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be enough to create the needed antibiotic development pipeline. Market entry rewards were a popular solution as were transferable exclusivity vouchers but GAO notes that HHS would likely need to request additional authority and appropriations from Congress to implement such a scheme. Lawmakers have debated this idea since at least 2016 (Also see “Antibiotic Development: ‘Wildcard Exclusivity’ Proposal Returns” – Pink Sheet, 16 Nov, 2016.).
R&D CHALLENGES REMAIN
On the drug development side, The GAO report identified a handful of challenges in conducting clinical trials of antibiotics that meet FDA regulatory requirements or the demands of purchasers.
FDA said the lack of rapid diagnostic tests to identify a patient’s infection type causes problems for trial enrollment as patients may sometimes get treatment before entering the trial that obscures the true efficacy of the drug being studied.
Meanwhile, antibiotic developers told GAO that it is more feasible to conduct non-inferiority trial designs for new antibiotics because this allows for smaller trial enrollment, but they have found that the lack of superiority data makes its hard to convince purchasers to use the new antibiotic, particularly if the new product is more expensive. Sponsors also cited difficulties in gaining FDA approval for multiple indications for an antibiotic that can treat infections in multiple parts of the body.
Companies working on nontraditional alternatives to antibiotics for drug-resistant infections are facing challenges because their products tend to target only one or a few types of bacteria, making trial enrollment cost-prohibitive. The GAO report also found there is a need for more research into how to measure the efficacy of these products and that additional trial endpoints need to be developed and validated for these products.
FDA CRITICIZED FOR POOR BREAKPOINT MONITORING
The GAO report hits on FDA for not “regularly monitoring” tests for antibiotic resistance that rely on breakpoints – the threshold that helps a clinician decide whether or not a pathogen is resistant to the antibiotic – to determine whether manufacturers are using up-to-date breakpoints or the impacts of using out-of-date breakpoints. These tests help guide a physician toward using the right drugs. Using tests with out-of-date breakpoints could lead to treating patients with ineffective antibiotics and further the spread of infection.
Since December 2017, FDA has conducted one unofficial survey of tests to assess breakpoints updates, GAO found, and that survey was limited in scope.
While FDA told GAO that out-dated endpoints being used in tests “should be a rare occurrence,” the CDC told them that “keeping tests updated is a significant concern.”
GAO found “several” FDA-authorized tests with breakpoints that were changed nearly 10 years ago, and CDC found in a 2017-2018 survey that one-firth of hospitals labs had not updated tests to reflect revisions in breakpoints for carbapenem-resistant Enterobacteriaceae implemented in 2010.
GAO also pushed HHS to conduct studies examining whether testing patients for antibiotic-resistant infections improves clinical outcomes. If the benefits of these tests are shown, clinicians may be more likely to use them and choose the appropriate antibiotics, the report said.