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.