National Center for Emerging and Zoonotic Infectious Diseases The Role of Breakpoint Committees for New Drugs Perspectives from the United States

Transcription

1 National Center for Emerging and Zoonotic Infectious Diseases The Role of Breakpoint Committees for New Drugs Perspectives from the United States Jean B. Patel, PhD, D(ABMM) Science Lead, Antibiotic Resistance Strategy and Coordination Unit Centers for Disease Control and Prevention

2 Who Sets Breakpoints in the U.S.? The Food and Drug Administration has legal authority to set breakpoints The 21 st Century Cures Act FDA moved breakpoints from a drug label to a website FDA can defer to breakpoints set by a standards development organization (SDO) Recognized SDO The Clinical and Laboratory Standards institute (CLSI) Breakpoints on the FDA website can be used on FDA cleared AST devices

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4 What is the Clinical and Laboratory Standards Institute? A not for profit laboratory standards development organization Recognized by ANSI/ISO as a standards development organization Establishes standards for human and animal medical laboratories in several disciplines Microbiology, Hematology, Immunology, Molecular Methods, New Born Screening, etc.. Full Disclosure: I am a long-time CLSI volunteer AST Subcommittee (former chairholder) Microbiology Expert Panel (current vice chairholder)

5 New Drugs & the CLSI Subcommittee for Antimicrobial Susceptibility Testing CLSI M23 Document describes the data needed for subcommittee decisions. Same data needed for regulatory approval Interactions during early development Antimicrobial susceptibility testing method questions Establishing quality control ranges Interactions during late stage development Preparing data for breakpoint decisions Provisional breakpoints Breakpoint decisions Recommendation: Engage SC at least 6 months before submitting materials for a breakpoint decision

6 Subcommittee Process: Why they make decisions with ~200 experts in the room? A commitment to transparency, inclusivity, & consensus decision making Open meetings A voting body that debates and votes in front of all attendees Liaisons with professional societies (IDSA, ASM, PID, CAP, SHEA, STMA, SIDP, APHL) Official representation of EUCAST on the subcommittee Ad hoc Work Group Standing Work Group Subcommittee 4-5 people Meet by teleconference Gather data and draft a proposal 8 to 12 people Open meetings 2x/year Vet proposals from ad hoc WG 10 to 12 people Open meeting 2x/year Vote on proposals from standing WG

7 Getting Started Reach out to CLSI AST Subcommittee Leadership CLSI Project Lead: Marcy Hackenbrack Subcommittee Chair: Mel Weinstein CLSI AST SC Meetings January and June Agenda items deadline is usually 6 weeks prior to meeting Meeting information available at and via Marcy Submitting QC data does not require pre-meeting interactions For other decisions an ad hoc working group will be assembled to work will sponsor prior submission of agenda items

8 Early Development Interactions

9 AST Methods for New Drugs Frozen broth microdilution with CAMHB is the gold standard Alternative methods Agar dilution Disk Diffusion What if gold standard method doesn t work? Fastidious media help bacteria to grow Media treatments help the drug work Fresh media - tigecycline CA 2+ supplemented media - daptomycin Iron depleted media - cefiderocol Consultation with CLSI is only required if gold standard AST method is NOTsuitable to measure activity of a new drug.

10 Aligning Disk Content CLSI and EUCAST have recommended different disk mass in the past Different approaches CLSI relies on the sponsor to pick a disk mass based upon M23 guidance. This is done early in development. The sponsor generates data for disk diffusion breakpoints EUCAST reference lab picks a disk mass late in develop and generates data for disk diffusion breakpoints Two different disks for the same drug creates challenges CLSI-EUCST collaboration to identify a common process and have a single disk per drug moving forward

11 Establishing QC Ranges Prior to Clinical Trials From Jan 2018 CLSI Agenda Materials

12 Data Needed for a Breakpoint Decision M23 Cutoff Description Epidemiological cutoff Non-Clinical PK/PD cutoff Clinical exposure-responsecutoff Clinical cutoff Upper-limit of wild type MICs from in vitro testing of isolates Basedupon non-clinical PK-PD models what is the expected MIC cutoff for susceptible Based upon clinical PK data and factors that affect drug exposure what is the expected MIC cutoff for susceptible Upper limit of MICs for infections with successful outcomes

13 Provisional Breakpoints and ECV for Drugs Still in Development

14 Provisional Breakpoints for Cefiderocol Decided at the June 2018 meeting and will be published as provisional in the January 2019 M100 document with a designation of INV and continue to review data as they become available Provisional breakpoints give drug & AST device manufacturers target breakpoints that will either stay the same or minor adjustments In public health, these are helpful if cefiderocol is considered for treatment of panr infections MICs (µg/ml) Susceptible Intermediate Resistant Enterobacteriaceae <4 8 >16 Pseudomonas aeruginosa <4 8 >16 Acinetobacter baumannii <4 8 >16 Stenotrophomonas maltophilia <4 8 >16

15 Reasons for Setting an Epidemiological Cutoff Value (ECV) To describe MIC distribution data during breakpoint setting process To describe a wild type population when a clinical breakpoint is not possible (i.e., no in-vivo data) No sponsored clinical trial A need to use a drug still in development

16 Few Drugs for Treating Infections Caused by NDM CRE FDA-Approved Phase 2 or 3 Drugs for serious MDRO Gram-Negative Infections Most Common CRE Types KPC NDM Colistin?? Ceftazidime-Avibactam X Meropenem-Vaborbactam X Impenem-Relebactam X Plazomicin V Aztreonam-Avibactam Cefiderocol New data suggests colistin may provide little clinical benefit NDM-CRE may carry a gene that confers resistance to all aminoglycosides including plazomicin Aztreonam-avibactam can be created by treating a patient with ceftazidime-avibactam and aztreonam

17 A CDC Program: Susceptibility Testing of New Drugs in the AR Lab Network Closes the gap between new drug approval and the availability of testing methods in hospital laboratories Answers the question, Will our drugs work? HP inkjet printer allows for on-demand reference susceptibility testing of new drugs in regional labs of the AR Lab Network Rapid reporting to improve care via AR Lab Network IT reporting to hospitals for tailored patient treatment

18 Susceptibility Testing of Ceftazidime-Avibactam + Aztreonam Recommended therapy for serious infections caused by MBL-producing Gram-negative bacteria in 2018 Sanford Guide Will test susceptibility of both Ceftazidime-avibactam + aztreonam and aztreonam-avibactam Will report MIC of aztreonam-avibactam when: Ceftazidime-avibactam + aztreonam and aztreonam-avibactam are within a doubling dilution No other FDA-approved drug is susceptible What is a normal MIC? ECV defines wildtype MIC of a species Pfizer & IHMA are sharing data In this case do we need to know the normal MIC of a carbapenemaseproducing species?

19 Using the intermediate & susceptibledose dependent category

20 The Intermediate Category Defintion Technical variability Treatment potential if drug exposure is high (increased dose or concentration at the site of infection) Technical variability of MIC testing +/- a single doubling dilution; best case scenario This means a normal MIC distribution of at least 3 dilutions Pitfalls of applying breakpoints without an intermediate category False resistance Inaccurate alternative test methods

21 Disk Diffusion Testing without Intermediate Range No. Vary Major (%) Major (%) R (2) NA S+R 29 10(34.5) 0 S NA 0 Total (5.9) 0 Sader et al, JCM June 2018; 187 for 134 isolates, random + challenge

22 Disk Diffusion Testing with an Intermediate Range No. Vary Major (%) Major (%) Minor (%) I (2) NA 4 (11) I+1to I (41) I NA 0 0 Total (5.9) 0 0 Sader et al, JCM June 2018; 187 for 134 isolates, random + challenge

23 Ceftaroline Breakpoints for MRSA Breakpoint at drug approval, Susceptible only 1µg/mL, 600mg q12 Problem MRSA lineages outside of the U.S. that have naturally elevated MICs of 2µg/mL First indication that breakpoints are problematic reports that the disk diffusion test doesn t work (Livermore, et al. JAC 2015)

24 PK-PD Analysis for Two Doses Study by Shampa Das et al.; COVERS clinical trial Dose of 600 mg q12 supports a susceptible breakpoint of 1-2µg/mL Dose of 600mg q8 supports a susceptible breakpoint of 2-4 µg/ml

25 A Revised Breakpoint that Incorporates SDD Category MIC (µg/ml) Dose Susceptible 1 600mg q12 Susceptible Dose Dependent mg q8 Resistant 8 Not applicable

26 CLSI Decision Regarding Intermediate & SDD Most breakpoints should have an intermediate or SDD designation Intermediate defintion hasn t changed SDD Applied when data indicates that the drug can be effective at a higher dose and not using SDD may unnecessarily eliminate an important drug for treatment of an MDRO infection Reporting options SDD, D, or I with a comment about dosing

27 Where to get more information about CLSI Marcy Hackenbrack Mel Weinstein

28 For more information, contact CDC CDC-INFO ( ) TTY: Thank You Jean Patel The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.