Study: Most new antibiotics approved by FDA based on non-inferiority trials with surrogate outcomes

Regulatory NewsRegulatory News | 14 December 2022 |  By 

All new antibiotics approved by the US Food and Drug Administration (FDA) used surrogate outcome measures, and about half had pivotal trials with a non-inferiority design, according to recent research published in BMJ Medicine.
Mayookha Mitra-Majumdar, MPH, of the Program On Regulation, Therapeutics, And Law (PORTAL) in the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine at Brigham and Women's Hospital/Harvard Medical School in Boston, and colleagues analyzed the clinical development and launch prices of antibiotics that were approved by FDA between October 2016 and December 2019, deriving the information from, drug labeling and IBM Micromedex Red Book.
The researchers found 15 antibiotics were approved in the timeframe based on 28 pivotal trials, with a median of two trials per drug and a median of 388 patients per trial. The drugs were approved for infections such as complicated urinary tract infections, complicated intra-abdominal infections, community-acquired bacterial pneumonia, acute bacterial skin and skin structure infections, multi-drug resistant tuberculosis, among others. One drug, the monoclonal antibody bezlotoxumab, was approved for use against Clostridioides difficile, was also the sole drug in the list approved that had a new mechanism of action.
Of these pivotal trials, 15 trials had an active-controlled non-inferiority design, and all drug trials had indirect clinical outcomes as endpoints. “Most pivotal trials focused on composite primary endpoints that incorporated more than one of the endpoint categories of survival, patient reported outcomes, observer reported outcomes, clinician reported outcomes, and biomarkers,” the researchers said.
Mitra-Majumdar and colleagues also found a total of 52 postmarketing requirements and commitments for all new approved antibiotics, with a median of 3 postmarketing requirements per drug. As of January 2021, there were 27 pending postmarketing requirements and commitments, seven postmarketing requirements and commitments were ongoing, three requirements and commitments were delayed, one was submitted, eight were released and four postmarketing requirements and commitments were fulfilled, the researchers said.
Concerning cost, the tuberculosis drug pretomanid was the most expensive ($36,399), while a drug for traveler's diarrhea, rifamycin, was the least expensive ($176). One drug, ozenoxacin, was less expensive than its comparator (cost ratio, 0.48), while other drugs were many more times expensive than the comparator, such as with intravenous omadacycline and its comparator oral moxifloxacin (cost ratio, 134).
“This study of antibiotic innovation in the past five years showed that new antibiotics meant to fill unmet medical needs for improved efficacy lacked evidence that they do so on real clinical endpoints before approval by the FDA,” the researchers concluded. “These trends should be taken into account by policymakers considering new incentives for the development of antibiotics.”
Non-inferiority vs. superiority trials for new antibiotics
Aaron Kesselheim, MD, JD, MPH, senior author, said that the results in combination with a previous study his group conducted on antibiotics approved between 2010 and 2015 showed that using non-inferiority trials tends to be the norm for evaluating new antibiotics.
“These products are not being tested in patients with resistant disease who lack other options,” Kesselheim told Focus in an interview. “Then, when many of these new antibiotics are made available at high prices, it’s not surprising that they are not being used very often.”
New policies intended to incentivize development of new antibiotics, such as the PASTEUR Act, have been promoted by organizations like the Infectious Diseases Society of America as a way to address the growing problem of antimicrobial resistance (AMR).
These policies fall short, however, when they don’t consider the added benefit of a drug in awarding contracts for new antibiotics, Kesselheim and colleague argued in their paper. Using indirect endpoints doesn’t always translate to clinical benefit and “is questionable in acute diseases when direct outcomes can be measured rapidly,” they wrote.
But proponents of policies like PASTEUR claim that insisting on superiority trials for new antibiotics is an “unattainable standard” to use as a basis for awarding a contract and “creates major ethical concerns” for patients receiving the standard of treatment.
“Conducting a superiority trial in a patient with a resistant bacterial infection who does not have other good available options would not be unethical, and more such studies of patients’ clinical response in those circumstances would help provide useful information that patients and doctors would want to know about potential new antibiotics,” Kesselheim told Regulatory Focus. “What is unethical is testing a drug in a non-inferiority study based on the premise that it might be effective in future patients with resistant disease, since those studies put patients enrolling in the trial at risk of getting a worse drug without clear potential benefits.”
John Powers, MD, coauthor, and professor of clinical medicine at George Washington University School of Medicine, said in an interview that misunderstandings about non-inferiority studies in infectious disease “have been longstanding and pervasive, seriously impacting getting better therapies for patients.”
“The discussion about non-inferiority revolves around misrepresenting these studies as evaluating whether a new drug is ‘just as effective as’ an older effective drug, yet this is misleading and false,” he said.
Research has shown non-inferiority trials, if not designed appropriately, may be worse in terms of effectiveness, he said, and patients typically do not get to decide the threshold of “worse effectiveness” in these trials.
“Furthermore, these studies do not show that the new drug ‘might be a little bette,” which is also commonly claimed,” he explained. “The smaller the study, the more imprecise the results, so it’s just greater uncertainty due to less precision. But this does not mean the new drug might be better—it means we just don't know.”
“Non-inferiority studies are not designed to evaluate anything about ‘might be a little better’—that's a superiority trial,” he said.
In antimicrobial resistance, “what is needed is improved effectiveness—and we don’t know whether new drugs work at all in patients with AMR,” Powers said. “A drug that is less toxic but is not effective is not a benefit to patients.”
BMJ Med Mitra-Majumdar et al.


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