Investigation raises questions over lack of “substantial evidence” for FDA approved antibiotic

Drugs approved in the US require “substantial evidence” that they are effective. But an investigation by The BMJ into the recent approval of the antibiotic Recarbrio from Merck suggests that these standards are being bypassed.

Peter Doshi, senior editor at The BMJ, describes how US Food and Drug Administration (FDA) scientists had serious doubts about Recarbrio - a product 40 times more expensive than an existing generic alternative - but the agency approved it anyway.

Did the FDA break its own rules in approving this antibiotic, and what does this case tell us about problems within the agency, he asks? 

Recarbrio is a combination therapy made up of a new beta-lactamase inhibitor (relebactam) and a decades old Merck antibiotic (imipenem-cilastatin) to treat complicated infections. It costs between $4,000 and $15,000 for a course, compared with a couple of hundred dollars for the generic version of Merck’s old antibiotic.

In its FDA application, Merck submitted results from two clinical trials comparing Recarbrio with imipenem in adults with complicated urinary tract infections and in patients with complex intra-abdominal infections.

But FDA reviewers noted that Merck had studied the wrong patient population to evaluate the added benefits of the new drug, and said the trial for urinary tract infections showed that Recarbrio was as much as 21% worse in effectiveness than the older, less-expensive imipenem.

The FDA concluded that “these studies are not considered adequate and well-controlled.” And of a third clinical study, the FDA called it a “very small,” “difficult to interpret” “descriptive trial with no pre-specified plans for hypothesis testing.”

Yet despite all three clinical studies not providing substantial evidence of effectiveness, FDA approved Recarbrio.

“Instead of basing its decision on the clinical trials in Merck’s application, FDA’s determination of Recarbrio’s efficacy was justified on past evidence that imipenem was effective, plus - to justify the new relebactam component - in vitro (lab) studies and animal models of infection rather than evidence from human trials as required by law,” writes Doshi.

Others are concerned that Recarbrio’s approval essentially amounts to a return to a way of regulating medicines that the FDA abandoned a half century ago prior to the agency’s “substantial evidence” standard.

Doshi explains that, under specific circumstances, the Director of the Center for Drug Evaluation and Research (CDER) can waive in whole or in part the FDA’s “adequate and well-controlled studies” approval criteria. But the FDA told The BMJ ”there was no center director memo in the file” for Recarbrio.

And when The BMJ contacted Janet Woodcock, CDER Director at the time, and now the FDA’s Principal Deputy Commissioner, she said she was not aware that the clinical studies of Recarbrio did not provide substantial evidence of effectiveness.

Woodcock was also unable to confirm that approvals of new drugs require at least one clinical study of the drug itself that demonstrates substantial evidence - evidence lacking in the case of Recarbrio.

A spokesperson for CDER told The BMJ that FDA “applied regulatory flexibility” in approving Recarbrio. 

It is unclear whether this regulatory flexibility enabled FDA to conclude Recarbrio had met the legal “substantial evidence” standard without “adequate and well-controlled investigations” of Recarbrio, says Doshi. FDA declined to answer the question, saying “We have no additional information to provide.”

The decline of science at the FDA has become unmanageable, argues David Ross, associate clinical professor of medicine at George Washington University, School of Medicine and Health Sciences, and former FDA medical reviewer, in a linked commentary.

He describes Recarbrio’s approval as “shocking” and says while much of the blame must go to the FDA’s reliance on industry paid user fees for around two-thirds of its annual drugs budget, “the corruption of the FDA’s scientific culture remains the primary culprit driving the deterioration of safety and effectiveness standards.”

To address this “dismal situation” he suggests tapering the FDA’s dependence on user fees and improving public access to the information received by the FDA, its reasoning, and its decisions.

“The Recarbrio approval is a sentinel event, warning of a return to an era when drug effectiveness was an afterthought,” argues Ross. “Although the FDA crowed about this approval, it would have been better advised to remember that “for a successful technology, reality must take precedence over public relations, for nature cannot be fooled,” he concludes.