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ECRAID:European Clinical Research Alliance on

Infectious Diseases

Herman Goossens, MD, PhDUniversity of Antwerp, Belgium

University of Utrecht, the Netherlands

COMBACTE-NetLAB-Net coordinator

PREPARECoordinator

Agenda

• COMBACTE AMR clinical trials• PREPARE Pandemic clinical trials• ECRAID: European Clinical Research

Alliance for Infectious Diseases• Concluding remarks

Antimicrobial Resistance

Established Medicines and Anti-infectives Development Unit

Current major “headaches” thatkeep pharma awake at night• Regulatory hurdles getting higher – more data required• ICH GCP guidelines are tighter• Higher competition for “treatment naive” patients between

Biopharma• More difficult contracting conditions with sites• Complexity of supply chain

– Cold chain, import / export, ancillary supplies

• Trial designs becoming more complex (more data collected& analysed) → drives cost and timelines

• Fear of adopting obsolete technology• Greater patient education and awareness creating need for

better ICFs

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David Hughes, Senior Global Program Head, Anti-infectives

Europe: AMR programme

New Drugs for Bad Bugs:• Part of the Action Plan against

the increased threats fromAMR

• Launched by the EuropeanCommission in Nov 2011

• Vision: delivering a pipeline ofnew antibacterial agents topatients

Innovative Medicines Initiative:• Largest public-private (EU-

EFPIA) partnership in lifescience R&D

• Speed up the developmentof better and safer medicinesfor patients

• IMI-1: part of EU FP7, 2008 -2014, 2 billion Euro

• IMI-2: part of EU H2020, 2014 –2024, 3.3 billion Euro

EFPIA: European Federation of Pharmaceutical Industries and Associations

COMBACTE: CombattingBacterial Resistance in EuropeFour consortia:

Two (shared Public-Private) objectives:Create a self-sustaining antibacterial development network• Expanding research and laboratory networks• Optimal alignment of clinical trials with investigator sites• Obtain clinical and epidemiological data

Increase efficiency of antimicrobial drug development• Align clinical trials with cutting edge molecular mehodologies and trial design• Deliver clinical trials with various candidate compounds from pharmaceutical

companies

CDI

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Slovenia:3 hospitals;3laboratories

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

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

BosniaandHerz.: 7 hospitals;5laboratoriesBulgaria:15hospitals;14laboratories

Croatia:15hospitals;10laboratories

Cyprus:1 hospitals;1laboratory

CzechRepublic:25 hospitals;20 laboratoriesDenmark: 8 hospitals;6laboratories

Estonia:5hospitals;2laboratoriesFinland:9 hospitals;1 laboratoryFrance: 93 hospitals;56laboratories

Georgia:1hospital

Germany: 53 hospitals;54laboratories

Greece: 44 hospitals;36laboratories

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

Israel:20 hospitals;15laboratoriesItaly:53 hospitals27laboratories

Italy:53 hospitals;27laboratories

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

Lithuania:1hospital;2laboratoriesLuxembourg:1 hospital;1laboratory

FYROM:5 hospitals;20laboratories

Moldova:6hospitals;2laboratories

Montenegro:8hospitals;10laboratories

Netherlands:34hospitals;26laboratories

Norway:3 hospitals;2laboratories

Poland:22 hospitals;5laboratories

Portugal:30 hospitals;14laboratories

Spain:68 hospitals;59laboratories

Romania:29 hospitals;20laboratories

Serbia:30 hospitals;26laboratories

Slovakia:10 hospitals;5laboratories

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

Turkey: 52 hospitals;48laboratoriesUkraine:1 hospital

UnitedKingdom:93 hospitals;29laboratories

COMBACTE network infrastructure(March 2017)

hospitals827

laboratories583

countries42

The 4 pillars of theCOMBACTE Clinical StudiesCLIN-NetHigh-quality clinical research network in all European countries with certification criteria and GCPTraining programLead: University Medical Center Utrecht, M. Bonten

LAB-NetHigh-quality laboratory network in all European countries with assessment of existing laboratorymethods, quality assessment system, specimens and strains repositoryLead: University of Antwerp, H. Goossens

STAT-NetNetwork to improve clinical trials delivery, perform advanced biostatistical and PK/PD modellingstudies, evaluate novel clinical design strategies using modern biostatistical conceptsLead: University of Geneva, S. Harbarth

EPI-NetNetwork to identify and map existing surveillance systems, to establish frameworks for datacollection to support antibacterial drug developmentLead: University of Tübingen, E. Tacconelli

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5518 patients enrolled

COMBACTE Clinical Studies

Participation COMBACTE studiesHospital sites in 27 countries participate in 13 clinical studies

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0 20 40 60 80 100 120

United KingdomUkraineTurkey

SwitzerlandSpain

SerbiaRomaniaPortugal

PolandNetherlandsMontenegro

KosovoItaly

IsraelIreland

HungaryGreece

GermanyFrance

EstoniaCzech Republic

CroatiaBulgaria

Bosnia and HerzegovinaBelgiumAustriaAlbania

ANTICIPATE

ASPIRE-ICU

ASPIRE-SSI

CREDIBLE-CR

CTTI

EURECA

EVADE

OVERCOME

REMAP-CAP

REJUVENATE

RESCUING

SAATELLITE

WP2B ATM-AVI

Established Medicines and Anti-infectives Development Unit

Lessons learned from theIMI/NVS/CRO collaboration to date• Tripartite contracts are slower to align and sign• Multiple contacts and “ownership” make issue resolution

more complex– Clear Governance and Oversight documentation very important

• External Service Providers (ESPs) may treat IMI as lowerpriority / non core business– Risk of low staffing headcount and experience– Timelines seen as less critical

• High proportion of Academic sites create additionalDifficulties / requirements for Investigator grants, training andequipment

• KPIs / KQIs need to be stronger and leading

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David Hughes, Senior Global Program Head, Anti-infectives

Epidemic ID clinical research

Clinical research responses to ID epidemicsare usually fragmented and too late

time

Public Health Response

Preclinical Research Response

Clinical Research Response

time

Public Health Response

Preclinical Research Response

Clinical Research Response

PREPARE:Fast-forward clinical research during ID

epidemics to improve patient management

Funded by theEuropean Union

PREPARE: Platform foR European PreparednessAgainst (Re-)emerging Epidemics

2014-2021Partners:Academia, clinical trialnetworks, industrysocieties

Our mission

Coordinator:Herman Goossens(University of Antwerp)

Deputy Coordinator:Menno de Jong(Academic Medical CenterAmsterdam)

To establish PREPARE as the Europeanclinical research framework

• for harmonised large-scale clinicalresearch studies on infectious diseases

• prepared to rapidly respond to anysevere infectious disease outbreak

• providing real-time evidence for clinicalmanagement of patients and forinforming public health responses

Funded by theEuropean Union

Clinical trials in PREPAREThree observational studies: Multi-centre EuRopean study ofMAjor Infectious Disease Syndromes (MERMAIDS) in primary careand hospitalized adult and pediatric patients, comprising:

- Sepsis-like syndrome (SLS) in infants and Acute respiratory infection(ARI) in children (PED-MERMAIDS)- Acute Respiratory Infections in Adults (ARI)- Arboviral compatible febrile illness

Two Adaptive platform design studies:- European multi-centre double-blinded randomised placebo-controlledInterventional Trial on Influenza-Like-Illness (ILI) in Primary Care(ALIC4E)

- Randomized, Embedded, Multifactorial Adaptive Platform trial forCommunity-Acquired Pneumonia(REMAP-CAP)

Funded by theEuropean Union

> 800 hospitals> 40 European countries

Hospital Care Network:Build on COMBACTE, PENTA and other networks

Funded by theEuropean Union

Primary Care Network:Build on GRACE

Europeancountries

ALICE4E Primary Care Network

participants inPREPARE ALIC4Estudy600 19Primary

care sites

>1100>20 000

> 1700

patients includedin 16 countries inGRACE studyparticpants in R-GNOSIS study

ECRAID:

European Clinical ResearchAlliance on Infectious Diseases

= a paradigm shift of Clinical Research onInfectious Diseases in Europe

ECRAID build on COMBACTE andPREPARE

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Antimicrobialresistance

Emerging InfectiousDiseases

• Fast completion ofclinical studies;

• Largest need inbacterial infections(antibioticresistance)

• Rapid initiation andcompletion of

clinical studies;• Mostly virus

infections

Need for operationalhigh quality large-scale clinical trial

research infrastructurewith European

coverageSimilar non-scientific

barriersOverlappingstakeholders

ChristopherButlerUniversity of Oxford

Oliver CornelyUniversity HospitalCologne

Bruno FrançoisUniversity MedicalCenter Limoges

Stephan HarbarthUniversity HospitalGeneva

Peter HorbyUniversity of Oxford

Menno de JongAcademic MedicalCenter

Jesús RodríguezBañoUniversity of Sevilla

EvelinaTacconelliUniversity of Tuebingen

Herman GoossensUniversity AntwerpCoordinator PREPARE

Marc BontenUMC UtrechtCoordinator COMBACTE

Frank DeegeConsulting

Chantal vanLitsenburgConsulting

ECRAID Ad-Hoc (!) Working Group:PREPARE and COMBACT Partners

Coordination Team Working Group

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Building an inclusive, multidisciplinarynetwork

Clin-Net827 hospitals in 42European countries.

Lab-Net583 microbiology labs in42 European countries

600 Primary care sites in19 European countries

Stat-NetEuropean network of

experts in statisticalresearch on IDs

European network ofexperts in epidemiologicalresearch on IDs

Epi-Net

Network of 90paediatric clinicalsites in 18 countries

Statistical analyses andsupport

Epidemiologicalresearch and

support

Laboratoryresearch and

support

Supporting services

Training,education andcapacitybuilding

Biobanking

ICT and datamanagement

Service enabling capabilities

Clinical Research and Services

Clinical research

Protocol Statistical analysis plan

(SAP) Database Training materials Interaction with

regulatory agencies

Study design Statistical

analysis Study report Manuscript

Study report

Site selection and training End point quality

assurance

Data management Site monitoring Safety monitoring

Study execution Trial progress review Recruitment/reten-

tion strategies

Protocol modification Protocol deviation review SAP validation

At UA ICFAgreement onuse after study

StudiesSamples (not considering

multiple aliquots) DNA extracts StrainsGRACE 13.305 9.199 784 yes yes

MOSAR 12.222

SATURN 5.273 27.539

R-GNOSIS 6.218 some studies

Kosovo study 1.711 1.466 no

ASPIRE-ICU 37.400 1.500 Yes Yes

ASPIRE-SSI 24.118 5.000 Yes Yes

SAATELLITE 3.234 1.293 Yes

ANTICIPATE 1.500 Yes

EURECA 800 Yes

EVADE 3.444 1.377 Yes

Total 57.318 9.199 45.501

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Collection of materials at the Laboratory of MedicalMicrobiology of the University Antwerp from EU studies

Hundreds of thousands of individuals have freely donated samples inexchange for the promise of advancing medical research.

But most of these samples are …. sitting unused in lab freezers.

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The power of a comprehensive real-timedatabase on hospital sites

Mock up slide of site selection and forecasting inclusion rates for VAP trial withPseudomonas specific antibiotic

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Detailed Design ofBusiness plan andoperating model

Construct &Implement

2016

High levelDesign

High Level designcompleted

end of currentfunding PREPARE

end of current fundingCOMBACTE-Net

20222017 2018 2019 2020 2021

FUNDING THROUGHIMI2 FOR AMR PART

FUNDING FOR EID STUDIESTO BE ACQUIRED

FUNDING THROUGH H2020

ECRAID High-level Roadmap

EU- Clinical Trial Network - Public Private Partnership• Provides unique opportunities:

• Incentive for pharma to invest in antibiotic discovery• Allows to broaden the spectrum to other antimicrobial drugs, vaccines,

diagnostic tests• Allows investigator driven trials• Allows new models of clinical trials (e.g. Adaptive Platform Trials)• Creates innovation of the public and private (e.g. SMEs) sector• Results in improving quality of care delivery to our patients• Allows rapid clinical research response in the event of a pandemic

threat• Reduces pressure on public sector budgets• Results in increased jobs for our European citizens

• Should develop rigorous performance criteria in terms of the interest of theEuropean citizen and pharma (e.g. delivery on-time and on budget ofclinical trials)

• Clinical trial research investments must reach EU citizens

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ECRAID