Manufacturers are required to use FDA-cleared breakpoints
In the United States, the regulatory process for updating breakpoints is complex. Three primary agencies are responsible for determining breakpoints: the Food and Drug Administration (FDA), Clinical and Laboratory Standards Institute (CLSI), and European Committee on Antimicrobial Susceptibility Testing (EUCAST). First, CLSI reviews data and determines if breakpoints for a given bug-drug combination must be updated. Then, the organization submits a rationale document to the FDA detailing why the breakpoints should change. If the FDA agrees with CLSI’s rationale, the new breakpoints will be posted on the FDA’s susceptibility test interpretive criteria website (STIC) and serve as the current breakpoints for that bug-drug combination. If the FDA disagrees with the rationale, the existing FDA breakpoints will remain on the STIC website, and CLSI will publish its updated breakpoints in the M100 document released annually.
AST device manufacturers are required to use only FDA-cleared breakpoints on their systems. If CLSI suggests breakpoint updates and the FDA disagrees with the rationale, manufacturers must continue using the FDA breakpoints on their systems. If CLSI proposes a change that the FDA acknowledges, manufacturers may then perform internal validation studies using the new breakpoints and submit the data to the FDA to receive clearance for the new breakpoints. The validation process performed to achieve FDA clearance takes considerable time and resources. Manufacturers may not always be immediately aware of when breakpoints are updated on the STIC website, and must balance competing priorities to determine when to seek clearance for new breakpoints. Even after validation data have been submitted, the FDA clearance process can take a very long time. In addition, clinical laboratories may be unaware of which drugs have received FDA clearance on their AST systems and which updates are needed.