“Challenging FDA’s Approval: Uncovering Concerns Surrounding a Controversial Antibiotic”

Recent revelations raise questions about the FDA’s approval of the antibiotic Recarbrio, highlighting doubts regarding its efficacy and substantial cost when compared to a generic alternative. The approval process has come under scrutiny due to allegations that the FDA deviated from its established standards, which typically require “substantial evidence” of a drug’s effectiveness. These concerns have sparked a broader discussion about potential internal issues within the agency and the potential compromise of safety and effectiveness standards.

The recent approval of Merck’s antibiotic, Recarbrio, has brought the legal standards for drug approval into question. A thorough investigation conducted by The BMJ suggests that these standards may have been circumvented.

The BMJ’s senior editor, Peter Doshi, sheds light on reservations held by FDA scientists regarding Recarbrio. Despite its exorbitant price, which is forty times higher than that of its generic counterpart, the FDA granted approval for this antibiotic.

The combination therapy known as Recarbrio consists of a new beta-lactamase inhibitor called relebactam, in addition to a Merck antibiotic called imipenem-cilastatin that has been in use for decades. A course of Recarbrio can cost between $4,000 and $15,000, while the generic version of Merck’s old antibiotic only amounts to a few hundred dollars.

Merck submitted results from two clinical trials to support their FDA application. These trials compared Recarbrio with imipenem in adults with complicated urinary tract infections and patients with complex intra-abdominal infections. However, FDA reviewers observed that Merck had focused on the wrong patient population to assess the new drug’s added benefits. Moreover, the trial for urinary tract infections revealed that Recarbrio was potentially 21% less effective than the older, more affordable imipenem.

The FDA itself acknowledged that these studies were inadequate and not properly controlled. Additionally, a third clinical study described as “very small” and “difficult to interpret” lacked pre-specified plans for hypothesis testing, making its results unreliable. Yet, despite the absence of substantial evidence in all three studies, the FDA still approved Recarbrio.

Doshi highlights that instead of relying on the clinical trials provided by Merck, the FDA justified Recarbrio’s efficacy based on past evidence of imipenem’s effectiveness. Furthermore, they referenced in vitro (lab) studies and animal models of infection to justify the new component, relebactam. This approach deviated from the legal requirement of evidence from human trials.

Some individuals are concerned that the approval of Recarbrio indicates a return to a previous approach to regulating medicines that the FDA had abandoned decades ago, before the establishment of the “substantial evidence” standard.

Doshi explains that, under specific circumstances, the Director of the Center for Drug Evaluation and Research (CDER) can waive, in part or entirely, the FDA’s approval criteria for “adequate and well-controlled studies.” However, when questioned about Recarbrio, the FDA stated that there was no record of such a waiver.

The BMJ contacted Janet Woodcock, former CDER Director and current FDA’s Principal Deputy Commissioner, who claimed to be unaware that the clinical studies of Recarbrio did not provide substantial evidence of effectiveness. Woodcock also couldn’t confirm that the approval of new drugs requires at least one clinical study demonstrating substantial evidence—an element missing in the case of Recarbrio.

According to a spokesperson for CDER, the FDA utilized “regulatory flexibility” in approving Recarbrio. Nevertheless, it remains unclear whether this flexibility allowed the FDA to conclude that Recarbrio met the legal standard of “substantial evidence” without conducting “adequate and well-controlled investigations” of the drug, as Doshi questions. The FDA declined to provide further information on the matter.

David Ross, former FDA medical reviewer and associate clinical professor of medicine at George Washington University, School of Medicine and Health Sciences, argues that the decline of scientific integrity at the FDA has become unmanageable. He describes the approval of Recarbrio as “shocking” and attributes much of the blame to the FDA’s reliance on industry-paid user fees for a significant portion of its annual drugs budget. Ross believes that the corruption of the FDA’s scientific culture is the primary factor driving the deterioration of safety and effectiveness standards.

To rectify this concerning situation, Ross suggests reducing the FDA’s dependence on user fees while simultaneously improving public access to the information received by the FDA, as well as its reasoning and decisions.

In conclusion, the approval of Recarbrio serves as a warning sign, signaling a potential regression to an era when drug effectiveness was given less consideration. The FDA should remember that prioritizing reality over public relations is crucial for the success of any technology, as nature cannot be deceived.

Reference: “Did the FDA break its own rules in approving the antibiotic Recarbrio?” by Peter Doshi, 15 May 2023, The BMJ. DOI: 10.1136/bmj.p1048. This study was funded by the BMJ Investigations Unit.

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• “Did the FDA break its own rules in approving the antibiotic Recarbrio?” by Peter Doshi, The BMJ Link
• FDA website Link
• Merck Pharmaceuticals Link
• FDA Regulations Link