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Diagnostic solutions for antimicrobial resistance:

Identifying unmet clinical needs

Herman Goossens Laboratory of Medical Microbiology

VAXINFECTIO University of Antwerp

University Hospital Antwerp

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I identified eight (because I was only given 20 min) unmet

diagnostic needs for antimicrobial resistance and

(sometimes) will provide solutions

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We need rapid diagnostic tests to reduce antibiotic prescribing and hence the selective pressure

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•  80% of antibiotics are prescribed in primary care •  Acute RTIs most common reason for GP consultation •  Most infections are due to viruses •  Evidence of over prescribing by GPs •  Overprescribing is linked to increased antibiotic resistance

Goossens et al, 365: 579-87, Lancet 2005

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We need rapid diagnostic tests to decrease broad-spectrum toxic antibiotics and hence morbidity and mortality

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Kettetal,LancetInfectDis2011;

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Vicious circle within the HCA-pneumonia guidelines

Yu,LancetInfectDis2011;11:248-52

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We need “diagnostic-friendly” healthcare delivery systems

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‘Surgical-site S. aureus infections acquired in the hospital can be reduced by rapid screening & decolonizing of nasal carriers’ Bode L et al. NEJM 2010;362:9-17

Bode L et al. NEJM 2010;362:9-17

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We need rapid diagnostic tests to enrich patient population in clinical trials: - to reduce costs - to develop narrow spectrum

antibiotics

4

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A P. aeruginosa - Focused VAP Programme

•  Standard non-inferiority Phase 3 study1 – Need 336/arm or 672 evaluable patients total

•  If only 10% yield P. aeruginosa, – We need 6,720 patients … for ONE trial!

Courtesy: John Rex

1Assumes 80% success rates, 10% margin, and 90% power.

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Examples of clinical trials in IMI where rapid diagnostics are needed

•  Phase II RCT with anti-α-toxin staphylococcal antibody MEDI4893 for prevention of HABP/VABP (MedImmune): – Diagnostic test needed: rapid detection of S. aureus in ETA

•  Phase II RCT trial with anti-pseudomonas antibodies MEDI3902 for prevention of HABP/VABP (MedImmune) – Diagnostic test needed: rapid detection of P. aeruginosa in

ETA

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S. aureus ETA Rapid Dx Weighting

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Rapid Diagnostic for POCT for P. aeruginosa colonization in endotracheal aspirates in patients on a mechanical ventilator Required diagnostic specifications: • High sensitivity (<102 cfu/mL) to identify patients as they become colonized (versus infected/pneumonia) • High specificity also desired • Validated for endotracheal aspirate samples (ETA) • Minimal hands on time (<30 min) for specimen processing • Rapid turn-around time for result (<2 hr) • Test can be run on demand without need for batching • Test can be performed outside of microbiology (ICU or step down unit) • Low cost (<$40)

• Supply up to 100 instruments to sites across Western Europe • Service and Technical support for the instruments and assay kits • Supply ~x,xxx tests between 2016 and 2020

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My lessons learned on role of diagnostics

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to aid patient enrollment in COMBACTE clinical trials with narrow-spectrum drugs (4/9 intervention trials)

Pharma: limited number of organisms in a specific sample Diagnostic companies: broad range tests

Schism between pharma and diagnostic

companies

How will test be used? What are required performance characteristics to aid patient enrolment?

Purchasing and logistical challenges Challenges to organise, track and train HCW Maintenance, Q-controls and test support Miscommunication between pharma, diagnostic company, micro lab, and CRO

Unclear exploitation How is the test developed into labeled product? Who will pay for the test?

Regulatory blind-spots Potential regulatory needs discussed too late and/or conflicting feed-back

Demand of pharma to perform test outside of

microbiology lab

Unclear function and performance

characteristics

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We need to drive reimbursement prices of rapid diagnosticstofightAMRbasedonby their medical&societalvalue

5

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Fast systems Alere: i Isothermal amplification: NEAR 15 min Influenza test

Handheld devices Micronics: PanNAT 1 hour 3 targets test H: 20 cm / Depth= 34.5 cm / Width: 12 cm

Tsunami of instruments

Multiple targets bioMérieux: FilmArray Reverse transcriptase Turn RNA into cDNA TAT: 1 hour

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We need to address psychological, social, and organisational barriers to support the uptake of diagnostics for antimicrobial stewardship

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GRACE Intervention Trial

•  Countries: UK, Poland, Spain, the Netherlands, Belgium

•  Baseline in 6,774 patients and 4,358 patients post-test

•  2x2 factorial design (Communication, CRP, Usual care)

Usual care Communication Usual care Usual care Communication training

CRP CRP training CRP + Communication training

58% 41%

31% 35%

Little et al, Lancet 2013

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Figure 2. Mean (SD) CRP concentration by microbiological diagnosis for LRTI subjects with (n=141) and without CAP (n=2963).

Mean (SD) CRP concentration by microbiological diagnosis for LRTI subjects with (n=141) and without CAP (n=2963)

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Confidential; manuscript in preparation

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Long road to successful uptake of diagnostics

• Rapid and cheap test available • Demonstrated benefit in reducing antibiotic

prescribing in a multinational, cluster, randomized, factorial, controlled trial (published in The Lancet)

•  Supported by microbiological and cost-effectiveness research

• Reimbursed in the Netherlands •  Yet not used in primary care

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We need different business models to support uptake of new, innovative, and expensive diagnostics

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NEXT GENERATION SEQUENCING

Epidemiology and Phylogeny of an Outbreak of MRSA Sequence Type 2371 at a Baby Unit

HarrisLID2013;13:130-36

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Value-based procurement of IVDs to address AMR •  Currentapproachtoprocurementbasedonprice-basedpurchasesreducesinnovation,discouragestheadoptionofnewtechnologies,makesthemarketunattractiveforSMEs

•  NewEUdirectiveonpublicprocurementinFebruary2014–  Moveawayfromup-frontprice-onlypurchasecosts–  Factorsinoutcome,quality,totalcostsacrosstheproductlifecycleandbroadersocio-economiccriteria

•  ItwouldencourageIVDcompaniestoinvestininnovation– Minimumvolumeassurances–  Enablingthemarkettorespondtoserviceneeds

•  ShouldbebasedonHTA(nextslides)•  Couldincentiviseclinicalvalueofdiagnostics•  Shouldaccelerateregulatoryapproval•  ShouldfacilitatebetterreimbursementofIVDtestsaddressingAMR•  Shouldbeaccompaniedwithmeasurestoaddresssocial,psychological,organizationalbarriers

HTA Reports by medical technology type

2014 2015 2016

TotalHTAreports 372 372 304

MedicalDevices(kneereplacement,spinalcordstimulation,silverdressing) 289 293 223

IVDs(e.g.serumbiomarkers,genetictesting,screeningforhumanpapillomavirus) 28 16 40

Imaging(e.g.PET/CT,MRI,Echocardiography) 29 25 22

Others(e.g.spermwashing,ReCellSpray-OnSkin,sterilewaterinjections,) 26 38 19

MedicalDevices78%

Imaging8%

IVDs7%

Other7%

2014

MedicalDevices79%

Imaging7%

IVDs4%

Other10%

2015

StatisticbasedonSynergusdatabase(link)*EU28+Switzerland+Norway

MedicalDevices74%

IVDs13%

Imaging7%

Other6%

ChartTitle

HTA for IVD (of ID / AMR) •  HTAofIVDsrepresented8%ofallHTAin2014-2016;HTAofnewIVDsinlessthan1%(Synergusdatabase)

•  HTAforIVD/ID/AMRareverycomplex(screening,diagnosis,treatment,prognosis,monitoring)

•  HTAdatarequirements/acceptanceasevidence,andtimepointsduringlifecycle,notalignedbetweencountriesandevenwithincountries

•  ResponsibilityanddecisionpowervariesbetweenHTAagencies•  HTAarerarelyusedtoinformdecisionatnational,regional,hospitallevel,communitylevelonaccess,reimbursement,use,valueofIVD

•  Need“fit-for-purpose”pragmatic,streamlined,standardHTAofIVDsaddressingAMR

•  Prepare public procurement of innovative rapid diagnostics for tailoring antimicrobial treatment

•  Deadline 18 April 2018

•  Build NGS platform for use of NGS tests in routine diagnostics for personalized medicine

•  Deadline 16 April 2019

•  Build fit-for-purpose HTA models •  Focus on personalized medicine and companion diagnostics •  Deadline 18 April 2018

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We need Clinical Trial Networks to demonstrate the clinical evidence of diagnostics

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3535

•  Per Performance Plan

•  PP to address Clinical Evidence, consisting of:

–  Scientific Validity: Literature Search Documented

–  Analytical Performance: Per applicable Requirements

–  Clinical Performance: Per clinical study, if necessary; Population

effects

•  Performance Report updated continuously throughout lifecycle

New IVD Regulation: Areas of Greatest Impact: Performance Evaluation

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Slovenia: 3 hospitals; 3 laboratories

Albania: 8 hospitals; 9 laboratoriesAustria: 11 hospitals; 6 laboratories

Belarus: 1 hospital; 2 laboratoriesBelgium: 22 hospitals; 17 laboratories

Bosnia and Herz.: 7 hospitals; 5 laboratoriesBulgaria: 15 hospitals; 14 laboratories

Croatia: 15 hospitals; 10 laboratories

Cyprus: 1 hospitals; 1 laboratory

Czech Republic: 25 hospitals; 20 laboratoriesDenmark: 8 hospitals; 6 laboratories

Estonia: 5 hospitals; 2 laboratories

Finland: 9 hospitals; 1 laboratory

France: 93 hospitals; 56 laboratories

Georgia: 1 hospital

Germany: 53 hospitals; 54 laboratories

Greece: 44 hospitals; 36 laboratories

Iceland: 1 hospital; 1 laboratoryIreland: 10 hospitals; 4 laboratories

Israel: 20 hospitals; 15 laboratoriesItaly: 53 hospitals 27 laboratories

Italy: 53 hospitals; 27 laboratories

Kosovo: 4 hospitals; 5 laboratoriesLatvia: 6 hospitals; 3 laboratories

Lithuania: 1 hospital; 2 laboratories

Luxembourg: 1 hospital; 1 laboratory

FYROM: 5 hospitals; 20 laboratories

Moldova: 6 hospitals; 2 laboratories

Montenegro: 8 hospitals; 10 laboratories

Netherlands: 34 hospitals; 26 laboratories

Norway: 3 hospitals; 2 laboratories

Poland: 22 hospitals; 5 laboratories

Portugal: 30 hospitals; 14 laboratories

Spain: 68 hospitals; 59 laboratories

Romania: 29 hospitals; 20 laboratories

Serbia: 30 hospitals; 26 laboratories

Slovakia: 10 hospitals; 5 laboratories

Sweden: 10 hospitals; 3 laboratoriesSwitzerland: 11 hospitals; 4 laboratories

Turkey: 52 hospitals; 48 laboratoriesUkraine: 1 hospital

United Kingdom: 93 hospitals; 29 laboratories

IMI- COMBACTE network infrastructure (March 2017)

hospitals 827

laboratories 583

countries 42

COMBACTE Clinical studies

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January 2018: 8070 patients enrolled

Studyname Sponsor Patients Type Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4ASPIRE-ICU UMCU ICU_VAP EpiSAATELLITE AZ/MI ICU RCTASPIRE-SSI UMCU Various EpiWP6Etbd AZ/MI ICU RCTANTICIPATE DaV Various EpiWP8D MedComp ICU RCT /210

EURECA SAS Various EpiREJUVENATE Pfizer ICU+ RCTREVISIT Pfizer ICU+ RCT /300

EVADE AZ/MI ICU_VAP RCT WP4B AZ/MI ICU_VAP RCT /980RESCUING ICS-HUB cUTI Epi 1013(recruitmentcompleted)WP6G AiCuris cUTI RCT /240WP6H AiCuris cIAI RCT /225

COMBACTE WP1 UnivLeeds Epi /tbcCDI WP2 UnivLeeds /tbc

MERMAIDS UOx ARBO Epi MERMAIDS UOx ARI Epi REMAP-CAP UMCU ICU adaptRCT

Shionogi CREDIBLE-CR Shionogi RCT 20/150MK-7655A RESTORE-IMI2 Merck ICU RCT 230/536HABP/VABP CTTI HAP/VAP Epi 1006/1000Colistin OVERCOME NIH ICU RCT 157/444(outsideofEurope)

preparationphase trialperiod 8070

70/285

425/1500746/20007/4000

40/40

20182014 2015 2016 2017

205/2851341/2000

580/5000

1019/1000

1368/2000

2019

PREPARE

COMBACTENET

COMBACTEMAGNET

COMBACTECARE

recruitment completed

recruitment completed

recruitment completed

recruitment completed

Time for a Paradigm Shift of Infectious Diseases Clinical Research

Expensive

Inefficient

Rigid design

One-off initiatives

Alienated patients

Irregular

Efficient

Coordinated and sustainable

Patient-centered

Participatory and precision medicine

Responsive and adaptive

Detailed Design of Business plan and operating model

Construct & Implement

2016

High level Design

High Level design completed

end of current funding PREPARE

end of current funding COMBACTE-Net

2022 2017 2018 2019 2020 2021

FUNDING THROUGH IMI2 FOR Dx PART (VALUE-Dx – 28.2.2018)

FUNDING FOR ID STUDIES TO BE ACQUIRED FROM PUBLIC AND PRIVATE SECTOR

FUNDING THROUGH H2020 (CSA call – 18.4.2018)

ECRAID: Our plan and timelines

•  Develop business plan to ensure sustainability of a clinical trial network •  Build on PREPATE and COMBACTE •  Deadline 18 April 2018

•  Develop a business plan for CTN on diagnostics •  Demonstrate the clinical and societal value of rapid diagnostics for AMR •  Build around CA-ART •  Deadline 28 February 2018

Unique opportunities for pharma, academia, the EU and its citizens

•  Incentiveforpharmatoinvestinantibioticdiscovery• Allowstobroadenthespectrumtootherantimicrobialdrugs,vaccines,anddiagnostictests

• Allowsinvestigatordriventrials• Allowsnewmodelsofclinicaltrials(e.g.AdaptivePlatformTrials)

• Createsinnovationofthepublicandprivate(e.g.SMEs)sector

• Allowsrapidclinicalresearchresponseintheeventofapandemicthreat

• Resultsinimprovingqualityofcaredeliverytoourpatients

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Many thanks!