On behalf of the Clinical and Laboratory Standards Institute (CLSI), the Expert Panel on Microbiology would like to respond to the recent commentary by Kirby and colleagues voicing concerns related to the verification of commercial antimicrobial susceptibility testing (AST) for new drugs that are introduced into the clinical laboratory (1). The CLSI Expert Panel on Microbiology oversees the direction and general guidance of the CLSI microbiology subcommittees, including the Subcommittee on Antimicrobial Susceptibility Testing, the Subcommittee on Antifungal Susceptibility Testing, and the Subcommittee on Veterinary Antimicrobial Susceptibility Testing. The authors of the recent commentary propose that verification studies are not needed when new drugs are added to commercial antimicrobial susceptibility test systems such as commercial panels and disk diffusion testing if the test systems have been previously verified. Instead, the authors argue that a laboratory could only perform recommended quality control (QC) testing and then implement testing and reporting of the new antimicro- bials without further verification. The intent of this approach is to support easier implementation of new drug AST in an era of extensive antimicrobial resistance, when the use of new antimicrobials may be necessary to save the lives of patients suffering from otherwise untreatable infections. The Expert Panel on Microbiology does not agree that QC strain testing alone is an adequate substitute for a verification study. First, the Expert Panel recognizes that labora- tories governed by Clinical Laboratory Improvement Act (CLIA) regulations are required to perform a verification study before a Food and Drug Administration (FDA)-cleared test or
a new component of an FDA-cleared test is implemented for patient care (2). QC testing alone does not fulfill this CLIA requirement. Second, testing of QC strains, which are selected for endpoint clarity and reproducibility, may not mimic testing challenges that occur with clinical isolates. Testing of clinical isolates allows a laboratory to establish accurate test performance prior to issuing results for patient care (3, 4). CLSI published M52, Verification of Commercial Microbial Identification and Antimicrobial Susceptibility Testing Systems, to provide practical guidance for laboratories to fulfill regu- latory requirements (5), and the Food and Drug Administration recognized the entire guideline (6). Commercial AST systems include manual and automated devices, as well as gradient diffusion strips and commercial disks for disk diffusion testing. The addition of an antimicrobial agent to an existing test system may seem simple, but important differences can lead to improper interpretation and reporting of results. For example, accurate endpoint determination for a new antimicrobial agent may require different reading conditions or measurements, and such factors must be accounted for in a verification study. In addition to assessing test performance, a verification study provides other benefits. For example, a verification study can be used to ensure that test results are reported correctly and that these results are accurately transmitted to the laboratory information system and the electronic medical record. Kirby and colleagues expressed concern that the current recommendations for test verification are too burdensome for many laboratories and that verification studies lack adequate statistical power to measure test accuracy (1). These are valid concerns. The unintended consequence is that laboratories may fail to implement susceptibility testing of new and potentially life-saving antimicrobials. This testing is needed to drive appropriate drug use. Wherever possible, steps should be taken to ease the burden of performing a verification study without compromising important benefits. Recall that CLIA regulations stipulate that the extent of verification studies is determined by the laboratory director. Steps to simplify a verification study include, but are not limited to, the following: (1) Providing laboratories with practical testing options that focus on the verifica- tion of test performance, not on reestablishing test performance. (2) Creating easy-to-use tools for study planning and documentation. (3) Getting buy-in from regulators and inspectors for study strategies that are streamlined but achieve the intended benefits. (4) Ensuring that laboratories have easy options for obtaining appropriate isolates for the verification study. Addressing these issues will require cooperation among all members of the clinical microbiology community. The CLSI Expert Panel on Microbiology will consider whether revisions to M52 are needed to fulfill the purpose and enhance the value of AST verification studies for new antimicrobials and to ensure that the guidelines are clear, useful, as simple as possible, and feasible for all laboratories. We will also engage partners, including representatives from government and laboratory accreditation organizations, to achieve consensus with M52 recommendations.
Patel JB, Thomson RB, Alby K, Babady E, Culbreath K, Galas MF, Lockhart SR, Lubbers BV, Morgan M, Richter SS, Sharp S, Shawar RM, Cardenas AM, Esparza G, Hubbard N, Papich MG, Schuetz AN. Expert Opinion on Verification of Antimicrobial Susceptibility Tests. J Clin Microbiol. 2020 Oct 21;58(11):e00945-20. doi: 10.1128/JCM.00945-20. PMID: 32493785; PMCID: PMC7587095.