The Antimicrobial Susceptibility Testing Device Manufacturer: Development Process, Timelines, and Challenges

Transcription

1 The Antimicrobial Susceptibility Testing Device Manufacturer: Development Process, Timelines, and Challenges Sheila Farnham, MT(ASCP) President Susceptibility Testing Manufacturers Association January 10, 2015

2 Workshop Material From STMA Much of the material being presented comes from presentations and a workshop presented by Susceptibility Testing Manufacturers Association (STMA) to Clinical and Laboratory Standards Institute (CLSI) Antimicrobial Susceptibility Testing (AST) Subcommittee. 2

3 STMA Member Companies BD Diagnostic Systems Thermo Fisher Scientific, Inc. biomérieux, Inc. Bio-Rad Laboratories Siemens Healthcare Diagnostics (MicroScan) Mast Diagnostics 3

4 Susceptibility Testing Manufacturers Association Informal group started in 1994 at CLSI meeting Formal group formed in 2002 Membership limited to AST companies and other support companies Three meetings per year Elected officers: one officer/company, rotating 4

5 AGENDA AST Device Manufacturer Development Process Timelines Challenges

6 AST Device Manufacturer DEVELOPMENT PROCESS 6

7 Antibiotic Qualification Process for AST Systems -- MIC Final Specifications Formulation Development Product Development Data Evaluation Verification and Validation FDA Submission External Internal FDA Review and Clearance Software Update Commercialization Abbreviations: MIC, minimum inhibitory concentration; FDA, US Food and Drug Administration.

8 Antibiotic Qualification -- MIC Final Specifications Testing range Breakpoints Indications Formulation Development Stability Solubility Quality Control Product Development Strain characterization Investigational product production Concurrent reference method testing Analysis development Instrument Software Development

9 Antibiotic Qualification -- MIC Product Development Strain characterization Need resistant and susceptible strains Helpful if mechanisms of resistance are known All resistance is not created equal Concurrent reference method testing the Mueller Hinton Broth question, they are different Investigational product production Feasibility lots Scale up to production Manufacturing of proposed low breakpoint concentrations of antimicrobials (+/- 2 dilutions) May be difficult to manufacture reproducibly for both test and reference methods Analysis development HPLC or other assays Abbreviation: HPLC, high performance liquid chromatography. 9

10 Antibiotic Qualification -- MIC Verification Validation External -- test site(s) Biologics Internal Biologics Software External- Clinical Trial Clinical strains Internal Biologics Software Challenge strains Reproducibility Quality Control

11 Antibiotic Qualification -- MIC Complete FDA Studies Evaluate Data Prepare FDA Submission FDA Review and Clearance Labeling Indications Performance

12 Commercialization: Drug X is ready to be on a panel/card with other drugs! Once clearance is received Once stability is completed Once analysis and/or panels are implemented in the software Once expert system is updated Once interface configurations are completed Once the software is validated, Once it is released by QA Then the work really begins. Abbreviation: QA, quality assurance. Commercialization New product configuration Update product information Build inventory and change catalog numbers User software installation User education 12

13 AST Device Manufacturer TIMELINES 13

14 AST Device Manufacturer Timelines MIC Tests: months (from start of development to FDA submission) Varies by manufacturer Software dependent Disk 6 months for RUO 2 years for commercial availability Used in P3 clinical drug trials Abbreviation: RUO, research use only. 14

15 AST Device Manufacturer CHALLENGES 15

16 FDA Guidelines for 510(k) Study Design for Antimicrobial Agents in AST Devices For each antibiotic a separate 510(k) is required. Establish performance characteristics by agreement with the CLSI standard reference method for each antimicrobial agent and the organisms intended for testing. Because variations in test procedures can affect performance, conduct agreement studies on all procedural options included in the package insert. Such procedural options include inoculation preparation methods and reading of results, eg: growth inoculation preparation method direct colony suspension inoculation method visual reading automated readings 16

17 FDA Guidelines for 510(k) Study Design for Antimicrobial Agents in AST Devices For each antibiotic and breakpoint change Number of clinical trial sites: 3 Organisms: 100/site fresh and stock 75 challenge set (on scale and R strains) at 1 site Reproducibility (on scale): 25/site or /site Interpretive Standards: FDA Stability: 3 lots (real-time data) QC (reference and test device) CLSI strains - 20 results/site At least 1 QC strain on-scale Inoculum density checks QC, fresh and reproducibility 17

18 On-scale MICs On-scale MICs are considered evaluable as they do not include inequality values On-scale concentrations for this series = MICs of 0.25 and >32 are considered off scale. 18

19 FDA Criteria for Satisfactory Performance of In Vitro Antibiotic Test Data For MIC Formats Accuracy (Fresh, stock & challenge Set) : Percent EA and CA > 90% Percent EA of evaluable organisms >94.5% VME rate of 0% - 2.3% 0 VME for <70 R isolates 1 VME for R isolates 2 VME for R isolates 3 VME for R isolates 4 VME for R isolates ME rate < 3% of S isolates Growth failure rate < 10 for any genus or species Reproducibility: > 95% QC Test Device: > 95% within expected range Abbreviations: EA, essential agreement; CA, category agreement; VME, Very Major Error; ME, Major Error. 19

20 Limitations You must include a statement of limitations. If the device has software-generated interpretations, these limitations should be incorporated into the software. Examples of some limitation statements: You should recommend the use of an alternative method for testing prior to reporting of any results when the spectrum of activity for any antimicrobial agent includes organisms with either unacceptable very major discrepancy or major discrepancy rates. If you did not test sufficient resistant organisms with an approved indication for use for the antimicrobial agent, you should include a statement in the labeling similar to this. 20

21 AST: Category Agreement Without Essential Agreement Hypothetical experiment: 30 isolates of Enterobacteriaceae were tested for meropenem (MEM) susceptibility by reference MIC method and an AST device. New MEM breakpoints: S/I/R = 1/2/4 Test MICs *With permission from J. Patel Reference MICs Essential agreement = 66% Category agreement = 100% Abbreviations: S/I/R, Susceptible, Intermediate, Resistant.

22 AST: Essential Agreement Without Categorical Agreement Hypothetical experiment: 30 isolates of Enterobacteriaceae were tested for meropenem susceptibility by reference MIC method and an AST device. New MEM breakpoints: S/I/R = 1/2/4 Test MICs Reference MICs Essential agreement = 100% Category agreement = 63% Abbreviations: S/I/R, Susceptible, Intermediate, Resistant. 22

23 Effect of S/NS Only vs S / I / R Breakpoints (BPs) on Agreement: Example With Intermediate S / I / R Breakpoints REFERENCE MICs <= = S I R > TEST_MICs Grand Total <= EA EA% CA S CA% I VME R VME% ME ME% 1.5 > MiE 6 Grand Total MiE% 3.2 S = 134 I = 5 R = 49 Abbreviations: EA, essential agreement; CA, category agreement; VME, Very Major Error; ME, Major Error; MIC, minimum inhibitory concentration; S/I/R, Susceptible, Intermediate, Resistant. 23

24 Effect of S/NS Only vs. S / I / R Breakpoints on Agreement: Example with S/NS Susceptible / Non-susceptible BPs REFERENCE MICs <= = S NS > Grand Total TEST_MICs EA 176 <= EA% CA CA% S VME NS VME% ME ME% MiE NA > MiE% NA Grand Total S = 134 NS = 54 Abbreviations: EA, essential agreement; CA, category agreement; VME, Very Major Error; ME, Major Error; MIC, minimum inhibitory concentration; S/I/R, Susceptible, Intermediate, Resistant. 24

25 Challenges If new breakpoints are close to wild type, category agreement and acceptable error rates are hard to achieve. Can only report results for which there are CDERapproved breakpoints (eg, colistin has no breakpoints). When should AST manufacturer start development? Redevelopment, re-analysis of data, new clinical trials, changes to algorithms/software if breakpoints change or are different than anticipated Breakpoints and organism indications are set late in the FDA drug approval process. Lack of R or on-scale organisms. Not all drugs or organisms have reference method reproducibility of ± 1DD. Inability to resolve discrepancies. Abbreviations: CDER, Center for Drug Evaluation and Research; DD, Dose-Dependent.

26 Thank You! 26