National Academies Report: Timely Diagnostics can Facilitate New Antimicrobials, Better Stewardship

In the second installment discussing this report, the authors point out that the approval of new diagnostics can help facilitate better stewardship.

Diagnostic testing and determination of antimicrobial susceptibility is a "rate-limiting step" in optimal antibiotic use, according to a new report from the National Academies of Sciences, Engineering and Medicine, which calls for hastening development, approval, and access to improved diagnostic technologies.

In the report section, "Bringing New Products to Market and Ensuring Their Reach," the Committee on Examining the Long-Term Health and Economic Effects of Antimicrobial Resistance in the United States, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), is critical of the separation between approval processes for therapeutics and for diagnostics, and anticipates synergy from greater coordination.

The committee notes that the inclusion of new antimicrobials on automated antimicrobial susceptibility testing (AST), the technology used by most clinical laboratories in the US, is a practical requirement for use, but not essential for approving a new antimicrobial safe and effective.

"If it were, the FDA would require the medicine and diagnostic be developed and reviewed simultaneously, eliminating any lag time between the availability of the drug and associated diagnostics," the committee pointed out.

Streamlining the validation and approval process for AST technologies is a pressing concern, according to Committee member Jennifer Dien Bard, PhD, Department of Pathology, Keck School of Medicine, University of Southern California (USC) and Director of the Clinical Microbiology and Virology Laboratories and Children's Hospital, Los Angeles (CHLA).

"The FDA's 2016 draft guidance (Coordinated Development of Antimicrobial Drugs and Antimicrobial Susceptibility Test Devices) followed by the 2019 guidance already describes how to synchronize development of antimicrobials and automated antimicrobial susceptibility testing (AST) devices, and the coordinated activity have reduced the time to AST device clearance without any reported delays on the approval of new drugs," Bard told Contagion.

Despite these changes in the FDA review of AST bringing the development timelines of drug and diagnostic closer, however, "There is still a lag time of up to several years between an antimicrobial being introduced into clinical practice and routine diagnostic testing of pathogens' susceptibility to it gaining regulatory clearance," the Committee observed. "This delay limits the market viability of the medicine."

An additional factor impeding use of AST for optimizing antimicrobial treatment is the delay in incorporating the break-points between susceptible or resistant as they are ascertained. The Committee estimates that after the Clinical and Laboratory Standards Institute (CLSI) has conducted sufficient research to revise a breakpoint, it can take several years for the new standards to be incorporated into AST.

"The Report focuses on an extension of what is currently in place through the 21st Century Cures Act, which has already increased the recognition of some CLSI breakpoints as well as coordination between FDA and manufacturers," Bard commented."Although much progress has already been made, there is still plenty of room for improvement."

The CDC has developed one strategy to provide timely diagnostics to guide use of current and new antimicrobials beyond the FDA approved target microbes, the Antibiotic Resistance Laboratory Network (ARLN). This network of public health laboratories, regional labs, and the National Tuberculosis Molecular Surveillance Center tests pathogens outside the capacity of clinical microbiology laboratories, and extends susceptibility testing for hard-to-treat infections.

The committee would like to see the ARLN expand its reach to the CLIA-certified laboratories at major medical centers, which have the infrastructure to offer susceptibility testing as a clinical diagnostic, according to Bard.

"ARLN can work with the laboratories to formalize that service for community hospitals and other medical centers that are unable to perform susceptibility testing, particularly for the newer, broad spectrum antibiotics," Bard said.

The committee declares that antimicrobials are "underpriced," for not factoring in future cost of resistance. One option, the Committee suggests, is to adjust the value calculation for using antimicrobials to subsidize the costs of timely development of the diagnostics that will inform their use.

"Unfortunately, a simple cost calculation can lead providers to skip diagnostic testing in favor of empiric therapy with broad-spectrum drugs. It's kind of a circular problem, if clinical guidelines do not emphasize diagnostic use, clinicians will not use them, which limits the generation of data that can prove its use," Bard observed.

"Generating evidence on the value of diagnostic tests is the first step in subsidizing their costs and to promote their use," Bard emphasized. "If the true value of the tests were more clear, it would be easier to justify the cost and would be grounds to promote their use,"

To view the first article in our series on the National Academies report, go here.