FDA Fleshes Out Guidance on Susceptibility Breakpoints for Antimicrobial Drugs, Devices

Regulatory NewsRegulatory News | 18 January 2019 |  By 

The US Food and Drug Administration (FDA) issued final guidance Thursday on the coordinated development of antimicrobial drugs and susceptibility assays, with additional clarifications.

The finalization follows concerns raised by AdvaMed and BIO with the 2016 draft guidance’s lack of language to address the issue of antimicrobial susceptibility breakpoints among drug and medical device sponsors. The issue relates to leveraging the use of ka breakpoint as a vehicle for a device manufacturer to coordinate the development of an antimicrobial susceptibility test (AST) device early in the drug review and approval process with the manufacturer of the corresponding antimicrobial.

The new clarifications on breakpoints in the final version of FDA’s guidance coincide with its goal, which is largely centered on encouraging earlier interactions in development processes with an enriched understanding of AST devices’ corresponding antimicrobials. The agency’s 11-page guidance document is specifically dedicated to encouraging coordinated development processes that involve drug and devices manufacturers, as well as FDA’s Center for Devices and Radiological Health (CDRH) and its Center for Drug Evaluation and Research (CDER) upon request.

Antimicrobial resistance is a growing threat worldwide, underscoring the need for FDA’s guidance. A current challenge with tackling antimicrobial resistance relates to delays in the approval of AST devices, which in turn also delays access among clinical professionals. The guidance sets the stage for how drug and device sponsors can use a coordinated approach to support the clearance of AST devices in a timelier fashion. For FDA, that includes clearing new and existing AST devices as closely after approving antimicrobials as possible if not simultaneously.

“Historically, the development of antimicrobial drugs and AST devices that test for in vitro antibiotic susceptibility of bacterial pathogens has not been optimally coordinated, with AST device development sometimes occurring late in the drug development process or after the drug development/approval process is completed,” the agency said.

A key recommendation that came with the revised section on considerations for coordinated development plans relates to the timing of a 510(k) submission. FDA said that it “recommends submission of a 510(k) for the AST device 4 to 5 weeks before anticipated drug approval.”

The final guidance also includes a new appendix, which offers a step-by-step guide for device manufacturers to undergo reviews via FDA’s Q-submission program and obtain feedback throughout the coordinated development process. Each step “should be considered optional and individual device manufacturers may use pieces of the process” outlined in the appendix “as applicable to their specific needs,” FDA said. “However, FDA emphasizes that close communication during AST development can facilitate 510(k) review and successful device clearance coincident with or soon after drug approval.”

A new flowchart was added to the 2016 draft version, as well. The figure is “intended to show the flow of information between the AST device manufacturer, the drug manufacturer and FDA,” FDA said. It is also based on Q-submissions to CDRH, though Q-submissions are recommended by FDA rather than being required. Q-submissions is a new theme in the final guidance in addition to that of drug breakpoints.


“During the workshop, stakeholders, including drug manufacturers and clinicians, stated that there is unmet medical need for ASTs as months-to-years can elapse between when a new antimicrobial is available and when the corresponding AST is available,” AdvaMed associate VP of technology and regulatory affairs Jamie Wolszon wrote in the group’s 2016 comment on the draft guidance.

Information on a breakpoint is proposed as part of a New Drug Application (NDA) for a new antimicrobial and can be used to support the validation of a new or existing AST panel.

“Breakpoints and claimed organisms can change very late in the drug approval cycle as labeling is one of the last items in the NDA to be negotiated between the drug sponsor and FDA,” Wolszon said. “These potential changes raise great uncertainty for AST developers and act as a disincentive for coordinated development.” New language in the agency’s final guidance provides some additional flexibility to help device sponsors incorporate up-to-date breakpoint information in device labeling early in drug review processes.

The guidance seeks to encourage information-sharing between drug and device sponsors as the lack of coordination has “contributed to delays in the availability of AST devices for newly approved drugs,” FDA noted. Industry groups had argued the draft guidance would fail to achieve the desired level of coordination without FDA’s clarifications around the use of breakpoints as this was not addressed in the draft version.

CDRH’s Q-submission program is intended to aid device manufacturers in development processes, with the final guidance further clarifying that CDRH intends to include CDER in joint meetings with a drug sponsor and an AST device manufacturer upon request. Citing the frequency in which an antimicrobial candidate’s breakpoint is finalized late in the NDA review process, BIO had urged FDA to include mechanisms such as Q-submissions to minimize uncertainties and safeguard committed resources.

FDA clarified that an AST manufacturer seeking to submit a 510(k) that did not coordinate development with a drug manufacturer as part of an NDA can opt to take the Q-submission approach. Coordinated development is still achievable via direct interactions between device and drug manufacturers in lieu of Q-submissions, with the 510(k) “occurring prior to or shortly after drug approval,” FDA said. But “there may be a delay in availability of the device due to a potentially longer review time and/or the need for additional information to be submitted” without prior FDA interaction via the Q-submission program.

Coordinated Development of Antimicrobial Drugs and Antimicrobial Susceptibility Test Devices


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