serious safety concerns or lack efficacy," the paper reads.

The pair go on to say: "Second, as we note, the number of clinical studies is no safeguard against valid inference if all other aspects of trial design are deficient. If the control arm is substandard, the endpoints dubious, the statistical plan generated post hoc, the power inadequate, or all of the above, erroneous conclusions may be reached even with two, three, or four studies."

They add that by putting focus on just one study it may, in fact, improve the FDA's standards and reduce the risk, as greater attention will be placed on the one trial. There will be cases in which two trials are still required, for example, if a study is seen to be "nebulous, pluripotent, or nonspecific mechanism of action; if it affects a labile, short-term, or surrogate outcome; or if a trial has some underlying limitation or deficiency."

While there have been cases in which drugs have been approved based on a single pivotal trial, Prasad and Makary said that there has been "confusion" from manufacturers as to the situations in which this would have been acceptable, which is why this is being rolled out for all therapies. As well as traditional approvals, this flexibility will be applied to breakthrough program designations, accelerated approvals, and priority review pathways.