SILVER SPRING, Md. — An FDA advisory panel voted 14-2 to recommend approval for cefiderocol, a novel antibiotic for complicated urinary tract infections (cUTI), including pyelonephritis, in patients with limited or no other treatment options.
While members of the FDA’s Antimicrobial Drugs Advisory Committee were mostly impressed by the data submitted for the drug, they raised concern about a mortality imbalance disfavoring cefiderocol in the CREDIBLE-CR study, which compared the drug to best available therapy in patients with a variety of carbapenem-resistant infections.
Part of FDA staff’s charge to the panel was to discuss how to interpret the excess mortality in this study with cefiderocol, and provide recommendations for labeling and the need for other studies — both of which the committee did.
Or as chair Lindsey Baden, MD, of Brigham and Women’s Hospital in Boston, quipped, “[Do we] find the mortality imbalance in CREDIBLE … credible enough?”
It was a mixed sentiment, where most committee members did not want to completely ignore the mortality signal, but acknowledged that the data were uneven, and also that the data in the CREDIBLE study did not seem to apply to the better-designed cUTI study, as manufacturer Shionogi was seeking approval only for treating cUTIs.
Even FDA staff in attendance were unsure of what to make of the CREDIBLE data when asked by committee members earlier in the day. Baden asked FDA staff in attendance for guidance in determining whether the increased mortality in the cefiderocol group was a “substantive finding” — in essence, if they believed the excess deaths likely occurred by chance.
FDA staff responded that they did not think the committee could “discuss the risk/benefit [of cefiderocol] for UTI alone without having this information [about increased mortality] at hand.”
The majority of committee members agreed that strong labeling will be essential for cefiderocol, given the tremendous disease burden of multidrug-resistant infections, and the near certainty that if this drug is approved for complicated urinary tract infections, it will be used off-label for other hard-to-treat infections.
Contributing over the phone, David “Davey” Smith, MD, professor of medicine at the University of California San Diego, said the drug needs “a circled and underlined warning” about a strong mortality signal.
Other committee members said a boxed warning — the strongest currently used by the FDA — discussing the potential mortality risk is warranted. It should make mention of special risk among patients with hospital-acquired bacterial pneumonia or ventilator associated bacterial pneumonia, they suggested.
“When was the last time you actually read a label for a new drug?” said Peter Weina, MD, PhD, of Defense Health Headquarters in Falls Church, Virginia. “Few of us completely read labels unless it’s in a black box that says ‘you’d better pay attention to this or you’re gonna get your butt sued.'”
Susanne May, PhD, a biostatistician at the University of Washington in Seattle, pointed out that even though the safety signal disfavoring cefiderocol in the CREDIBLE study was not statistically significant, it still involved mortality. She also seemed to provide a rebuttal to the manufacturer’s hypothesis that chance alone could have accounted for the increased mortality.
“When we have positive results, we tend to believe them whether or not we understand the mechanism. If we have a negative result, then we say it’s by chance. It’s an easy way out,” she said.
Weina and May provided the two “no” votes on the up-or-down question of whether to recommend approval, with both saying that additional studies are needed to assuage their concerns.
“Maybe what we need to do is go back and design another trial that looks at specific data. To paraphrase [the TV show] “M*A*S*H,” ‘Really sick people die and rule number two is doctors and new drugs can’t change rule number one,'” Weina said.
Consumer representative Roblena Walker, PhD, who voted “yes,” said that she was moved by the public comment section of the hearing.
“I was a little torn here, but I thought about my 90-year-old grandmother who suffered from a UTI when she was 88 and I listened to the public comments [and] the physicians [who said] patients … could’ve benefited from this,” she said.
Arthur Lyons, PhD, medical director of Executive Medicine in Washington, D.C., summed up the thinking of many of the panelists.
“For the specific indication addressed here, the sponsor has satisfied the requirements. But for other more serious infections … there need to be more studies,” he said.
Baden said that the label needs to “strongly note uncertainty with CREDIBLE data,” and additional studies are needed to better understand the mortality signal.
The FDA does not have to follow the advice of its advisory committees, but it often does.