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Bill Brasso Sr. Staff Scientist, BD Diagnostic Systems

Sept. 13, 2017

I. Introduction to STMA II. Commercial AST development III. Critical challenges to timely

development & release IV. Proposals for addressing issues

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BD Diagnostic Systems (Phoenix & Sensi-Disc) Beckman-Coulter, Inc.

(MicroScan) bioMrieux, Inc. (VITEK2 & ETEST) Thermo Fisher Scientific (Sensititre & Oxoid Disks)

Accelerate Diagnostics, Inc.

Bio-Rad Laboratories Hardy Diagnostics Mast Diagnostics

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Communicate directly with Pharmaceutical companies for new antimicrobics being developed, as well as those approved and in use Advocates for Antimicrobial Resistance (AMR)

legislation in US Congress, e.g., 21st Century Cures Act as liaisons, representatives from AST industry on

Standardization Committees (CLSI, EUCAST, USCAST) Working groups, Ad Hoc WGs, document reviewers, etc.

Maintain the database for antimicrobic codes for AST industry, regulatory agencies

Central mechanism for supplying bulk antimicrobic powders to industry

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STMA participates together in development of updates to FDA-CDRH Guidance Documents Have submitted concerns, suggested revisions to Class II Special

Controls Guidance Document (Docket # FDA-2000-D-0128, Dec. 7, 2016)

In Sep. 2016, STMA participated in FDA Workshop in Silver

Spring, MD provided extensive comments to FDA Draft Coordinated

Development Document suggested substantial equivalence based on Essential Agreement

only could eliminate need for refiling resulting from breakpoint

changes 5

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1. the susceptibility of a bacterial pathogen, 2. if the infecting organism is resistant to the drug(s) of choice,

or

3. to detect emerging resistance through surveillance.

Most labs use automated systems for AST, while some still use manual AST methods (disk diffusion, broth microdilution, etc.)

Focus on automated Broth Microdilution methods

Antimicrobic Susceptibility Test (AST) Methods Used by Clinical Labs provide therapeutic guidance to physicians and the clinical laboratory to determine

1 3.5 years!

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3 9 months

Pharma/AST Contracts

New Antimicrobic APPROVAL Processes for Pharmaceutical Companies

In response to the GAIN Act 2012, the Food and Drug Administration has developed four distinct and successful approaches with Pharmaceutical Companies to make new drugs available as rapidly as possible:

Priority Review Breakthrough Therapy Accelerated Approval Fast Track

*https://seekingalpha.com/article/687421-gain-act-should-benefit-antibiotic-makers

But there were neither provisions for AST manufacturers in GAIN nor in 21st Century Cures!

All antimicrobic susceptibility test (AST) systems, and all antimicrobics included for distribution and sale in the U.S. in these systems, must receive premarket clearance from the FDA.

a manufacturer who intends to market a device of this generic type should (1) conform to the general controls of the Federal Food, Drug & Cosmetic Act,

including premarket notification requirements in 21 CFR 807 Subpart E, (2) address the specific risks to health associated with automated short-term

incubation cycle AST system identified in this guidance and, (3) obtain a substantial equivalence determination from FDA prior to

marketing the device.1

9 1 From Guidance for Industry and FDA. Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems, U.S. Dept. of Health and Human Services, Center for Devices and Radiological Health. Issue date Aug. 28, 2009.

For each antibiotic AND organism group, a separate

510(k) is required.

1. Communications with the FDA Dec. 7, 2016 - STMA submitted concerns, suggested revisions

to Class II Special Controls Guidance Document (Docket # FDA-2000-D-0128) Several requests are highlighted in the next slides Some could be considered as

2. Internal challenges for AST Device Manufacturers Commercialization Volume of New drug applications & breakpoint changes

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Issues Impacts Proposals Current requirements for age of strains (e.g., fresh

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Issues Impacts Proposals Difficult to achieve species-specific categorical agreement (CA) and error rates

Large wildtype population near the breakpoint Applying acceptance criteria to single species/small groups with small sample size

Lengthy 510k reviews, requests for additional testing or labeling limitations Unnecessary limitations for species/organism group reporting due to small sample size

Use Essential Agreement (EA) as primary measure of performance A categorical error within essential agreement should not be an error (regardless of existence of I category)

STMA welcomes opportunity to work with FDA to better define acceptance

criteria

The issues: No AST method is an exact method, yet the current FDA

AST Guidance document & process assume the reference method is always correct. Impact of variability of the reference method is significant The CLSI Broth Microdilution ad hoc Working Group has published &

presented statistical data demonstrating this variability. The published acceptance criteria from the FDA are unrealistic

not achievable and do not necessarily add to the safety and efficacy of the product The acceptance criteria are the same regardless of the relationship between the

test organisms and the breakpoints Application of the same acceptance criteria at the species level when the number

of isolates is limited leads to the expectation of perfect data

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C. freundii 42086

Incubation Temperature: 35C 34C 34C 34C 34C 36C 36C 36C 36C

Inoculum Plate Age: 20 hr 18 hr 18 hr 24 hr 24 hr 18 hr 18 hr 24 hr 24 hr

Inoculum Density: 0.08 0.06 0.10 0.06 0.10 0.06 0.10 0.06 0.10 MIC Sum Set 1 Set 2 Set 1 Set 2 Set 1 Set 2 Set 1 Set 2 Set 1 Set 2 Set 1 Set 2 Set 1 Set 2 Set 1 Set 2 Set 1 Set 2

0.25 33 1 2 2 4 1 3 2 6 3 2 3 1 1 2 0.5 134 9 8 8 6 7 4 8 4 9 6 8 7 9 8 7 6 10 10

S 1 5 1 1 1 1 1 I 2 4 1 1 1 1 R 4 0

8 2 1 1 Testing done on CLSI frozen reference panels Variables (incub. temp, plate age and inoc. density) ALL

within CLSI reference method parameters in M7-A10 CLSI Ad Hoc working group looked at parameter refinement

determined further refinement could not be done

MODE RANGE

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Ex. 2 - Replicate broth-microdilution testing on six S. marcescens isolates with Ceftriaxone

Same lot of BMD panels used Three individuals tested each isolate

once on each of three days Provides a total of 9 MICs for each

isolate

Ceftriaxone Broth -microdilution MIC Distributions

Organism

Ser. m

arcescens

Isolate 1 2 3 4 5 6

0.016

0.031

0.063 x

0.125

0.25

0.50

1.0 x

2.0 x x

4.0 x

8.0 x

16.0

32.0

Median MIC (x)

Current CLSI Breakpoints

MIC Range

Therefore, when broth-microdilution data compared to itself cannot meet the current acceptance criteria, how can an alternate AST method (i.e., a commercial device AST) be effectively compared to it, and be expected to meet the criteria?

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Issues Impacts Proposals Inherent variability of reference method and inability to resolve discrepancies contribute to perception of poor commercial AST performance

Projects cancelled without submitting to FDA Organism groups not submitted to FDA (limitations passed on to customers)

Allow discrepancy resolution - testing 3 replicates in the reference method, and replace original reference result with the median of the triplicate ref. results. (ISO 20776-2)

Analysis and acceptance criteria for trending (bias) are not defined in guidance document

Do not add trending information to labeling when performance criteria as cited in guidance document have been met.

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Issues Impacts Proposals Ability to test & report species not included on the indications and usage is limited and/or inconsistent.

Not able to provide MICs and/or interpretive criteria to clinicians when treatment options are limited e.g., colistin, daptomycin with E. faecium Clinical labs are not able to report CLSI breakpoints or follow testing recommendations Inability to include in AST clinical studies extends duration to collect additional strains of other species

Allow commercial AST devices to report MICs for clinically relevant/similar species

Not able to follow most current testing and reporting recommendations e.g., CLSI, CDC

Allow reporting of interpretive criteria from recognized breakpoint setting organizations (e.g., CLSI) for new and existing drugs & CLSI report groups

STMA welcomes opportunity to work with FDA to better

define report groups

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Issues Impacts Proposals Numerous/on-going breakpoint changes

Extensive external clinical studies with current expectations Costly development, competes for resources to develop AST for new antimicrobial agents Costly to implement in clinical labs e.g., software updates, validation studies, QC

Provide specialty organism set to evaluate AST (can be subset of organisms used to revise interpretive criteria, characterized with multiple replicates)

Allow re-analysis data from original 510(k) with new breakpoints

Allow single site evaluation (can be

internal) with only Challenge and QC strains

Extensive testing/data requirements to obtain clearance

Reproducibility studies Additional fresh/recent isolates May require developing/obtaining clearance for extended dilutions

Single submission for each antimicrobial agent to address breakpoint changes

Need New Product Cat # for the panel to add single new agent The new product assigned a new name and number early on (e.g.,

NBPC50 = Neg Breakpoint Combo 50) Decisions are made on older products, possibly obsoleting some

catalog numbers, adjusting inventories Update to Product Label Information (Customer Labeling,

including box label, panel/card label) Update Package Insert, with Instructions for Use in every box Therapy Guide and Expert System Guide updates Letter to the Customer (usually with background material) New software updates, and notification of new codes to interface software vendors Building new inventory

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Additionally, ~ 29 CLSI and/or FDA breakpoint changes since 2010. And with at least 12 new NDA approvals likely by 2021!

Volume of new/revised drugs exceeds capacity

x x x x x x x xx x x xx x x x x x x x x x x x xx x x x

Volume of new/revised AST exceeds capacity for AST development, new panel/card commercialization and REQUIRED Clinical Lab validations

Where is the business incentive for AST device manufacturers? No additional revenue (sales) for AST manufacturers for changing

breakpoints on panels or switching out old drugs on panels for new ones.

New Antibiotic Pipeline (since 2010)

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= FDA approval

= theorhetical new drug approvals

X = Breakpoint changes

2020

Mero/Vaborb

2018 2019

Oritavancin

Tedizolid Ceftaz/Avibac

Broad-spectrum

Delafloxacin

Gram-Negative

Gram-Positive

DalbavancinCeftaroline Ceftoloz/Tazo

2015 2016 20172010 2011 2012 2013 2014

The AST device submission process has had small changes over time, resulting in significant changes to AST device clinical trials

Current process impact: Limits use of new antimicrobial drugs without AST test Result drug not available on local formularies

Patients may be treated with new antimicrobial agents without an approved diagnostic test

The current process can be improved More coordination between antimicrobial drug sponsor, FDA and

AST device manufacturers is vital Changes will require revisions to existing AST device guidance Fast track process has worked for antimicrobial drug sponsor Fast track process would provide assurance of quality AST device results

while providing accurate commercial AST methods to clinical labs sooner

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Thank you!!

Industry Perspective on the Challenges of AST Methods and the Role of STMAAgendaSlide Number 3I. STMA What We DoSTMA Communication with the FDAII. Commercial AST developmentSlide Number 7Slide Number 8Clinical Trials for FDA SubmissionIII. Critical challenges to timely ASTdevelopment & product release1. Extensive FDA Clinical study design2. Acceptance criteria3. reference method variabilityTo illustrate the reference method variability, consider the following 2 examples:Slide Number 153. reference method variability4. Not Able to report all clinically relevant species and CLSI breakpoints 5. Challenge to support Breakpoint changes AST COMPANIES MUST REDUCE Commercialization ROADBLOOCKS Slide Number 20ConclusionsSlide Number 22