Stephanie Fox-Rawlings, PhD, National Center for Health Research, October 17, 2019
Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Stephanie Fox-Rawlings, the Center’s Research Manager. Our center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug or medical device companies, so I have no conflicts of interest.
There is a need for new antibiotics and the cUTI trial provides encouraging evidence that cefiderocol can improve the symptoms of cUTI [complicated urinary tract infections] and reduce bacterial colony counts. However, the safety and efficacy for this indication is based on only a single pivotal trial. As you know, replication is the key to scientific evidence. Independent trials could result in different rates of symptom improvement or adverse events due to differences in the demographics or treatment profiles of patients or other factors, or even due to chance.
Unfortunately, this trial has several limitations that raise concerns about how generalizable it is for patients in the U.S. Less than 2% of the patients in the trial were from the U.S., and medical practices often differ between other countries and here. In addition, about 96% of patients were white and most of the rest were Asian.
The sponsor considers treatment a success if patients just had a reduction in cUTI symptoms and at least a temporary reduction in bacterial colony counts. Patients were not necessarily cured by the treatment. Using colony counts as part of the primary endpoints is not meaningful to patients. They are also not relevant in clinical practice nor are they validated surrogate endpoints. While the 2018 FDA guidance on developing drugs to treat cUTI was finalized after this study was started, it is useful to note that it recommended the primary endpoint evaluate resolution of symptoms instead of just improvement.
The second study, CREDIBLE-CR, was an open label, descriptive study. It was not a pivotal study and included to provide additional information. It doesn’t provide adequate support for efficacy and instead raises major concerns about the drug’s safety. Most concerning, the number of patients that died were much higher for cefiderocol compared to the best available treatment – an estimated hazard ratio of 1.77. While many of these deaths were in patients with bacterial pneumonia or blood infections/sepsis, this may suggest that there is a set of patients for whom the risks greatly outweigh the benefits.
If the much higher number of deaths and other adverse events were caused by differences in baseline characteristics in the treatment arms just due to chance, that’s still a problem. In that case, the trial still cannot provide adequate evidence that the drug is effective.
In summary, there is a single study that provides some evidence for safety and efficacy and another study which raises serious concerns. Another study is needed, treating patients representative of those that would be treated using this drug here in the U.S.
While there is a need for new antibiotics, those products need to have sufficient evidence of efficacy and safety. To continue to be the “gold standard” for approval, FDA needs to maintain high standards of evidence for approval.
The Antimicrobial Drugs Advisory Committee voted 14 to 2 in favor of approval. You can read more about the meeting here.