innovation in clinical microbiology
TRANSCRIPT
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INNOVATION IN CLINICAL MICROBIOLOGY
YOU TOO CAN BRING A NEW IDEA TO MARKET!(BUT IT WON’T BE EASY)
Romney Humphries, PhD D(ABMM)Chief Scientific Officer, Accelerate DiagnosticsProfessor, University of Arizona
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Disclosures1. Employed by Accelerate Diagnostics2. Shareholder of Accelerate Diagnostics3. Consulting, Qpex Pharmaceuticals4. Member, CLSI AST Subcommittee5. Member, CAP Microbiology Committee6. Member, IDSA Diagnostics Committee
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Learning Objectives1. Describe the general process for new test development2. Discuss financial considerations to new test development3. Evaluate important features of a commercial test post-launch
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For this talk…• I am going to discuss a bacterial respiratory assay that:
• Identifies bacteria in BALs• Performs AST for these bacteria
• Yes, this is a test under development at AxDx, but this is not a promotional talk • I won’t be discussing how well the test itself works• I won’t be discussing when it’ll be in trials / available • I will be discussing the journey for the test development, in general terms!
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So you have a great idea!• Unmet clinical need
• Something that irks you day to day in the lab
• You’ve already invented something!
Idea Market Research Discovery Develop’t Validation /
VerificationFDA
Review Marketing Updates
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Idea
Data from Washington University presented at Microbe 2019 – 1 year history of BAL TATs
Gee, wouldn’t it be great if I could get organism ID and AST for patients with hospital pneumonia… the same day?
0 10 20 30 40 50 60 70 80
P. aeruginosa
Enterics
S. aureus
Hours
Time to ID Time to PBP2a Time to AST
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Market researchID targets
DrugsTested
SpecimensTested
LOD
I want:- All bacteria- All fungi- All viruses- Oh yeah, but only if clinically relevant (and
we will debate what that means)
I want:- Drugs used in the U.S.- Drugs used in Europe- Drugs used in China??- Drugs using only in my
institution under research protocolsI want:
- BALs only- ETAs only- Both BALs and ETAs- Hey… what about sputums?- Forget respiratory – I want to validate this for CSF
I want:- Nothing below 104 CFU/mL- Most are on therapy so I want 102 CFU/mL- Guidance says 105 CFU/mL
Hopefully somemiddle ground
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Differences between guidance documentsGuideline Specimen TestATS / IDSA ETA Semi-quantitative cultureBSAC Don’t use ETA
Use BALDon’t do quantitative cultures
AMMI ETA Do quantitation
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I (think) I know what I want to include…now how do I evaluate it?• Three considerations:
• Standard of care that labs use today• Standard of care that FDA accepts as reasonable• Standard of care that works!
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Example: BAL Culture Practices in the U.S.Gram stain rejection criteria for
culture?
NoYes Q ScoreYes, WBC and SquamousYes, Other
Quantitation?
NoneCalibrate loop 1 & 10 uLOtherCalibrated loop 1 uLCalibrated loop 10 uLQuandrant Streak
How much plated?
1 uL loop10 uL loop1 dropSwab dipped in BALStick dipped in BALVaries by tech2 drops of a sediment
~50% used cytospin for the G/S
DivC Survey in 2019 (data posted to DivC)
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Example: BAL cultures in the US (2)How long incubated
(h)?
48 72 96 >96
Organism Reporting
1-2 pathogens <=4 pathogensAll pathogens
0
10
20
30
40
50
60
70
80
Stenotro
phomona
s
M. catar
rhalis
S. pneu
moniae
H. inf lu
enza
e
C. stria
tum
P. aerugin
osa
Enteroba
cteria
ceae
S. aureus
Reporting pathogens
Always Pure Culture Predominant If seen on GS
Critical care doctor: “If P. aeruginosa is not reported, it’s not there.”
DivC Survey in 2019 (data posted to DivC)
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Disconnects between lab and physiciansInterview with lab director and physician…. At the same institution
Take home message: frequent conversations between lab and physicians are needed!
Lab Director
We do not do quantitation
P. aeruginosa only reported if predominant
S. pneumoniae is not reported if NOF present
PulmonologistMy lab does full
quantitation
P. aeruginosa always reported
S. pneumoniae is an important cause of
pneumonia
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How well does SOC pick up pathogens?• Study conducted at AxDx, goal to look @ organism loss in shipping• Standard of care (SOC) per lab’s protocols
• Specimen plated at hospital lab• Specimen then shipped to AxDx for testing
• Reference lab (RL) protocol:• 72 hr incubation• 10 uL and 1 uL full quantitation (CMPH method)• Reported all pathogens (MALDI-TOF)
Campeau et al 2018 ECCMID Abstract
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SOC vs. Reference Laboratory Reporting
01234567
Enterob
acterales
P. aeru
ginosa
S. aure
us
H. influ
enzae
S. pne
umon
iae
Stenotroph
omon
as
Organisms reported only by SOC or RL
SOC RL
Overall, 66% of potential pathogens would be reported differently based on the 3 participating laboratory’s SOPs
- not reported in some cases- reported in other cases
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Take home: laboratory SOPs vary1. How specimen is planted, and how results are reported2. Standardizing clinical practice (e.g., “thresholds to treat”) is
challenging with these differing practices3. From a device development perspective: what is “truth”?
• Analytical accuracy is important• Clinical accuracy is equally important
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Back to evaluating your new test…
Data on file, AxDx
• My test detects viable organisms, so I should compare to culture
• What is the frequency of positives?
68%16%
16%
BAL Culture Results
NegativeTypical pathogenOdd pathogen
Typical pathogens:- Enteric- P. aeruginosa- A. baumannii- Stenotrophomonas- H. influenzae- S. pneumoniae- S. aureus
Odd pathogens:- Achromobacter- C. striatum- Group B Strep- Group A Strep- Burkholderia- Shewanella- etc
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What does FDA require?
LOD determination Test across concentrations, confirm 90% detection @ LOD, for each target
ID Inclusivity Test each target with multiple speciesID Exclusivity Check for cross-reaction against typical
organismsInterfering substances Check for inhibitors that might be present
in BALsPrecision Test each target at least 4 times per site, x
3 sites
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FDA class II special controls document for AST
225 specimens per antimicrobial
10 (minimum) organism / antimicrobial combinations
48 resistant results per antimicrobial
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How can I get all this?• Ultimately, I need ~ 500 positive specimens• If only 16% are positive, that means I need to test 3125 specimens (at least!!!) to get what I
need• Resolution to this conundrum is combination testing with:
• fresh, never frozen specimens• Frozen remnant specimens• Specimens (or matrix) seeded with “recent” isolates (last 6 months)• Specimens (or matrix) seeded with “challenge” isolates
Example: rare resistance types, on-scale MICs, etc
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The challenges associated with seeding• Negative BALs are toxic to bacteria….• Data from Accelerate Diagnostics:
• 61% of specimens inhibit pathogens26% inhibit S. aureus43% inhibit E. coli52% inhibit Providencia17% inhibit the pathogen that was isolated from the specimen
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Examples• Specimens screened in-house to evaluate‘toxicity’.• Lawn of S. aureus or E. coli plated, and a 100uL drop
of BAL added • Incubated overnight – and zone of inhibition evaluated
What does it mean?• Negative BALs are negative for a reason!• Seeding into remnant negative BALs won’t work• Does this affect quantitation? Does it affect culture
detection?
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Ok... What now?1) Must develop a way to screen for BAL “toxicity”2) Must develop a way to clean up the BALs
PhenoPrepTM Instrument:- Cleans and resuspend BALs- Removes the inhibitory substances- Great for testing clinical specimens- … not so great to “mimic” BAL for FDA analytical studies
- Must prove to FDA they are equivalent!
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What causes inhibition anyway?
In the end, it doesn’t really matter at this point… focus efforts on changing protocol
• Antimicrobials?• Ertapenem, Gentamicin, Levofloxacin, Linezolid, SXT, vancomycin cause similar inhibitions• Ceftriaxone, aztreonam, gentamicin, pentamidine do not
• Host factors?• Blood (10%) does not inhibit• Mucin does not inhibit
• Other drugs / solutions do no have an effect.• Ephedrine • Guaifenesin (expectorant)• Lidocaine• Nebulizing NaCl
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What do you do when you get to this point?
”Patti and Ribhi are so nice!”- Carrie, AxDx Regulatory lead
• Pre-sub process with FDA• What is it?
• Method to discuss study design with FDA prior to doing the study and completing it
• Company proposes pathway• FDA rebuts or agrees• Discussion centers on:1. Risk2. Least burdensome approach
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You’re ready…1. Developed a great test2. Developed a great plan with FDA to do your trial3. You have set up your reference method, your collaborating sites4. You have all your data – and FDA has granted you clearance to market!
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NOW WHAT?
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How am I going to sell this?
Investment Community• Show me labs
will adopt it quickly
• Show me the money!!
Clinical Community• Show me it
works• Tell me it's not
going to break the bank!
Clinical Outcome Data!
Two customers
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Hierarchy of evidence-based medicine
TIME$$$$
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2017 COCHRANE REVIEW:Interventions to improve antibiotic prescribing practices for hospital inpatients
§ 221 studies (58 RCTs and 163 non-randomized) published through 2014§ “We found high-certainty evidence that interventions increase appropriate use of antibiotics,
reduce duration of antibiotic treatment, and shorten hospital stay without increasing the risk of mortality”
Davey P, Marwick CA, Scott CL, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No.: CD003543. DOI: 10.1002/14651858.CD003543.pub4.
LESS
Solely focusing on unnecessary treatment
Comparing antibiotic stewardship to no intervention
Controlled before-after studies
Non-randomized trials
MORE
Comparing different interventions
Patient safety outcome measures
Microbial outcome measures
Coordinated, multihospital RCTs
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WHY RCT?
Sales • RCTs produce the strongest level of clinical evidence when comparing interventions
Patients• theoretical benefit to patient outcomes, with reduced time to
targeted antibiotic therapy and potential reduced morbidity and mortality
Society• May guide clinicians and laboratories in the effective
implementation of new diagnostic tests, and appropriate resource allocation to the technology
Science• There is limited certainty in the evidence of new diagnostics• RCTs are the gold standard of research method - as close
to “truth” as possible
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What is a good endpoint for a clinical study?
• Show the test works analytically?• Show the test changes clinician practice?• Show the test impacts hospital bottom line (i.e.,
length of hospital stay)?• Show the test saves lives?
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Thoughts from ASM
Miller et al. 2019 JCM57:e00495-19
• Clinical utility means:• test informs treatment decisions by
diagnosing, monitoring or predicting disease progression
• Accuracy alone does not demonstrate clinical utility, but is a pre-requisite
• Studies should reflect potential patient populations (in systems similar to your own)
• “… sufficient to show a connection between changes in decision making and potential clinical outcomes”
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Clinical impact of diagnostics testsLab
Results reported
Clinician Action
Patient
Analytical performance
Time to results
Therapy changed
Adverse drug eventsLOSMortality
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An example:• How many patients do you think would need to be enrolled in a RCT to evaluate time to
therapy optimization for patients with pneumonia, using the test we’ve talked about versus standard cultures?
• A) 100 per arm• B) 250 per arm• C) 500 per arm• D) 1000 per arm• E) 6000 per arm
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Answer: 6000 patients per arm• Why?• Most BALs are negative• ~ 16% of subjects will have a positive, on-panel result• Data from critically ill patients:
• Time to optimal therapy is 44.2 h with rapid diagnostics and 70.2 h with standard methods
• In contrast, tests that look at 100% opportunity to act (e.g., those from positive blood cultures) it’s closer to 200 patients per arm
Any guess on how much this study would cost? $20 million
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Do clinicians treat patients … differently?Accelerate Diagnostics Registry Study: Impact on time to therapy changes by disease severity
MILD (0-1) MODERATE (2-3) SEVERE (≥4)
P = 0.51 P = 0.007 P = 0.52
P = 1.00 P = 0.003 P = 0.27Why?
More comfort de-escalating therapy for patients who aren’t actively dying More patient heterogeneity in the critically ill (co-infections, etc)
MacVane et al. 2019 ASM Microbe
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How do the different customers view this?
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Investment Community
• Does this mean the test isn’t useful?
• Does this mean the test will only be used for moderately ill?
Clinical Community
• Makes sense• Knowing sooner
helps reduce worry window
• More data needed for critically ill patients
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RCT data!!• ARLG-funded (NIH) RCT at
UCLA and Mayo Clinic for Gram-negative bacteria in blood
• Primary endpoint: time to first antibiotic change
• Successfully achieved primary endpoint
13 h vs 54 h for Gram negative therapy change (p<0.001)
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Study reported on secondary endpoints, including LOS and mortality… but not powered to show difference
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“This is concerning – length of stay and mortality are two major metrics used by hospitals to calculate cost savings. Since [these tests] are a net-cost-add for hospitals, failure to improve LOS or mortality could lead hospitals questioning the value of the system.” – Investment Analyst
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So – how do hospitals decide to adopt a new technology?
• Clinical demand• Reduce lab complexity / cost• Guidance from professional societies, CDC, CMS
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BUT… “clinical deployment has been restrained by skepticism from payers and hospital administrators over clinical, and ultimately cost, benefits.”
Miller et al. 2019 JCM57:e00495-19
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How do I make sure my test is reimbursed?
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Coverage – and MACs• Medicare Administrative Contractors
• Private health care insurer• Awarded geographic jurisdictions to process Medicare Part A and B medical claims• One role is to establish local coverage for selected claims
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• Palmetto initially proposed a non-coverage (local coverage determination)• Palmetto stance, “one size fits all” panels do not meet Medicare’s coverage criteria of “reasonable and necessary”
tests• final LCD allows limited coverage in susceptible populations
• limits coverage to panels of 3-5 pathogens
• tests ordered in a healthcare setting equipped to care for critically ill patients • tests ordered by an infectious diseases specialist
• Contrast with final LCD for GI pathogens:• Up to 5 targets if immune competent• If concern for C. difficile, will cover up to 11 targets if C. difficile is one of them
• >=12 targets covered if immunocompromised
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How do the MACs make their decisions?
1. Clinical evidence• Shows up here again!
2. Lobbying• Clinician testimonies to MAC Directors is very impactful
3. Case studies• A good story is worth more than clinical evidence
4. Guidance documents from professional societies
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What guidance documents apply to microbiology?
• Other sources lab use:
• CAP • CLSI• ASM• Other professional
societies
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What do these guidelines say for hospital pneumonia?
• Only mention of diagnostics: cultures• Do not use CRP / PCT to help diagnosis
• Recommendations based on available evidence
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How about for blood culture diagnostics?
Note: review completed in 2014Updates and reviews: only once every 5-10 years
“On the basis of low overall strength of evidence of effectiveness, no recommendation is made for or against the use of the three assessed practices of this review due to insufficient evidence; however, the overall strength of evidence is simply classified as suggestive due to the fact that most studies received a fair study quality rating.”
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"AMR is both a public health crisis and a national security imperative that demands systemic policy action. CMS’s realignment of inpatient payment incentives is intended to stabilize the antibiotic development pipeline in the short term and guarantee an arsenal of innovation to fight AMR in the long term."
- Seema Verma, CMS Administrator on her blog
How about hospitalized patients? Under DRG?
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Misaligned financial incentives• DRG system incentivizes use of older, cheaper tests and drugs over newer, more expensive
tests and drugs• Result: slow uptake, low prescription volumes• Patients with MDR infections by nature are more costly:
• Longer time in hospital• More complicated to treat• More diagnostic testing
• New! Changes to ICD-10 coding of these as a CC (extra payment)
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What is NTAP?
Bottom line: provides mechanism for hospitals to get paid for using technologies for inpatients, and to not just get paid for outpatients
• New Technology Add-on Payment• Developed by Congress in 2000• Bridge gap between DRG reimbursements & cost of novel technology• Designed for technology that:
• exceeds certain cost parameters • is new and not similar to an existing technology• substantially improves diagnosis and treatment of patients
• How does it work?• A special ICD-10 code is assigned to a technology• The hospital bills with that ICD-10 code and gets reimbursed 65% of the cost of the test• In place for 2-3 years after NTAP application approved (2-3 years after FDA approval/clearance)
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NTAP 2020• One diagnostic company (T2 Biosystems) – first IVD Infectious Diseases test!• Six cancer therapeutics• 2 other drugs
• Other changes for 2020 NTAP:• Increased payments to 65% of cost• Increased QIDP (qualified infectious diseases products) payment to 75%• Allowed breakthrough designation products to bypass clinical evidence requirement
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THE FUTURE OF INFECTIOUS DISEASES
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A lot of effort to incentivize new drugsAnd yet:- Almost all publicly listed antibiotic companies are struggling
- Achaogen and Melinta bankruptcy- Financing for antibiotic development evaporated
- Nearly half of all funding is for oncology drugs- Merck only big pharma company left that still sells antibiotics- <10 clinical studies underway in anti-infectives
- Compare to >4000 for oncology
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What can be done?• More incentives for drugs
• Examples: $1 billion market entry award for companies that develop new, critically needed antibiotics
• Incentives for antibiotic stewardship• Now a requirement for participation in Medicare
• But what about diagnostics?
We want the right drug for the right patient at the right time. This involves both diagnostics and drugs!
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IDWeek 2019 PresentationBy Dr. Yu
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IDWeek 2019 PresentationBy Dr. Yu
• Laboratory even further from patient than ID
• ID physicians do not control testing• Laboratory budgets shrinking• Test utilization based on cost, not best tests
Laboratory tests?
• Laboratory test utilization pricing limited by DRG
• Laboratory test utilization pricing limited by reduced payments for outpatients
• Laboratory stewardship towards reducing use, not optimizing
• Lab/clinicians not advocating for pricing to accommodate new technology
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Things in the works• DISARM
• Act at Congress for antibiotic pull incentives• VALID Act
• FDA regulation of LDTs• Would re-classify as in vitro clinical tests (IVCT) • Oversight would be risk-based
• IDSA Diagnostics Committee• ASM Corporate Council• AMP Activities
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What can you do?1. Support your diagnostic colleagues!
• Specimens for test development• Provide feedback, work with industry
2. Get involved!• ASM • IDSA
3. Advocate!
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Thank you!Accelerate Diagnostics Team- Carlos Michel, Landon Prisbrey, Elise Blackmore- Shelley Campeau, Shawn MacVane, Amira Bhalodi- Malcolm Boswell
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