1

Shared challenges

of

Antimicrobial Resistance

and

Emerging Infectious Diseases

Herman Goossens, MD, PhD

University of Antwerp, Belgium

University of Utrecht, the Netherlands

“There are only two infectious diseasesituations that can be consideredinevitable, serious pandemic threats: influenza and antimicrobial resistance”

Osterholm and Olshaker,

Diedliest enemy: our war against killer germs, March2017.

Shared global challenges

of AMR and EID

3

Antimicrobial

resistance

Emerging Infectious

Diseases

• Fast completion of

clinical studies;

• Largest need in

bacterial infections

(antibiotic

resistance)

• Rapid initiation and

completion of

clinical studies;

• Mostly virus

infections

Hence, need for

operational high

quality large-scale

clinical trial research

infrastructure with

European coverage

Similar EARL

barriers

Shared Infrastructure challenges

of AMR and EID

Antimicrobial ResistanceInitiatives in Europe:

IMI – Public Private Partnership

Europe: AMR programme

New Drugs for Bad Bugs:

• Part of the Action Plan against

the increased threats from

AMR

• Launched by the European

Commission in Nov 2011

• Vision: delivering a pipeline of

new antibacterial agents to

patients

Innovative Medicines Initiative:

• Largest public-private (EU-

EFPIA) partnership in life

science R&D

• Speed up the development

of better and safer medicines

for 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: Combatting Bacterial

Resistance in Europe

Four consortia:

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

6

CDI

7

Slovenia: 3 hospitals; 3

laboratories

Albania: 8 hospitals; 9 laboratories

Austria: 11 hospitals; 6 laboratories

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

Bosnia and Herz.: 7 hospitals; 5 laboratories

Bulgaria: 15 hospitals; 14 laboratories

Croatia: 15 hospitals; 10 laboratories

Cyprus: 1 hospitals; 1

laboratory

Czech Republic: 25 hospitals;

20 laboratories

Denmark: 8 hospitals; 6

laboratories

Estonia: 5 hospitals; 2

laboratories

Finland: 9 hospitals;

1 laboratory

France: 93 hospitals; 56

laboratoriesGeorgia: 1 hospital

Germany: 53 hospitals; 54

laboratories

Greece: 44 hospitals; 36 laboratories

Iceland: 1 hospital; 1 laboratory

Ireland: 10 hospitals; 4 laboratoriesIsrael: 20 hospitals; 15 laboratories

Italy: 53 hospitals 27 laboratories

Italy: 53 hospitals; 27 laboratories

Kosovo: 4 hospitals; 5 laboratories

Latvia: 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 laboratories

Switzerland: 11 hospitals; 4 laboratoriesTurkey: 52 hospitals; 48 laboratories

Ukraine: 1 hospital

United Kingdom: 93 hospitals; 29 laboratories

COMBACTE network infrastructure(March 2017)

hospitals827

laboratories583

countries42

Overview COMBACTE studies

8

Observational Interventional

Therapeutic

RCT

SAATELLITEEVADE

OVERCOMERESTORE-IMI

REVISIT

Single arm

REJUVENATE

ASPIRE-ICUASPIRE-SSIANTICIPATE

CTTI-HABP-VABPRESCUING

EURECA

REMAP-CAP(PREPARE)

Platform Trial

COMBACTE Clinical studies

9

January 2018: 8070 patients enrolled

Study name Sponsor Patients Type Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

ASPIRE-ICU UMCU ICU_VAP Epi

SAATELLITE AZ/MI ICU RCT

ASPIRE-SSI UMCU Various Epi

WP6E tbd AZ/MI ICU RCT

ANTICIPATE DaV Various EpiWP8D MedComp ICU RCT /210

EURECA SAS Various Epi

REJUVENATE Pfizer ICU+ RCTREVISIT Pfizer ICU+ RCT /300

EVADE AZ/MI ICU_VAP RCT

WP4B AZ/MI ICU_VAP RCT /980

RESCUING ICS-HUB cUTI Epi 1013 (recruitment completed)

WP6G AiCuris cUTI RCT /240WP6H AiCuris cIAI RCT /225

COMBACTE WP1 UnivLeeds Epi /tbc

CDI 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 230/536

HABP/VABP CTTI HAP/VAP Epi 1006/1000Colistin OVERCOME NIH ICU RCT 157/444 (outside of Europe)

preparation phase trial period 8070

70/285

425/1500

746/20007/4000

40/40

20182014 2015 2016 2017

205/285

1341/2000

580/5000

1019/1000

1368/2000

2019

PREPARE

COMBACTE

NET

COMBACTE

MAGNET

COMBACTE

CARE

recruitment completed

recruitment completed

recruitment completed

recruitment completed

Participation COMBACTE studiesHospitals in 27 countries participate in 13 clinical studies

0 20 40 60 80 100 120

United Kingdom

Ukraine

Turkey

Switzerland

Spain

Serbia

Romania

Portugal

Poland

Netherlands

Montenegro

Kosovo

Italy

Israel

Ireland

Hungary

Greece

Germany

France

Estonia

Czech Republic

Croatia

Bulgaria

Bosnia and Herzegovina

Belgium

Austria

Albania

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 the

IMI/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 lower priority / non core business– Risk of low staffing headcount and experience

– Timelines seen as less critical

• High proportion of Academic sites create additional Difficulties / requirements for Investigator grants, training and equipment

• KPIs / KQIs need to be stronger and leading

11

David Hughes, Senior Global Program Head, Anti-infectives

My lessons learned on role of diagnostics

12

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-spotsPotential 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

Emerging Infectious Diseases Initiatives in Europe:

DG Research

Responses to Infectious Diseases epidemics

14

Infe

cted

pat

ien

ts

Public Health response

Preclinical research response

time

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 the

European Union

PREPARE: Platform foR European Preparedness

Against (Re-)emerging Epidemics

2014-2021

Partners:

Academia, clinical trial

networks, industry

societies

Our mission

Coordinator:

Herman Goossens

(University of Antwerp)

Deputy Coordinator:

Menno de Jong

(Academic Medical Center

Amsterdam)

To establish PREPARE as the European

clinical research framework

• for harmonised large-scale clinical

research studies on infectious diseases

• prepared to rapidly respond to any

severe infectious disease outbreak

• providing real-time evidence for clinical

management of patients and for

informing public health responses

Funded by the

European Union

Clinical studies in PREPARE

Three observational studies: Multi-centre EuRopean study of

MAjor Infectious Disease Syndromes (MERMAIDS) in primary care

and 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-controlled Interventional Trial on Influenza-Like-Illness (ILI) in Primary Care (ALIC4E)

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

Funded by the

European Union

PREPARE Clinical studies

February 2018: 4531 patients enrolled

Funded by the

European Union

Primary Care Network for ALIC4E:Build on GRACE

European

countries

ALICE4E Primary Care Network

participants in

PREPARE ALIC4E

study600 19 Primary

care sites

>1100 >20 000

> 1700

patients included in 16 countries in

GRACE study

particpants in R-GNOSIS study

Funded by the

European Union

Outcomes

A1Antibiotic

trialOutcomes

Macrolide

trial

Patient

Randomized, Embedded, Multifactorial, Adaptive Platform

Steroid

trialOutcomes

Antibiotics

Macrolide

Steroids

Outcomes

A2

A3

B1

B2

C1

C2

Clinical Trial Networks (CTN):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

Public and Private Sector Support for CTN

“… we commit to: Support the creation of open and sustainable

clinical trial networks globally, with our expertise and experience. As

proposed by the AMR Review, this would build on work started in

Europe and US with the goal of improving the speed and efficiency

of conducting clinical trials”

Industry roadmap for Progress on Combating Antimicrobial Resistance, Sep 20, 2016

“we encourage governments to consider the need for establishing a global

clinical studies network on drug resistance that provides access to a large

clinical research infrastructure for the design, coordination and conducting

of clinical trials and studies in cooperation with the existing global experts

networks to ensure the common benefit of the outcomes”

G7 Health Ministers’ Meeting, Kobe, Japan,

11-12 September 2016

Our Vision: To efficiently generate rigorous evidence

for new or improved diagnosis, prevention and treatment of infections and to better

respond to infectious disease threats. This is facilitated by a European

multidisciplinary clinical research network and innovative research approaches.

ECRAID: European Clinical Research Alliance on

Infectious Diseases

24

Building an inclusive, multidisciplinary

network

Clin-Net827 hospitals in 42

European countries.

Lab-Net583 microbiology labs in

42 European countries

600 Primary care sites in

19 European countries

Stat-Net

European network of

experts in statistical

research on IDs

European network of

experts in epidemiological

research on IDs

Epi-Net

Network of 90 paediatric clinical sites in 18 countries

Detailed Design of

Business plan and

operating model

Construct &

Implement

2016

High level Design

High Level design

completed

end of current

funding PREPAREend of current funding

COMBACTE-Net

20222017 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

26

Antimicrobia

l Resistance

First Steps towards integration PREPARE and COMBACTE

27

Antimicrobia

l Resistance

ECRAID database

• Data related to clinical site performance captured for both COMBACTE and PREPARE

• Both projects capturing data related to turnaround time for ethics, regulatory and other local approvals and for contracting.

• Projects working together to create a combined system for monitoring clinical site performance.

28

Antimicrobia

l Resistance

ECRAID database: 3 functions

1. Performance indicators: turnaround time for all approvals (ethics, other regulatory and local approvals) and contracting: allows for (rapid) site selection

2. Systematically capture barriers and solutions: can mitigate barriers, share solutions

3. Map variability in practice across Europe: reference guide for setting up future studies -builds ‘institutional memory’ so that experience and learning can inform set up of future studies.

29

Antimicrobia

l Resistance

Process of development

• PREPARE and COMBACTE – regular meetings

• Review of current processes –identifying an integrated process

• Documenting standard operating procedure for integrated system

• Pilot using REMAP-CAP clinical sites

• Refine through lessons learned from REMAP-CAP

30

The power of a comprehensive real-time

database of hospital sites

Mock up slide of site selection and forecasting

inclusion rates for VAP trial

What ECRAID could offer

• Clinical Trial Network for infectious diseases in hospital care and primary care, adults and children

• European coverage and globally embedded

• Faster and easier clinical research

• As a single-point of access into a high quality, business oriented research network

• Rapid access to and knowledge of well trained clinical(hospital/primary care) and laboratory (specialized androutine) sites

• An active network, continuously including patients in platform trials

• Focus on services that alleviate the administrative, technical and organizational burden in clinical research and reduce timelines (lower costs, faster processes)

• Strong practice based scientific expertise and commitment

Benefit for the EU and its Citizens: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. AdaptivePlatform Trials)

• Creates innovation of the public and private (e.g. SMEs) sector

• 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

• Results in improving quality of care delivery to ourpatients (next slide)

32

Benefit for EU Patients: Being treated in a hospital active in clinicalresearch is strongly associated with better

outcomes

Downing A, et al. Gut 2016

Final remarks…

34

Unless we seize this unique, once-in-a-lifetime opportunity to

gear up the public and private resources already invested in

COMBACTE, and PREPARE, we may one day stand accused of

having turned our back on the prospect of the effective

investigation and treatment of infections for our citizens.

It is imperative that governments, industry and academia effect

a far more robustly step change in their commitment and

capability partnerships than it has done so far to tackle

pandemic infectious diseases.