Combacte Magazine 2018

COMBACTE Magazine 2018

42 Is there life after COMBACTE? There is vast potential for a more sustainable future

Combatting Bacterial Resistance in Europe

08 RESCUING CELEBRATING THE ENROLMENT OF 1,000 PATIENTS Study results are now in the process of being analyzed and published

16 MUTUAL MOTIVE

Driven to develop new treatments

36 THE ART OF RECRUITING

There can be no research without patients. But how does one find suitable candidates?

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QUOTE

INNOVATIVE MEDICINES INITIATIVE

AWARE

'Promoting the achievements of COMBACTE - and the benefits and the necessity of large-scale publicprivate collaboration in precompetitive pharmaceutical R&D - is crucial for the engagement of stakeholders in the project, for maximization of the impact of the project achievements and for the long-term future of the projects and the Innovative Medicines Initiative' Innovative Medicines Initiative Read all about COMBACTE’S COMMUNICATIONS on page 52

FOREWORD

EUROPEAN COMMISSION

COMMITTED

Robert-Jan Smits As we know the health threat posed by antimicrobial resistance has repercussions not just within the EU but also beyond, and if unchecked will soon reach crisis proportions. This is why in 2011 the European Commission launched an action plan inspired by the One Health initiative. Plans without action are not much good - and so I am especially impressed by the progress being made by COMBACTE as part of the Innovative Medicines Initiative’s (IMI) New Drugs for Bad Bugs program.

It’s a major achievement to bring together 887 hospitals and 652 laboratories in several European countries to lay a strong foundation on which Europe can build a network for performing high quality clinical trials. And I am sure that by working together with the pharmaceutical industry COMBACTE will help transform Europe’s capacity and readiness to develop new antibiotics.

The 2011 action plan succeeded in stimulating political commitment and action within Member States as well as fostering international cooperation, but more needed to be done. So in June 2017, building on these successes, the Commission launched a new European One Health Action Plan against AMR to tackle this growing challenge.

And in October 2017 the Commission launched the Work Program for Horizon 2020, covering the budgetary years 2018 to 2020 and representing an investment of around €30 billion. A significant part of this investment will be dedicated towards finding innovative solutions for tackling infectious diseases.

Because in this and related areas the Commission is strongly committed to boosting research and innovation.

Robert-Jan Smits Director-General Research & Innovation European Commission

The European Commission is committed to boosting research and innovation against antimicrobial resistance

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TABLE OF CONTENTS

COMBACTE MAGAZINE

08 RESCUING

OVERVIEW

16 MUTUAL MOTIVE

54 INFOGRAPHIC Overview of all COMBACTE projects

The Issue The Challenge The Projects

COLOPHON Issued by the COMBACTE Consortium, March 2018 Chief Editor and Project Management Claire-Marie Martis, COMBACTE Communications office (UMC Utrecht) Concept COMBACTE Communications office (UMC Utrecht) Today, Utrecht JCM Context, Utrecht Design Today, Utrecht Copywriting JCM Context, Utrecht Photography Michiel Spijkers Printing Platform P, Utrecht Contact Questions or suggestions are welcome at info@combacte.com.

Please let us know if you would like to acquire additional copies of COMBACTE Magazine.

Celebrating the enrolment of

A reflection on the collaboration

1,000 patients

between pharmaceutical companies and academics

12 OUR CHOICE: PFIZER LTD The motives of our recent industry partner

14 COMBACTE-CDI A brand new project focussed on understanding Clostridium difficile infections

24 STUDY OVERVIEW A list of all trials and studies of all COMBACTE projects

28 FUNDING Infographic showing the investments per project

32 COMBACTE-MAGNET Molecules against Gram-negative infections in Intensive-care units

36 THE ART OF RECRUITING 5 successful recruiters share their experiences in enlisting candidates

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20 COMBACTE-NET

30 NEXT STAGE TRIALS MY COMBACTE COMMUNITY

Building and maintaining strong

SAATELLITE and EVADE assess the use

networks to improve clinical trials

of antibodies against common venti-

for antibacterials

lator-associated pulmonary infections

38 COMBACTE-CARE

45 MORE SUCCESSFUL TRIALS

Meeting the challenge of carbapenem-resistant

With PPI, trials prove more

Enterobacteriaceae

successful, working together

40 MICROBIOLOGIST & MICROBIOLOGIST Different backgrounds, different motives, same objective

42 IS THERE LIFE AFTER COMBACTE?

13 HALIMA RAKHILA Meet my COMBACTE colleagues

with patients instead of on them

48 NATIONAL COORDINATORS Linking this project to local experts and national institutes

52 COMMUNICATION

There is vast potential for a

Ensuring transparent

more sustainable future

communication in the interests of a bright future

19 JELLE WEST Meet my COMBACTE colleagues

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REFLECTING

NATHALIE MOLL, EFPIA

COMMITTED

A reflection over the years

Unusual partners, committed to the same goals Marc Bonten, academic lead, 2016: “When the call came from IMI on behalf of ND4BB, I, too was skeptical, like the other academics. Why help the pharmaceutical industry develop new antibiotics with European tax money? But I

Marc Bonten, academic lead, 2016: “There wasn’t even a clinical trial network specializing in antibiotic resistance research, which is more complex than research into many other conditions.

The number of infections is relatively small, so assembling a large enough research population is more difficult.

On top of that, doctors must treat infections quickly, so just a few hours remain to start research.”

Nathalie Moll, EFPIA, 2018: “Despite these obvious hurdles, R&D-based pharmaceutical industry continues to invest millions of euros in new antibiotics. But we are in need of appropriate “pull” mechanisms that would reward this, including the creation of the appropriate regulatory frameworks and the introduction of the right incentives across the lifecycle of novel antibiotics and vaccines to stimulate R&D and support innovation.”

instantly saw opportunities for scientific research, my primary motivation to get involved anyway.”

Nathalie Moll, EFPIA, 2018: “We welcomed sincerely the call from IMI, as we are convinced that it is only through comprehensive collaboration with all stakeholders that we can find

Nathalie Moll

Director General, European Federation of Pharmaceutical Industries and Associations (EFPIA)

effective, viable solutions to address antimicrobial resistance (AMR). ND4BB represents an unprecedented partnership between industry, academia and biotech organizations, showing the collective stakeholder commitment to this effort.”

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I am confident we will find effective solutions for this life-threatening problem Marc Bonten, academic lead, 2016: “We bring together Europe’s best academic partners, partly by linking up existing local networks. Partners in regions with less experience in advanced

Marc Bonten, academic lead, 2016: “Our network

research, which often are areas where

enables pharmaceutical companies to develop

resistant bacteria are more frequently

new antibiotics faster, more effectively and more

found, such as Eastern Europe, also

economically. In part because academics have better

receive our assistance.”

knowledge about how to select the right sites, and thanks to our academic background, garner a greater commitment from hospitals and laboratories.”

Nathalie Moll,

Nathalie Moll, EFPIA, 2018:

EFPIA, 2018: “A collaborative

“What industry brings to the table is

approach allows us to make significant inroads into the many

expertise in R&D and a deep under-

common areas, including antibiotic

standing of regulatory processes

stewardship, vaccination and rapid

involved. We are capable of carrying

diagnostics. Yet in order to boost R&D efforts we need to seek out new economic models and market interventions to encourage sustainable investment in this area and improve predictability of the demand.”

Marc Bonten, academic lead, 2016: “I think we collaborate really well, in spite of our inherent different perspectives. We feel we’ve made great strides in just a few years’ time. And we’ve only just begun.

So from that perspective, we have a bright future.”

out large-scale research across the globe, in state-of-the-art facilities, backed by significant investment.

Combined with the academic contribution, the fight against AMR would receive a significant boost.”

Nathalie Moll, EFPIA, 2018: “There has been significant progress in launching and developing a collaborative approach towards fighting this threat and in raising awareness about AMR in Europe and globally, maintaining the momentum for political action. I am confident that – through collaborative effort – we will find effective solutions for this life-threatening problem.”

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STUDY

COMBACTE-MAGNET

MILESTONE

RESCUING Celebrating the enrolment of 1,000 patients RESCUING is a retrospective study that lays the groundwork for improvements in management and treatment of patients with healthcare-associated complicated urinary tract infections with multidrug-resistant bacteria, a growing problem in hospitals across Europe. After collecting data from more than 1,000 patients, results of the study are now in the process of being analyzed and published.

RESCUING, one of the first trials conducted by a COMBACTE-led public-private collaboration, entered the year 2018 with a track record of success.

After some early and minor glitches, the project went ahead on full steam in 2017. It has demonstrated great value, not just to academic researchers, but to the industry partners as well.

“Within the RESCUING collaboration, new approaches and ideas were explored that we would not have investigated if we had not been a partner,” says Irith Wiegand, Principal Scientist at AiCuris, a biotechnology firm based in Wuppertal, Germany and co-leader of the RESCUING study. “Moreover, if such a study had been carried out just by us, all that new data would probably get little distribution. We are really happy, and we knew from the start that we are generating something that helps the public at large.”

Urinary tract infections Pathogenic bacteria resistant to antibiotics are a major threat to the health of any of us, but no people are more vulnerable to multidrug-resistant pathogens than severely ill patients with other health

problems. Many such patients develop urinary tract infections, including hard-to-treat complicated ones. In recent years, a growing number of complicated urinary tract infections (cUTIs) appear to involve multi-drug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli.

Especially disturbing is the emergence of multi-drug resistant pathogens in many countries, all the more so because the development pipeline for new anti-microbial agents is running dry. Furthermore, there is a lot to be learned about, for example, current patient populations, treatment successes or failures, or even the burden urinary tract infections have on patients and health care systems in Europe.

A lack of knowledge The lack of knowledge limits the effectiveness of current efforts to treat patients. It also limits our ability to develop and test the efficacy of new treatment options, including candidate drugs such as AIC499, a potential new beta-lactam antibiotic that is being developed by AiCuris. As part of COMBACTE’s efforts to develop new molecules against gram-negative infections (MAGNET),

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We now have a large body of data, enough to carry out a wide range of analyses

the RESCUING study was designed to help fill the gaps.

It is a crucial investigation that will help clinicians pick the best ways to manage current patients. And by engaging a large pan-European network of clinical centers, RESCUING also helps lay the foundations on which companies can build efficient and effective Phase II and Phase III trials of potential new treatments.

1,000 patients The RESCUING study was designed to retrospectively gather observational data on about 1,000 patients who entered hospitals with complicated urinary tract infections in 2013 or 2014, or who developed such an infection during their hospital stay. Twenty medical centers in seven Southern-European countries and Israel participated – countries where the prevalence of drug resistance was suspected to be relatively high.

Besides characterizing pathogens and resistance, however, much more data was collected on the patients, on their infections, and on how these infections were managed by the hospital. Each record contained, for instance, data on patients’ demographic status, comorbidities, functional capacity, place of infection

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Besides characterizing pathogens and resistance, much more data was collected

and predisposing risk factors. Also collected were clinical, pathological, microbiological, and imaging test data, as well as records on infection management, antibiotic therapy, clinical outcome, hospital discharge, readmission and/or mortality within two months.

Important milestone By late 2016, one very important milestone had already been reached. “We had successfully recruited 1,006 patients from countries with high prevalence of multi-drug resistance,” says Miquel Pujol, Clinical Head of the Department of Infectious Diseases of the Bellvitge University Hospital in Barcelona (Spain) and academic lead of the RESCUING study. “We now have a large body of data on treatment failures in a variety of patients with complicated urinary tract infections, enough to carry out a wide range of analyses.”

Many of those analyses are still being done, while others are in various stages of publication in highimpact peer-reviewed journals. One analysis, for example, will estimate the added financial cost of multidrug-resistant complicated urinary tract infections in all eight countries, both per case and nationally. It will also try to identify factors that are associated especially with higher healthcare costs.

“The analyses have already shown that the cUTI diagnosis covers many different infections in different patient groups with very different outcomes,” Pujol says.

Unique “We have been very fortunate to be able to participate in COMBACTE-MAGNET and ND4BB, the biggest public-private partnership in Europe,” adds Cuong Vuong, Principal Scientist at AiCuris and Deputy Coordinator of the COMBACTEMAGNET effort. “It is important to be part of this group of leading experts who are trying to address microbial resistance. Most partnerships involve just one or two companies and a few academic groups, but here we have a group of global companies working closely together with smaller companies and many academic groups. That is unique, that has never happened before.”

For more information contact Irith Wiegand at irith.wiegand@aicuris.com, Miquel Pujol at mpujol@bellvitgehospital.cat, or Cuong Vuong at cuong.vuong@aicuris.com.

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‘‘Analysis shows that the cUTI diagnosis covers many different infections in different patient groups with very different outcomes’’ Miquel Pujol

Academic Lead RESCUING

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OUR CHOICE

CHARLES KNIRSCH, PFIZER

WELCOME

OUR CHOICE PFIZER LTD. During 2017, Pfizer joined COMBACTE. They became both a strategic partner in the new COMBACTE-CDI project and a leader of COMBACTECARE as well, establishing a key role across the projects. Let’s find out what drove their decision.

Charles Knirsch: “As a member of the IMI infection scientific governance group, I was aware of and supportive of COMBACTE’s suite of projects. And the extension to Clostridium difficile infections gave Pfizer the opportunity to continue work with leading academics under the rubric of IMI. It suits us well, given that collaboration is a key driver of innovation at Pfizer and can accelerate the pace in which good scientific ideas can become promising therapies. That’s why we embrace partnerships like COMBACTE.” We are pleased to welcome Pfizer – one of the world’s premier innovative biopharmaceutical companies – as our new partner.

Charles Knirsch, MD, MPH Vice President Pfizer Vaccines Clinical Research

Benefit “Public-private partnerships have proven potential to address major public health issues facing society. Through this project, Pfizer works with other partners to help accelerate breakthrough research that can facilitate drug and vaccine development for priority pathogens designated by national and international health agencies. Furthermore, COMBACTE offers academic investigators the opportunity to collaborate with the private sector to invigorate the early development infectious disease therapeutic pipeline,” according to Knirsch. “If each sector focuses on its core strengths and we work together, the health ecosystem and society at large could benefit from new and improved medicines and vaccines.”

Collaboration is a key driver of innovation at Pfizer

Clostridium difficile Pfizer became EFPIA coordinator in the new COMBACTE-CDI project (pages 14-15), which aims to gain a detailed understanding of the epidemiology and clinical impact of Clostridium difficile infections. Knirsch: “We believe our most useful contribution to this project is our expertise in laboratory and clinical research, drug development, and manufacturing and supply chain capabilities.

Together with our academic collaborators, we hope to gain in-depth insights and further our understanding of these complex infections, which we believe will ultimately prove beneficial for patients by preventing or treating life-threatening infections.”

Candidate drug By acquiring AstraZeneca’s late-stage small molecule antibiotics portfolio, Pfizer obtained the candidate drug aztreonam-avibactam (ATM-AVI) along with EFPIA leadership of COMBACTECARE, focused on carbapenem-resistant Enterobacteriaceae. ATM-AVI is intended to treat patients with serious Gramnegative bacterial infections, including those caused by a particular type of carbapenem-resistance (metallo-βlactamase), for which there are limited or no treatment options. COMBACTE-CARE is supporting its development via leading a Phase II safety and pharmacokinetics study and partnering on a global Phase III clinical trial. Knirsch: “The consortium facilitates the development of this novel antibacterial agent in highly specialized medical centers, making this invigorating public private partnership an important enabling framework as well.”

MY NETWORK

COMBACTE

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TOGETHER

My COMBACTE Community

Miranda Hopman

Project Manager CLIN-Net, Utrecht

The network of one of our colleagues

“A good collaboration between CLIN-Net and the team in Limoges is of great importance for further consolidation of the network in France. Halima is the central hub for all interactions with French investigators and clinical sites. This is pivotal for streamlined communication in the building of a clinical research network.”

Tuba VILKEN

LAB-Net Researcher, Antwerp “Halima and I schedule the site initiation visits for ASPIRE-ICU and ASPIRE-SSI in France.

During those visits, she explains the monitoring section

Halima Rakhila

and I present the sample collection and management section. Halima makes sure the site staff receives all information needed to start the trial. She even translates information into French if necessary.”

From her Limoges office, Halima serves as the link between COMBACTE and all French research teams and sites. She ensures smooth interactions between all parties and, as project manager, monitors the progress of COMBACTE-NET’s ASPIRE-ICU, ASPIRE-SSI and ANTICIPATE. In addition, she assists in trials being conducted at Limoges University Hospital. Halima is in regular contact with CLIN-Net in the course of her duties and advises on the deployment of French sites and study teams within COMBACTE as well.

Daniel Prins

Project Manager ASPIRE-ICU, Utrecht “I work closely with Halima and see her as a very engaged person. In her drive to succeed, she frequently comes up with suggestions on how to best conduct ASPIRE-ICU in France. For example, it was due to her recommendations that we decided to spread study newsletters in French in addition to English.”

Elodie Couvé-Deacon

Clinical Researcher ASPIRE-ICU, Limoges

Marie-Noëlle Bouverne

Clinical Operations Director, DA VOLTERRA, Paris

“Halima really helps me in conducting ASPIRE-ICU

“We work together on the ANTICIPATE study,

in the best possible way. She has a great sense of

in which Halima played a key role in the success

planning and organizing and is highly competent

of patient recruitment at French sites. She

in both good clinical practice and the required

supported the French National Coordinating

administrative procedures. In return, I provide her

Investigator in Limoges hospital and made a

with my network in the hospital and my practical

valuable contribution to regulatory submissions,

experience in performing clinical trials.”

follow-up and regular contact with country sites.”

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CLOSTRIDIUM DIFFICILE

COMBACTE-CDI

NEW

COMBACTE-CDI Understanding the epidemiology and clinical impact of Clostridium difficile infections

COMBACTE-CDI is dedicated to developing a detailed understanding of the epidemiology and clinical impact of Clostridium difficile infections (CDI) across Europe. The project contributes to improved treatment options for patients suffering from such infections that are responsible for extensive morbidity, mortality and health care costs.

COMBACTE-CDI merges outstanding European expertise on clinical, diagnostic and therapeutic issues related to CDI. It brings together experts who previously partnered in large international CDI projects, such as EUCLID, LUCID, ORCHID and ECDIS-NET, and combines all that knowledge with CLIN-Net and LAB-Net, the largest existing clinical and laboratory networks in Europe for carrying out challenging epidemiological and interventional studies. Add to the sum EPI-Net, a network mapping all European surveillance activities related to antimicrobial resistance. The combination of all these parties has invigorating potential. It is an ideal platform to extend our knowledge of this key infection, and ultimately to help with the development of better management modalities.

Promising participants In COMBACTE-CDI, eight academic and research organizations will collaborate with six EFPIA members, namely Pfizer Ltd., GlaxoSmithKline, bioMérieux, AstraZeneca/MedImmune, Sanofi Pasteur and Da Volterra. Participating academic institutes and research organizations are University Medical Center Utrecht (the Netherlands), Leiden

University Medical Center (the Netherlands), University of Leeds Teaching Hospitals (United Kingdom), National Laboratory of Health, Environment and Food, Maribor (Slovenia), University Clinic of Cologne (Germany), Eberhard Karls University Tübingen (Germany), University of Antwerp (Belgium) and the Lazzaro Spallanzani National Institute for Infectious Diseases, Rome (Italy).

Structure The three-year project – started in November 2017 – is subdivided into three scientific work packages: • A large epidemiology study will be undertaken across Europe to quantify the burden of CDI – in terms of incidence, distribution, recurrence, morbidity, mortality and transmission – across the whole health care economy.

• This will be followed by a case/control study, which along with data collected in a questionnaire will enable the consortium to assess current practices in Europe and their potential impacts, including guidelines, testing, surveillance, treatment and costs.

• The next stage is creating a rich, European research platform to provide support for future proof-of-concept and clinical studies of new prevention and treatment strategies for CDI.

There are limited therapeutic and preventive options for Clostridium difficile infections

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There is a lack of robust, comprehensive data on infections across Europe BACKGROUND Clostridium difficile infection is one of the most prevalent infections associated with health care, affecting both hospitalized patients and individuals in the community. Notably, there is an increasing realization that cases also occur in subjects not recently exposed to antibiotics or other health care interventions. CDI carries a considerable level of threat, with far-reaching impacts in both endemic and epidemic settings. It is a major cause of diarrhea and more serious intestinal conditions, such as colitis. Infections pose an extensive burden in terms of morbidity, mortality and health care resource utilization, so they require effective prevention and management strategies.

Missing the big picture Despite much progress in our understanding of Clostridium difficile, therapeutic and preventive options remain limited. There is a lack of robust, comprehensive data on infections across Europe.

Epidemiological data is limited. In addition, studies have typically examined only part of a health care economy and have usually focused on single countries or health care systems. Furthermore, large variations in the frequency of testing and the accuracy of CDI diagnostics mean that the size of the problem is probably underestimated.

Management Board Charles Knirsch, Pfizer, Coordinator M arc Bonten, UMC Utrecht, Managing Entity M ark Wilcox, University of Leeds, Academic Deputy Coordinator Andrew Nyborg, MedImmune, EFPIA Deputy Coordinator

For more information, visit www.combacte.com or contact Marc Bonten or Charles Knirsch: m.j.m.bonten@umcutrecht.nl, charles.knirsch@pfizer.com

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ACADEMICS & PHARMACEUTICALS

COMBACTE-CARE

COLLABORATION

Mutual motive Driven to develop new treatments

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The spectre of untreatable drug resistant infections has brought pharmaceutical companies and academics together to try innovative collaboration models. While neither party can overcome the challenge posed by antimicrobial resistance (AMR) on its own, they are determined to combat this threat together. After a few years of intensive cooperation, the progress can rightly be termed impressive. What drives both parties?

“I think it is accepted, that pharmaceutical companies need sustainable incentives including push and pull, and reimbursement reform to support antibiotic R&D. Yet in recent years, several pharmaceutical and biotech companies have chosen to enter that market, in part as a result of R&D collaborations, operating as push incentives, similar to IMI ND4BB. This is great. If we continue on our present path, there is some hope for new antibiotics. But on balance, it’s not enough, and requires governments to adopt new sustainable pull incentives” explains pharmaceutical company lead Seamus O’Brien. He concludes: “It’s time that we acknowledge our conventional system isn’t up to the task. We must try something new instead.”

We need one another Academic lead Jesús Rodríguez-Baño is in full agreement: “We can’t simply remain on the sidelines, pointing a finger at the pharmaceutical industry. We need to reflect on our own part in this, and acknowledge that academics aren’t capable of bringing new medicines to market only on their own grounds – in other words, we need one another.”

Which is why he immediately embraced the Innovative Medicines Initiative:

“Collaboration is a good idea in any circumstances. It allows us to break free of the old, rigid and inefficient ways of doing things. Until now, for instance, trials performed with new medicines have been frequently developed far away from real-life practice and present medical needs. By working together more closely, we can make those trials more realistic and problem-solvingoriented. That is a real gain, especially from the patient’s perspective.”

We need to find a sustainable form of collaboration Open dialogue Seamus O’Brien was also enthusiastic from the start: “This collaboration is an important initiative that helps de-risk the research and provide industry with a push it needs to get started. What also motivates the pharmaceutical players is a unique opportunity to engage in open dialogue in real time with clinical experts. Working together, sharing insights and building capability will

allow us to achieve so much more.

And perhaps, in doing so, we can change the old ways of working as well.”

The sum is greater than its parts Rodríguez-Baño: “We help pharmaceutical companies to better tailor their research set-up to the medical needs of real-world practice while developing important epidemiological and clinical research, and collaborate to better design of trials. This enables them to recruit suitable patients more quickly and efficiently, and to provide more relevant results.” O’Brien: “We offer academics an extensive platform for conducting research, where they can make use of our asset related trials, data and tools.” It’s a real incentive for the development of new medicines – a state of affairs that both men find exciting.

A willingness to understand one another It sounds great on paper. But how is the collaboration progressing in reality? Rodríguez-Baño: “Surprisingly well actually, especially when you consider how different our backgrounds are.

Misunderstandings are sometimes inevitable; confidentiality and deadlines for milestones are important for everyone but are critical for industry.

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Using knowledge gained from clinical practice, a lean-and-mean trial for EURECA was designed Such issues, however, are resolved fairly easily each time.” When asked what such resolutions require, he grins. “A positive attitude like Seamus’. He is genuinely interested in the academics’ point of view, and is constantly inquiring about our ideas. That obviously goes a long way towards overcoming our differences.”

Seamus O'Brien Coordinator in COMBACTE-CARE, WP co-Lead for EURECA and member of COMBACTE-NET Executive Director, External Scientific Affairs, Anti-Infectives at Pfizer seamus.obrien@pfizer.com

Jesús RodríguezBaño Academic Deputy Coordinator in COMBACTE-CARE and WP Lead in EURECA Head of the Infectious Diseases division at Hospital Universitario Virgen Macarena, Seville jesusrb@us.es

Overcoming obstacles “It takes people who are open-minded, with the courage to give new working methods a try,” according to O’Brien.

“Particularly in the beginning, but even now from time to time I come across employees who feel uncomfortable with their role in such a unique collaboration: including working side by side on project teams to sharing information in real time, which goes against the more traditional ways of working. When that happens, I talk to them about our shared goal and the optimal way for us to achieve it.

And the answer to that question is nearly always collaboration. Then the mind-set changes and we’re motivated to work in partnership.”

Thinking bigger “That same reticence also exists in the world at large, and it will be that

Our partnership is a fantastic model for the future, with a great deal of potential

way for quite some time, I expect,” says Rodríguez-Baño. “No matter how noble our goal, investing public funds in collaboration with a pharmaceutical partner remains a controversial step.

The only way to counter that is by ensuring transparent communication, each and every day.” He remains keen to improve the cooperation as well.

“The public is critical, and we need to be, too. We have embarked on a valuable partnership. Despite the success, we can’t rest on our laurels just yet.

This is a unique opportunity; now is the time for us to push ahead and to think bigger – as in expansion to Asia, for instance, or cooperation with BARDA. There are also opportunities for other infectious diseases and epidemiology.”

More sustainable collaboration O’Brien: “His enthusiasm together with his expertise – that’s what I really like about Jesús. He is genuinely concerned about difficult to treat infections, and prepared to cooperate with any partner who can contribute to a greater understanding and development of new treatments. That is precisely the right attitude to advance our collaboration.

The future unmet need will require more collaboration and at a greater scale.

What’s more, we need to find a more sustainable process for such R&D collaborations and more broadly for the development of antibiotics. Only then can we acknowledge the boost IMI provided supporting this much needed research, and hopefully be able to proceed with a sustainable business model.”

MY NETWORK

COMBACTE

19

TOGETHER

My COMBACTE Community

Lisa Grimsditch

Project Management Office Lead, COMBACTE-CARE, Pfizer (UK)

The network of one of our colleagues

“We work together closely to deliver COMBACTE-CARE financial reporting requirements to time and quality and within the agreed format.

Our working relationship is a great representation of the high level of collaboration between the EFPIA Coordinator and the managing entity for COMBACTE.”

Sophie Monteau

COMBACTE Project Manager, coordinator COMBACTE-CARE Andalusia “My responsibility is the

Renzo Dettingmeijer

economic and administrative management of COMBACTE in Spain. I report all the costs we

Jelle West

Financial Officer COMBACTE-NET, Utrecht

Jelle manages the annual expense accounts for COMBACTE-CARE. He sees to it that all partners report the costs they have incurred in the proper fashion, after which he submits the accounts to IMI and the EFPIA

“Jelle and I are both respon-

partners. Following approval, IMI allocates a new budget for the subsequent year. Jelle and his team then allocate

and for getting all consortium

have made to Jelle. He makes sure to send them to IMI. Our goal as a team is to achieve the greatest possible success in the field of infectious diseases.”

this budget to the COMBACTE-CARE partners. He will also be assuming responsibility for the finances of the new COMBACTE-CDI.

Nathalie Seigneuret

IMI Senior Scientific Project Manager, Brussels “As the IMI scientific officer in charge of tracking the project, I am in regular contact with Jelle, mainly by e-mail, about the respective obligations of the coordinator and managing entity of COMBACTE-CARE towards IMI for the project, including reporting and amendments.”

Ron de Winter

COMBACTE Project Coordinator, Utrecht “Each year, Jelle and I take on the challenge of compiling the financial reports. We spar with one another about the best way to collect the costs incurred from every last partner.

This can be difficult, since they all have their own schedule. Luckily, however, Jelle is extremely thorough and precise.”

sible for gathering the annual costs according to IMI guidelines, submitting them to IMI and the EFPIA partners, partners to submit their costs in good time. We try and work as much as possible along similar work methods.”

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NETWORKS

COMBACTE-NET

BUILDING

COMBACTE-Net Network to improve clinical trials for antibacterials

COMBACTE-NET is dedicated to building strong clinical, laboratory and research networks across Europe. In doing so, the consortium enables more efficient clinical testing of novel antimicrobial drugs. In addition, it performs several of those clinical trials itself.

The main aim of the project is to improve the quality and efficiency of clinical trials for new drugs against multi-resistant bacteria. To this end, COMBACTE-NET will provide a large network for rapid evaluation of novel treatment strategies.

It aims to generate innovative trial designs to facilitate the registration of novel antibacterial agents and to design and validate tests to support the diagnosis of patients, identify the most appropriate treatments, and monitor the patient’s response.

Unique collaboration To achieve these goals, COMBACTE-NET has organized an unprecedented sharing of knowledge and research, connecting laboratories and clinical sites across the continent and bringing together the best and brightest of 35 clinical centers and five pharmaceutical companies. All are experts in the field, collaborating closely and openly

Swift access to clinical trial sites across the continent is much needed

discussing the scientific, regulatory and organizational issues at hand.

Pan-European networks One of the key outcomes of COMBACTE-NET is a high-quality European clinical trial and laboratory network, in which new antibacterial drugs can be evaluated for the treatment and prevention of infections caused by multi-resistant bacteria.

Over 650 laboratories and over 850 clinical trial sites all over Europe are already interconnected (page 22, 23). These networks will enable the collection of data required to accurately identify clinical needs and come up with ideas for developing effective new antibacterial treatment options.

Clinical trials The COMBACTE-NET consortium will top off the construction of this clinical trial backbone by carrying out several clinical trials of candidate drugs: • Suvratoxumab (formerly MEDI4893) is a monoclonal antibody from MedImmune, the global biologics research and development arm of AstraZeneca, that could protect mechanically ventilated patients against infections with Staphylococcus aureus, preventing bacterial toxins from damaging their organs and tissues.

Read more about this study – named SAATELLITE – on page 30,31.

• Da Volterra’s DAV132 is a promising new therapeutic agent for the prevention of serious Clostridium difficile infections. In the ANTICIPATE study, it is tested for safety and pharmacokinetics. In essence, it adsorbs small molecules such as antibiotics, preventing bacteria present in the gut from harming the patient. Read more about Da Volterra and DAV132 on page 50.

• The Medicines Company offers an intravenous formulation of minocycline, effective against infections due to Acinetobacter species.

COMBACTE-NET performs the regulatory tests required to make it available in Europe.

21

BACKGROUND There is an urgent need for new medicines, but few new antibacterial drugs are actually being developed. Many factors contribute to this sparingly filled development pipeline. At the earliest stages, there is a need for better understanding of how existing antibiotics work, how bacteria develop and spread resistance to them, and how novel classes of antibiotics can be designed to which resistance would ideally develop more slowly.

Return on investment Further down the pipeline, any potentially new antimicrobial agent faces stumbling blocks on its way to the market: the clinical trials required for regulatory approval need very large numbers of study participants. Such testing is not just very expensive, but also very hard to set up because of a lack of knowledge, capacity, harmonization and organization in clinical centers in many different countries. After coming out of the pipeline, for some novel treatments it will prove difficult to generate a return on all these investments, especially since doctors will need to minimize prescriptions in order for the new treatments to maintain their life-saving effects.

Speeding up research & development The challenge is to make governments, hospitals, academic researchers, small and medium-sized enterprises and large pharmaceutical companies work together in new and more efficient ways.

An unprecedented sharing of knowledge and resources is needed to speed up the research and development of antimicrobial treatments.

Management Board H asan Jafri, MedImmune, Coordinator M arc Bonten, UMC Utrecht, Managing Entity Annie Ducher, Da Volterra, EFPIA Deputy Coordinator Michael Dudley, The Medicines Company, EFPIA Deputy Coordinator

Linking pharmaceutical and clinical expertise delivers far more effective and efficient trial design

Bruno Franรงois, Centre Hospitalier Universitaire de Limoges Academic Deputy Coordinator H erman Goossens, University of Antwerp, Academic Deputy Coordinator

For more information, visit www.combacte.com or contact Marc Bonten or Hasan Jafri: m.j.m.bonten@umcutrecht.nl, jafrih@medimmune.com

22

CLINICAL SITES

COMBACTE-NET

CONNECT

CLIN-NET CLIN-Net establishes, trains and maintains a European network of GCP-qualified clinical investigation sites. In which experience and expertise is being collected and shared among each other. This network enables us to swiftly target and select the most relevant sites.

Considerably reducing the duration and costs of clinical trials. >850

SITES IN DATABASE

273

• Qualitatively expand through performance measurement • Utrecht based team of 10 people • National Coordinators play a crucial role in site selection • GCP-training: face-to-face and e-learning

PARTICIPATING IN STUDIES

REGISTER

CONNECT

Selecting suitable clinical sites and laboratories

SCREEN

LABORATORIES

COMBACTE-NET

23

ACTIVATE

LAB-NET LAB-Net maintains a high-quality geographically representative European laboratory network to enhance antibacterial drug development and to support clinical trials for any infectious disease.

We select suitable trial sites and provide training to laboratory and clinical investigators to prepare them to engage in a clinical trial.

656

LABORATORIES IN DATABASE

163

PARTICIPATING IN STUDIES

• Antwerp-based team providing laboratory expertise within clinical trials • Selecting laboratories based on study-specific criteria • Preparing sites by providing study-specific trainings and manuals • Central laboratory providing sample kits, biobanking and performing analysis on study samples and strains • Coordination of biomarker research • Assessing performance and supporting qualitative development of laboratories

Fast and targeted selection based on trial-specific criteria

DATABASE

SELECTION FOR TRIALS

TRIAL EXECUTION

SUPPORTED BY CENTRAL LAB

Reflection on our cooperation

LABORATORY EXPERTISE

BIO BANKING

BIOMARKER RESEARCH

24

TRIAL-OVERVIEW

COMBACTE

RESEARCH

FOUR CONSORTIA, NINETEEN STUDIES Four COMBACTE consortia, each bringing together researchers from academia and industry, will use the European clinical and laboratory networks to perform a total of nineteen studies. Some will be prospective randomized clinical trials, others will be retrospective, observational and/ or epidemiological studies.

The EFPIA partners and their compounds Compound

EFPIA Partner

Project

Suvratoxumab

MedImmune/AstraZeneca

COMBACTE-NET

DAV132

Da Volterra

COMBACTE-NET

Minocycline IV

The Medicines Company

COMBACTE-NET

Aztreonam-Avibactam (ATM-AVI)

Pfizer

COMBACTE-CARE

MEDI3902

MedImmune/AstraZeneca

COMBACTE-MAGNET

AIC499

AiCuris

COMBACTE-MAGNET

Type of study OBSERVATIONAL

DATABASE ANALYSIS

PHASE I

PHASE II

MATHEMATICAL MODELLING

PHASE III

INTERVENTION

2020

ASPIRE-ICU

2019

A prospective observational study to determine the frequency and determinants of

Test Subject: -

ICU pneumonia caused by S. aureus and by P. aeruginosa among ICU patients to identify

EFPIA Partner: Medimmune/

high-risk patients, in order to support the design of late-stage intervention trials.

AstraZeneca

2018 2017 2016

COMBACTE-NET

STATUS: ACTIVE RECRUITING 2015

25

2020

ASPIRE-SSI

2019

A prospective observational study to determine the frequency and determinants of

Test Subject: -

S. aureus SSI among surgical patients and develop an algorithm to identify high-risk

EFPIA Partner: Medimmune/

patients for these infections, in order to support the design of late-stage intervention trials.

AstraZeneca

2018 2017 2016

COMBACTE-NET

STATUS: ACTIVE RECRUITING 2015

2020

SAATELLITE

2019

A phase II, randomized, placebo-controlled safety and efficacy trial of Suvratoxumab

Test Subject: Suvratoxumab

(previously MEDI4893), a novel, extended half-life monoclonal antibody against S. aureus

EFPIA Partner: Medimmune/

alpha-toxin, for the prevention of S. aureus pneumonia in ICU patients.

AstraZeneca

2018 2017 2016

COMBACTE-NET

STATUS: ACTIVE RECRUITING 2015

2020

ANTICIPATE

2019

Identify the risk factors for Clostridium difficile infections and better prevent this

Test Subject: -

severe pathology. And indicate for whom prevention will prove the most effective.

EFPIA Partner: Da Volterra

2018 2017 2016

COMBACTE-NET

STATUS: RECRUITING COMPLETED 2015

2020

WP8 A-B-C-D

2019

Testing minocycline intravenous, which has been registered in the US for treatment of

Test Subject: Mminocycline IV

serious multi-drug resistant Acinetobacter s. infections. The work package consists

EFPIA Partner: The Medicines

of three Phase I studies and a Phase III study, and aims for European authorization.

Company

2018 2017 2016

COMBACTE-NET

STATUS: IN PREPARATION 2015

2020

WP6E

2019

A Phase III, multi-center, multinational, randomized, double-blind, placebo-controlled

Test Subject: Suvratoxumab

study to evaluate the efficacy of a single dose of suvratoxumab in mechanically ventilated

EFPIA Partner: Medimmune/

adult and adolescent subjects at risk of S. aureus pneumonia.

AstraZeneca

2018 2017 2016

COMBACTE-NET

STATUS: IN PREPARATION 2015

2020

EURECA

2019

How patients with serious carbapenem-resistant Gram-negative bacterial infections

Test Subject: -

are currently treated and which sub-groups of patients respond well to which

EFPIA Partner: Pfizer, GSK

treatments.

2018 2017 2016

COMBACTE-CARE

STATUS: ACTIVE RECRUITING 2015

26

2020

REJUVENATE

2019

A phase II, pharmacokinetic and safety study of ATM-AVI, a beta-lactam-beta lactamase

Test Subject: ATM-AVI

inhibitor combination in hospitalized patients with complicated intra-abdominal

EFPIA Partner: Pfizer

infections (cIAI).

2018 2017 2016

COMBACTE-CARE

STATUS: RECRUITMENT COMPLETED 2015

2020

REVISIT

2019

A global, phase III, randomized, comparative clinical trial to determine the efficacy and

Test Subject: ATM-AVI

safety of ATM-AVI for the treatment of serious bacterial infections caused by Gram-

EFPIA Partner: Pfizer

negative bacteria including metallo-beta-lactamase producing MDR pathogens.

2018 2017 2016

COMBACTE-CARE

STATUS: IN PREPARATION 2015

2020

EVADE

2019

A phase II, randomized, controlled safety and efficacy trial of MEDI3902, a bispecific

Test Subject: MEDI3902

monoclonal antibody against two Pseudomonas aeruginosa proteins, for the prevention

EFPIA Partner: Medimmune/

of ventilator-associated pneumonia in ICU patients.

AstraZeneca

2018 2017 2016

COMBACTE-MAGNET

STATUS: ACTIVE RECRUITING 2015

2020

WP4B

2019

A phase III, randomized, controlled efficacy trial of MEDI3902, a bispecific monoclonal

Test Subject: MEDI3902

antibody against two Pseudomonas aeruginosa proteins, for the prevention of

EFPIA Partner: Medimmune/

ventilator-associated pneumonia in ICU patients.

AstraZeneca

2018 2017 2016

COMBACTE-MAGNET

STATUS: IN PREPARATION 2015

2020

WP4C

2019

An open label study to determine the safety and pharmacokinetics of MEDI3902

Test Subject: MEDI3902

in children at risk for developing Pseudomonas aeruginosa infection.

EFPIA Partner: Medimmune/ AstraZeneca

2018 2017 2016

COMBACTE-MAGNET

STATUS: IN PREPARATION 2015

2020

RESCUING

2019

Collecting data to identify the optimal treatments and clinical management procedures

Test Subject: -

for patients with complicated urinary tract infection and to identify patient categories

EFPIA Partner: AiCuris

and clinical centers that can be used for future Phase II and III clinical trials.

2018 2017 2016

COMBACTE-MAGNET

STATUS: DATA COLLECTING COMPLETED 2015

27

2020

WP3A

2019

Specimen analysis of the ASPIRE-ICU cohort participants to detect and characterize

Test Subject: -

P. aeruginosa pneumonia. It will contribute to the assessment of host- and pathogen-related

EFPIA Partner: Medimmune/

factors on ICU pneumonia and therefor further optimize patient selection for clinical trials.

AstraZeneca

2018 2017 2016

COMBACTE-MAGNET

STATUS: ONGOING 2015

2020

WP3B

2019

A mathematical modeling effort to develop an analytical framework and statistical

Test Subject: -

tools to describe the burden of P. aeruginosa in European ICUs and determine the

EFPIA Partner: Medimmune/

most impactful interventions.

AstraZeneca

2018 2017 2016

COMBACTE-MAGNET

STATUS: ONGOING 2015

2020

WP6G

2019

Phase I clinical trials (drug-drug interactions, mass balance/metabolite

Test Subject: AIC499

identification, TQT, and renal impairment)

EFPIA Partner: AiCuris

2018 2017 2016

COMBACTE-MAGNET

STATUS: IN PREPARATION 2015

2020

WP6H

2019

Phase II randomized trials of intravenous AIC499 plus BLI in hospitalized subjects

Test Subject: AIC499

with complicated urinary tract infections and complicated intra-abdominal infections.

EFPIA Partner: AiCuris

2018 2017 2016

COMBACTE-MAGNET

STATUS: IN PREPARATION 2015

2020

WP1

2019

A large epidemiology study to quantify the burden of Clostridium dificile infections -

Test Subject: -

in terms of incidence, distribution, recurrence, morbidity, mortality and transmission -

EFPIA Partner: GlaxoSmithKline

across the whole healthcare economy.

Biologicals

2018 2017 2016

COMBACTE-CDI

STATUS: IN PREPARATION 2015

2020

WP2

2019

Assess current practices in Europe and their potential impacts, including guidelines,

Test Subject: -

testing, surveillance, treatments and costs.

EFPIA Partner: bioMérieux

2018 2017 2016

COMBACTE-CDI

STATUS: IN PREPARATION 2015

28

FUNDING

WWW.IMI.EUROPA.EU

DISTRIBUTION

FUNDING COMBACTE PROJECTS IMI FUNDING € 208 mln.

€192 mln.

TRANSLOCATION, iABC, ENABLE, DRIVE A/B

FUNDING IMI 1 ND4BB PROGRAM

€656

€464 mln.

mln.

EFPIA IN KIND € 256 mln.

FUNDING IMI 2 ND4BB PROGRAM

€4,6 mln.

29

mln.

€105

€109

EFPIA

IMI

TOTAL

COMBACTE-NET

€214 mln.

€59

€24

EFPIA

IMI

TOTAL

COMBACTE-CARE

€83 mln.

€92

€75

EFPIA

IMI

TOTAL

COMBACTE-MAGNET

€167 mln.

€2,3

€2,3

EFPIA

IMI

TOTAL

COMBACTE-CDI

€4,6 mln.

ADDRESSING THE BARRIERS IN CLINICAL TRIAL DEVELOPMENT

€468,6

TOTAL COMBACTE PROJECTS

30

TRIALS

COMBACTE-NET, COMBACTE-MAGNET

ANTIBODIES

Next stage trials SAATELLITE and EVADE SAATELLITE and EVADE were the first multinational Phase II interventional trials within the COMBACTE consortium. They are designed to test the dosing, safety and efficacy of antibodies against pathogens that cause ventilator-associated pneumonia. Taking off took a bit longer than expected, but both studies have now reached cruising speed and are building an international clinical trial network.

For both SAATELLITE and EVADE, the ultimate goal is getting to a new, immunological approach against common ventilator-associated pulmonary infections. Rather than using more or new antibiotic drugs against full-blown infections, the aim is to help the immune systems of high-risk patients keep pathogens in check without causing disease. Preventing pneumonias rather than treating them could reduce the use of antibiotics and hence the emergence of antibiotic resistance.

To reach the goal, SAATELLITE is testing suvratoxumab (formerly MEDI4893), a monoclonal antibody against the alpha toxin of Staphylococcus aureus, in 285 patients across Europe. In parallel,

EVADE is testing MEDI3902, a bispecific monoclonal antibody against two Pseudomonas aeruginosa virulence factors, in 286 patients. Both antibodies were developed by MedImmune, the global biologics research and development arm of AstraZeneca. Both trials need to recruit intensive-care patients who need mechanical ventilation and have tested positive for the pathogen in their lower airways. In a brief window of opportunity, patients can be randomized, given one intravenous dose of either antibody or placebo, and be monitored for pneumonias thereafter.

Unique environment “We are all very motivated to test this exciting new approach,” says Jean

Chastre, EVADE’s academic leader from the Hôpital Universitaire Pitié Salpêtrière in Paris, “although doing this trial is very difficult. It is hard to find and include the right patients at precisely the right time.

We had enrolled less than a quarter of the patients late last year, a bit less than we had originally scheduled.”

The SAATELLITE trial has had its growing pains as well, says Hasan Jafri, senior director for clinical research and development in infectious diseases and vaccines at MedImmune, the EFPIA Lead of both trials and coordinator of COMBACTE-NET and COMBACTEMAGNET. He has been up since 4:30am the day we talked to him – a byproduct of joining European teleconferences

31

Looking forward to a full scientific exploration of a mountain of valuable data lead for SAATELLITE and a clinician at the Centre Hospitalier Universitaire in Limoges (France), and academic deputy coordinator for COMBACTE-NET. “You select them based on the numbers, you don’t meet the people there. Within SAATELLITE however we have made personal contact with almost every investigator. Combined, I think Hasan and I have visited two thirds of the sites in our network. The others we know through routine calls – we aim to interact with each site at least once every quarter. We get to know them, they can ask us questions. It’s pretty different from how it’s often done.”

from the US. “It took much collective effort to get the consortium off the ground,” Jafri says, “but that’s no surprise because it’s truly a new consortium in which many people in many countries are figuring out how to work together.

SAATELLITE was the first-ever clinical trial done under this IMI program.”

Among the hurdles, Jafri explains, were legal arrangements needed to extend the trial’s reach to up to 80 hospital sites governed by different national regulations. “Once we had all the subcontracts and procedures in place, things have been moving forward nicely. These experiences will also help future trials.

SAATELLITE has helped build a unique environment where industry experts work very collaboratively with academic clinicians, ICUs, microbiology labs and pharmacies.”

On the road Building such a network requires much time on the road, its leaders have found. “Often, when you coordinate a trial, you don’t really know the trial sites,” says Bruno François, academic

“Spending a few hours at sites, meeting not just principal investigators but their colleagues as well is very helpful,” adds Jafri. “You learn how they’re organized, what issues may come up. People at the sites really appreciate that you come, which strengthens long-term relationships.” Sites also visit the hospital in Limoges to see first hand how they are orginsed in a collaborative way across the ICU study staff, microbiology lab, and pharmacy department. Quite often they enroll their first patients shortly after returning home.

Twins According to François, public-private collaboration has worked quite well

Patient recruitment efforts will intensify in part by enlisting new study sites

at all levels, not just at the leadership level. “Many of our counterparts at MedImmune have academic backgrounds, which may have helped,” he says. “Both sides are really co-managing the programme. Hasan and I are from different continents and different cultures, but we work together like twins.” Jafri agrees: “Working as a true team I think has really worked very well.

I can’t think of a better way of developing drugs, especially when creating new paradigms in challenging patient populations. And it has really been an absolute pleasure.”

Cross-Atlantic collaboration This year, SAATELLITE aims to complete the enrollment, followed by data cleaning, preliminary analysis and full scientific exploration of a mountain of valuable data. Work on a follow-up Phase III trial will commence as well.

For EVADE as well as SAATELLITE patient recruitment efforts will intensify in part by enlisting new study sites.

To that end, discussions are underway with the Antimicrobial Resistance Leadership Group (ARLG) - the American counterpart to COMBACTE, which is funded by the US National Institutes of Health. Some US study sites could then join the trials. Hasan Jafri: “Collaboration between COMBACTE and ARLG would confirm the confidence of the global infectious disease research community in COMBACTE, and would be a very positive step in cross-Atlantic collaboration on development of antibacterial molecules, to which Europe and the U.S. agreed in Stockholm in 2016.”

For more information contact Bruno Francois at bruno.francois@chu-limoges.fr, Jean Chastre at jean.chastre@psl.aphp.fr or Hasan Jafri at jafrih@medimune.com.

32

GRAM-NEGATIVE

COMBACTE-MAGNET

INTENSIVE-CARE UNITS

COMBACTE-MAGNET Molecules against Gram-negative infections in intensive-care units

COMBACTE-MAGNET focuses on the most vulnerable category of patients: those who are critically ill and being treated in intensivecare units. Most ICU-associated infections are caused by Gramnegative bacteria. This project aims to find better options to deal with this threat.

COMBACTE-MAGNET aims to provide groundbreaking multinational phase I, II and III studies targeting multidrug-resistant Gram-negative bacteria. It will analyze data about current microbial threats, treatment and drug resistance patterns in European countries where ICU patients are most at risk, gather information on biological markers of Pseudomonas aeruginosa infections, create mathematical models of the infection’s effects, and provide a better understanding of why various patients may respond differently. Such knowledge will enable researchers to design more efficient and effective clinical trials of new molecules, accelerating the drug-development process enormously.

Network of epidemiological data The project brings together top-tier researchers from five pharmaceutical companies and more than 30 leading academic medical centers from 10 European countries. They combine their knowledge and capabilities to deliver the aforementioned aims. As part of the solution, they created EPI-Net (page 34), a European network of epidemiological data and surveillance systems that strengthens our ability to monitor the spread of healthcare-associated infections and antibiotic resistance across the continent.

Clinical trials COMBACTE-MAGNET performs pharmaceutical trials of two potential new treatments. The first is MEDI3902, a bispecific monoclonal antibody that inhibits two key virulence factors of Pseudomonas aeruginosa, PcrV and Psl. It has shown promising activity against P. aeruginosa in laboratory and animal studies, and has already undergone Phase I safety testing in adult humans. The consortium will carry out Phase II and Phase III studies in adult ICU patients to learn more about the antibody’s safety, its optimal dosing, and its efficacy in ICU patients.

The current status of this study – called EVADE – can be read on pages 30 and 31.

The other candidate drug is AIC499, potentially a new and potent member of the family of beta-lactam antibiotics. Given alone or in combination with a beta-lactamase inhibiting drug (BLI), AIC499 has shown strong activity against a broad range of multidrug-resistant strains of P. aeruginosa and Acinetobacter, both in laboratory and animal studies. AIC499 is being developed by the Germanbased biotechnology firm AiCuris. COMBACTEMAGNET carries out Phase I and Phase II trials to assess the safety and the efficacy of AIC499.

We increase our understanding of the needs of patients and doctors in ICUs

33

Gram-negative bacteria have become resistant to an array of antimicrobial drugs

BACKGROUND Pathogenic bacteria that are resistant to many antibiotics are a major threat to the health of all of us, but no people are more vulnerable to multidrugresistant microbes than critically ill patients who are receiving intensive care. Already-weakened patients in hospital intensive-care units (ICUs) are particularly prone to infections of their urinary tract, or their intra-abdominal area. For them in particular, becoming infected with a multidrug-resistant pathogen can prove to be fatal. Very often, ICUassociated infections are caused by Gram-negative bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. In recent years, these microbes turn out to have become increasingly resistant to an array of antimicrobial drugs.

Need for better options Clearly, there is an urgent need for better options to deal with the threat. Novel ways are needed to detect and identify ICU-associated infections early and then keep those infections in check. We also need drugs that target Gram-negative pathogens for cases where infections are growing despite all effort. The reality is, however, that the drug development pipeline for new antibiotic compounds has been running dangerously dry. Over the course of the last three decades, only two new classes of antibiotics have managed to reach the market.

That leaves growing numbers of patients at great risk and therefore presents our healthcare system with a major challenge.

Management Board Hasan Jafri, MedImmune, Coordinator M arc Bonten, UMC Utrecht, Managing Entity Alisdair MacGowan, North Bristol NHS Trust, Academic Deputy Coordinator Cuong Vuong, AiCuris, EFPIA Deputy Coordinator

For more information, visit www.combacte.com or contact Marc Bonten or Hasan Jafri: m.j.m.bonten@umcutrecht.nl, jafrih@medimmune.com

34

OUTBREAKS, SURVEILLANCE

COMBACTE-MAGNET

INSIGHTS

EPI-Net EPI-Net harmonizes and connects various European systems of disease surveillance and outbreak data. Building one standardized European surveillance system which allows greater insights in the determinants and distribution of serious bacterial infections across the continent.

Staphylococcus aureus | Enterococcus | Escherichia coli | Klebsiella pneumoniae Enterobacter | Acinetobacter | Pseudomonas aeruginosa | Helicobacter pylori Gonorrhoea | Salmonella | Campylobacter

Regional systems

National systems

International systems

ECDC

Google

Scientific publications

Experts

EUCIC, PENTA-ID and CEFAIA

127.823

10.770.589

Animal strains

Human strains

RAW DATA Homogenized by statistical experts

Overall incidence per resistant bacteria shown on European map (expected in 2018)

Insights and guidance documents to homogenise reporting and decrease the burden of resistant bacteria (expected in 2018)

ADVANCED STATISTICS

Lorem COMBACTE-NET

ipsum

IMPROVING DESIGN

35

STAT-Net Experts with strong track records in pharmacokinetics/pharmacodynamics (PK/PD), biostatistics, infectious diseases, and clinical development, investigate multiple approaches to improve the data-driven design of clinical trials. Using advanced statistical and pharmacological modeling and the latest biostatistical and epidemiological concepts.

Utrecht

Evaluating novel design strategies which so far only had a theoretical basis

Bristol

Systematic review of previous PK/PD studies

Rotterdam

PK/PD experts re-analyze old data with the newest PK/PD modeling techniques

Paris

Using extensive clinical expertise to identify and define new endpoints

Geneva

Program management

Freiburg

A mathematical effort extracting more information out of current data

Zurich

Specialists in Bayesian statistics assess how the use of historical data can improve efficiency of randomized control trials (RCT)

Results

• All gained insights are translated into recommendations and summarized in a whitepaper.

• We have shared our insights with EMA. We hope and expect they will improve RCT efficiency.

EFPIA partners: GlaxoSmithKline and MedImmune/AstraZeneca Academic partners: Erasmus University Medical Center, Faculty of Medicine and Medical Center - University of Freiburg, Geneva University Hospitals and Medical Faculty, Inserm/Université Paris Diderot, Ulm University, University Medical Center Utrecht, University of Zurich

36

RECRUITING

COMBACTE

ON TOP

The art of recruiting There can be no research without patients.

But how does one find suitable candidates?

Our field – infections caused by resistant bacteria – poses an additional challenge.

This is because once a diagnosis has been established, the attending physician has little time before having to start the treatment. In consequence, the window for recruiting a patient is quite small, sometimes only a few hours. And yet we manage to do it.

Biljana Carevic

Department of Hospital Epidemiology, Clinical Centre of Serbia, Belgrade, Serbia “Recruiting patients for COMBACTE actually fits quite logically into our day-to-day work.

My Infection Control team, for instance, scouts for infectious diseases among patients every day anyway. At the same time, and with the same amount of effort, we identify potential candidates for ASPIREICU or EURECA. We then visit the candidates immediately to recruit them. When we do, it’s crucial that we provide clear, compre-

Delia HergHEa

Coordinator of the Department of Prevention and Control of Healthcare Associated Infections, Prof. Dr Ion Chiricuta Oncology Institute, Cluj Napoca, Romania

hensive information regarding the research protocol. I also make sure to attend what staff meeting. We also hung posters and

are known as ‘open hours’ in the ICU.

handed out flyers throughout the entire

This gives next of kin a chance to approach

institute. This interaction with doctors has

me with any questions about the study that

been quite successful, as my team is called

they may have, and I take plenty of time to

in regularly and promptly. After that, it’s

answer them as well as I can. That builds

up to us to recruit candidates successfully.

trust. Ultimately, we are able to recruit

We try to use patience and clear communi-

virtually every candidate we identify.”

cation to gain their confidence. As the study progresses, we’re able to share increasingly

“We have a clear division of labor. Doctors

specific information about what we’re doing

identify potential patients for ANTCIPATE,

in the study, and it becomes easier to con-

after which my team attempts to recruit

vince candidates to take part. Sometimes,

them. To ensure top-of-mind awareness

patients even convince one another.

among physicians of all specializations,

When that happens, not much effort is

I presented the study protocol during their

required on our part.”

Sometimes the window to recruit a potential candidate is mere hours

37

Victoire de Lastours

Associate professor of Internal Medicine and Infectious Diseases, APHP Beaujon, Paris, France “We are taking part in ANTICIPATE, a study that will yield outcomes that should interest us directly. As a result, my team is especially motivated. The greatest challenge is that we must recruit the patient for the study within six hours of the first dose of antibiotics being administered. We have the advantage that our hospital is relatively small and everyone knows one another; our antibiotic stewardship team does rounds in the emergency room

A clear explanation of the content and procedure of the study is essential Emmanuel Roilides

Head of the Infectious Diseases unit, Hippokration Hospital, Thessaloniki, Greece

and short-term hospitalization unit every day.

These short lines of communication give us a

“The major interest in research into carba-

great view of which new arrivals are potential

penem-resistant (CR) organisms keeps our

candidates for recruitment. That’s the key to

physicians motivated and allows us to recruit

successful recruiting. To help us move faster,

as many patients for EURECA as we do in our

technical nursing staff assists us with the

hospital. The Infectious Diseases unit employs

paperwork. They are a big help. Lastly,

highly driven internists and pediatricians.

ANTICIPATE is purely observational and

Whenever they see patients with CR infec-

doesn’t interfere with patients’ treatment.

tions on their daily rounds, they immediately

We have found that this really increases

mention the study to them. If patients show

patients’ willingness to take part.”

an interest, ID consultants visit them to go over the criteria, and to recruit them. The fact that this succeeds so often is partially due to the large size of our hospital: we have a relatively large number of potential participants and sufficient manpower to recruit them. In addition, the study involved is purely observational, meaning that participation doesn’t require any effort on the patient’s part.”

Marc Bourgeois

Head of the Intensive Care unit, AZ Sint-Jan AV, Bruges, Belgium

part in the study. Because these patients are typically unconscious, they are usually recruited by obtaining permission from the family. A clear explanation of the content and procedure is essential. After that, surveillance coaches administer the tests that show whether a patient meets the study criteria three times a week. This works well. The antibodies we give the patients

“If the doctors don’t have time for their daily

are virtually free from side effects. If the

rounds in the ICU, study nurses go instead.

treatment proves effective, it’s a positive

That way, we don’t miss a single potential

outcome for the patient. Finally, there’s no

EVADE participant. Only those patients

competition from other studies within the

who are intubated or on a ventilator and

hospital. All these factors allow us to be

colonized with Pseudomonas qualify to take

quite successful at recruiting patients.”

38

CARBAPENEM RESISTANCE

COMBACTE-CARE

HETEROGENEITY

COMBACTE-CARE Meeting the challenge of carbapenem-resistant Enterobacteriaceae Carbapenem-resistant gram-negative bacteria are often resistant to most other antibiotics as well, leaving infections very difficult to treat.

COMBACTE-CARE counters that threat by laying the groundwork for tests of new treatment options.

COMBACTE-CARE’s ultimate goal is to better understand multi-drug resistant bacterial infections such as carbapenem resistant Enterobacteriaceae (CRE) and to support the development of new treatment options. To that end, the consortium will analyse observational clinical and epidemiological data sets to inform the design of randomised trials.

Furthermore, the consortium is making a significant contribution to the development of a novel treatment option, aztreonam-avibactam (ATM-AVI), for patients with serious Gram-negative bacterial infections, including those caused by a particular type of carbapenem-resistance (metallo-β-lactamase), for which there are limited or no treatment options.

First clinical studies underway The consortium is conducting both prospective observational and interventional clinical studies.

• The EURECA study is a prospective observational research assessment of the clinical management

CRE are multidrugresistant, if not extensively-drugresistant to many classes of antibiotics

of patients with serious carbapenem-resistant Gram-negative infections. It will evaluate the risk factors for infection, current treatment options and clinical outcomes for patients with such infections across Europe.

• The REJUVENATE study – which has completed patient recruitment – is a Phase II trial evaluating the pharmacokinetics and safety of ATM-AVI in patients with a complicated intra-abdominal infection (cIAI). Read more about this study on pages 46 and 47.

• REVISIT is a phase III study, in preparation, evaluating the efficacy and safety of ATM-AVI for the treatment of serious infections due to Gram-negative bacteria, including metallo-β-lactamase producing multidrug resistant pathogens. COMBACTE-CARE is providing global medical partnership and European patient data via network and site coordination. REVISIT is also supported by the US Government’s Biomedical Advanced Research and Development Authority (BARDA) via a research agreement with Pfizer.

Extensive collaboration This project unites the knowledge and capabilities of leading drug resistant bacterial infection experts in the field by bringing together prominent clinical and microbiology research groups in Europe to address the challenges of the observational and interventional clinical studies. The collaboration is supported by the COMBACTE clinical and laboratory networks and is developing academic research organization capability within the consortium. The consortium is collaborating with global partners such as BARDA to support global solutions.

In all, the COMBACTE-CARE consortium includes 18 academic centers and 3 pharmaceutical companies, with Pfizer operating as coordinator. COMBACTECARE is focussing on capability building across Europe but in particular on clinical sites in countries in south and eastern Europe, where rates of multi-drug resistance and CRE are a particularly concern.

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More than 20 carbapenem-resistant genes have been reported so far

BACKGROUND Among the emerging AMR threats, the rise of multidrug resistant Gram-negative bacterial pathogens is among the greatest. Increasingly, hospital patients who get infected by Enterobacteriaceae family of bacteria (such as Escherichia coli or Klebsiella pneumoniae) or other species such as Pseudomonas aeruginosa and Acinetobacter baumannii no longer respond effectively to treatment with carbapenems.

This is alarming, because carbapenems, as a beta-lactams, are a key drug of last resort when treatments with other β-lactam antibiotics have already failed. Furthermore, these carbapenem resistant isolates increasingly demonstrate resistance to many other classes of antibiotics and are thus multi-drug(MDR) if not extensively-drug (XDR) resistant.

Significant heterogeneity with limited options There are many different types of carbapenemases – enzymes produced by many CRE that inactivate the carbapenems. More than 20 different resistance genes encoding carbapenemases have so far been reported, including NDM, KPC, VIM, and OXA-48.

This enormous heterogeneity makes it very difficult to detect CRE infections early on during routine microbiological screenings. It also makes it hard to identify the best available therapy for patients with a CRE infection and to develop effective alternative antibiotic treatments for a range of rare but emerging resistance problems.

CRE infections are most common in hospitals and other healthcare settings and can be very serious, as the patient may have failed previous therapy and have significant underlying disease. At present, physicians have limited options when they are confronted with a patient who turns out to have a serious CRE infection and require a diverse pipeline to counter the growing threat. Gaining knowledge about more effective treatments against CRE is urgent, but setting up effective trials for such a diverse bacterial adversary is a daunting task in itself.

Management Board Seamus O’Brien, Pfizer, Coordinator M arc Bonten, UMC Utrecht, Managing Entity J esús Rodríguez-Baño, Hospital Universitario Virgen Macarena Seville, Academic Deputy Coordinator

For more information, visit www.combacte.com or contact Marc Bonten or Seamus O’Brien: m.j.m.bonten@umcutrecht.nl, seamus.obrien@pfizer.com

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SPECIALISTS

ALEXEY RUZIN, OLIVIER BARRAUD

DIFFERENT ANGLES

Microbiologist & Microbiologist Both working in COMBACTE Alexey Ruzin: “I received my PhD in biology from New York University. I’ve worked at pharmaceutical companies since 1999.

First, at Wyeth, I studied the mechanism of action of mannopeptimycins, a novel class of glycopeptide antibiotics active against Gram-positive bacteria. Then I focused on mechanisms of resistance to potential antibacterial agents. My biggest achievement was contributing to the development of tigecycline, a broadspectrum antibiotic that received FDA approval. In 2015, I joined MedImmune, the global biologics research and development arm of AstraZeneca, to help develop antibody-based approaches against serious bacterial and viral infections.”

Alexey Ruzin Medimmune

Olivier Barraud Limoges University Hospital

Olivier Barraud: “I received my degree as a medical biologist here at Limoges University, in France, in 2007. Then, for my PhD, I studied antimicrobial resistance, or to be precise, integrons that are involved in the acquisition and dissemination of antibiotic resistance genes in Gram-negative bacteria. Since 2014, I’ve been assistant professor and clinical microbiologist at Limoges University Hospital (Centre Hospitalier Universitaire à Limoges, CHUL).”

Daily activities Alexey Ruzin: “My work involves mostly diagnostics, biomarkers and patient data to identify patients at risk, to find factors that correlate with disease protection and outcome, to characterize antibody targets and to monitor resistance. Day-to-day work is mostly meetings and discussions

with colleagues and external collaborators – I don’t work in the lab anymore.

Nowadays, I use my clinical microbiology expertise to understand lab data collected by others.”

“Within COMBACTE, I lead translational science for the development of suvratoxumab (formerly MEDI4893) and MEDI3902, monoclonal antibodies that target virulence factors of Staphylococcus aureus and Pseudomonas aeruginosa.

I also support epidemiological studies of those infections in Europe and serve as co-leader for LAB-Net, our shared laboratory surveillance network.”

“I interact with many clinical microbiologists from Europe, mostly through teleconferences and web meetings.

The last in-person meeting I had was at COMBACTE’s General Assembly in Brussels in early 2017. We had ‘biomarker breakout sessions’ where we jointly reviewed and discussed the data with 30 to 40 colleagues from Belgium, the Netherlands, Germany, Switzerland, Spain, France and other countries.”

Olivier Barraud: “My role at the hospital laboratory is to look at Petri dishes, identify pathogenic bacteria and test their susceptibility to antimicrobials. The most interesting part of my job is having daily calls with clinicians to discuss patients, infections and microbes. I give them early test results and help them find solutions for individual patients, especially if multidrug-resistant bacteria are involved.”

41

"We look at the same problem from different angles." assay that didn’t perform as well at an academic lab, so our academic partners came up with an alternative. We tested it and ultimately we all agreed it performed better. As you can see, we have much to learn from each other. Having such a diverse group of people is good, I think, because we look at the same problem from different angles. This helps us to collaboratively solve problems.”

“As an assistant professor, I teach students and coordinate their practicals. We let them analyze broths as if they were urine samples. It’s fun to see students discover live bacteria for the first time, identify species and determine their susceptibility to antibiotics.”

in a respiratory sample. In the other, I find Staphylococcus aureus in a routine patient sample and check with the intensive care unit whether the patient meets the other criteria. I think one third of the 80 patients we enrolled in Limoges came in through that second route.”

“As part of an INSERM unit (national institute for health and medical research) I also do research, like trying to detect integrons in humans, animals or the environment. I really like translational research.

For example, we recently led a pilot study using next-generation sequencing to test the microbiome and resistome of patients with urosepsis.”

Personal perspective Alexey Ruzin: “Scientists who work in academia have different perspectives, experiences and knowledge compared to those in industry, and that can be challenging sometimes. For example, in industry we have very strict clinical guidelines, scientific practice guidelines, assay development guidelines. For us, it’s natural to always follow them. While people in academia are oriented more to basic research, they are not always constrained by our guidelines and are not required to follow them. Thus, we have different organizational cultures.”

“At the hospital, we have a small, dedicated team that manages samples for dozens of clinical trials. We handle five COMBACTE trials. For SAATELLITE and EVADE, for example, we use two routes to enroll patients. In one, a clinician flags a patient who might qualify for the trial and lets me check whether the bug is present

“Then again, we can learn from their creativity. Recently, we had an industry

Olivier Barraud: “I find participating in COMBACTE highly rewarding: it gives me the opportunity to know the latest in antimicrobial resistance, to use new techniques. We regularly welcome clinicians and colleagues from all over the world in our lab to share experiences in the SAATELLITE and EVADE trials, so I also learn a lot about practices in other countries. That’s interesting, because it makes you realize, for example, that while here in Limoges the ICU and our lab are very close, elsewhere it may take hours for patient samples to reach the microbiology lab.”

“COMBACTE also taught me how some things can be perceived differently in industry or academia – although, from a microbiologist’s perspective, there are not too many differences. In my personal opinion, it’s key to have industrial partners in trials of new drugs or antibodies. We may sometimes have different perspectives on things, but we are all working toward the same goals.”

42

FUTURE

COMBACTE + PREPARE

BETTER, FASTER, CHEAPER

Is there life after COMBACTE? Much is being invested in the establishment of CLIN-Net and LAB-Net. Wouldn’t it be a shame if European society ceases to benefit from this after 2021? The answer is obvious. This story is about looking at the future and a fruitful cooperation.

“If we fail to put the infrastructure that’s been built to good use, we’ll have a divestment of value to answer for,” according to COMBACTE managing entity, Marc Bonten. “That’s why we began considering an independent post-2021 life for ourselves back in 2016. The networks have vast potential, especially if we pool our resources with another European program: PREPARE. The focus of that program is on being able to set up clinical research quickly in the event of impending epidemics.”

Herman Goossens is PREPARE coordinator as well as Academic Lead for LAB-Net. He is also a staunch proponent of a shared future existence. In fact, it has already been given a name: ECRAID, which stands for European Clinical Research Alliance for Infectious Diseases.

Broad outline The broad outline for life after 2021 calls for an active European network for clinical trials in the field of infectious diseases, built on the foundations laid by COMBACTE (>850 clinical care sites) and PREPARE (600 primary care sites). In this network, trials will be conducted continuously, allowing us to expand our experience and knowledge ever further.

According to Marc Bonten, such a net-

work of academics could set up trials much more effectively and efficiently than CROs. “The access to the network is quite direct.

Furthermore, academics are well aware of which site they should look to for a particular condition, for example. This allows us to shorten the preparation stage and realize the necessary inclusion with a smaller selection of hospitals. At the same time, we can significantly reduce the processing time and costs of trials as well.”

Game-changer Herman Goossens claims that this initiative, which sounds so logical it’s practically selfevident, is nothing less than a game-changer.

“We have a once-in-a-lifetime opportunity to gear up the considerable public and private resources already invested in the EU. In 2018, we should start designing and subsequently building an ambitious infrastructure on tackling AMR as well as other infectious disease threats. We will never be in such a privileged and pivotal decision point in our lifetimes ever again.” Such an infrastructure would be the only one of its kind in the world. It puts Europe in a position to take on a leadership role in infectious diseases’ clinical research.

“There is a great deal of interest, and the

Herman Goossens Coordinator, PREPARE Deputy Academic, Lead COMBACTE-NET Academic Lead, COMBACTE LAB-Net

Marc Bonten Academic Coordinator, COMBACTE Managing entity, COMBACTE CLIN-Net

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There is a great deal of interest in a permanent European clinical trial network

PREPARE PREPARE stands for Platform for European Preparedness Against (Re-)emerging Epidemics. It is a EU-funded network for harmonized large-scale clinical research studies on infectious diseases, prepared to respond rapidly

response from the pharmaceutical industry has been similarly positive, although risk aversion is understandably strong in that group. The current system with CROs is functional, so why take a risk? Therefore, we will need to convince pharmaceutical companies by getting the job done better, faster and cheaper.”

to any severe ID outbreak. Currently, it takes two to three years to launch a study – about as long as an epidemic typically lasts. PREPARE is aimed at responding to an epidemic much more quickly and starting trials immediately in order to prevent fatalities. Furthermore, pandemics occur maybe once every 10 to 20 years. When they do, there must be a well-prepared, properly trained and experienced network in place to manage them immediately. That is what PREPARE is today, and what ECRAID will be after 2021.

ECRAID • Faster and easier clinical research • Single-point access to a high quality, business-oriented research network • Rapid access to and knowledge of welldeveloped clinical and laboratory sites • A n active network that continuously includes patients in platform trials • A 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

What's in it for the clinical sites?

Drawing up a business case An ECRAID Working Group – including representatives from both programs – has now been established to draw up and elaborate the business case further. Bonten and Goossens are keen to see this done right, and in such a way that a permanent and leading European clinical trial network will be in place from 1 January 2022. The working group is hoping to receive EU funding to develop a sustainable business model for clinical research of Infectious Diseases in Europe, built on COMBACTE and PREPARE Clearly, the EU recognizes the potential of a shared future existence of these projects.

Logic behind the collaboration For COMBACTE, teaming up with PREPARE is a logical step, says Herman Goossens. “Naturally, there are differences between the two worlds of infections with antibiotic-resistant bacteria and viral pandemics. With antibiotic trials, the emphasis is on completing the trial quickly, while with a viral pandemic, you need to start as soon as possible. What they have in common is a need for a network of clinical sites with thoroughly trained staff in conducting trials. A network in which you can roll out a protocol and get approval from medical committees quickly, and in which the accompanying administrative tasks can be wrapped up quickly as well. PREPARE is already collaborating with CLIN-Net and LAB-Net. We compliment echt other’s set of skills and strengthen each other’s networks. In the future, when we collaborate within ECRAID, we intend to round out the network of laboratories and clinical investigation sites with a European network of well-trained general practitioners. Just imagine the possibilities for research in epidemiology and infectious diseases. Yes, there is true potential in a shared future.”

• O ptimum training in conducting clinical trials • E stablishing a reputation as a top medical center

For more information contact Marc Bonten or Herman Goossens at

• Financial compensation for trials

m.j.m.bonten@umcutrecht.nl or herman.goossens@uantwerpen.be.

44

MY NETWORK

COMBACTE

TOGETHER

My COMBACTE Community

Marlieke de Kraker STAT-Net, Geneva

The network of one of our colleagues

“Belén’s strong epidemiological expertise is of great use.

Together we are setting up a solid work schedule for EURECA in Seville. At the moment, she is taking care of all direct interaction with the participating centers, while for my part, I am managing a portion of the data quality and data analysis. The result is efficient cooperation.”

Jan Beyersman Institute of Statistics, Germany

“Belen and I closely interact on the sampling design of EURECA, with a lot of support from Jesús Rodríguez-Baño

Belén Gutiérrez-Gutiérrez

and Jan Feifel. The design preferably samples the truly informative (infected or colonized) patients, which will then be exploited in the statistical analysis.”

Belén collaborates in coordinating the EURECA study in Spain. Together with colleagues from Hospital Universitario Virgen Macarena in Seville, she acts as the hub connecting the participating Spanish sites and EURECA partners. Belén additionally maintains contact with the national coordinators in other

Maddalena Giannella

Team Member EURECA, Bologna “We share an interest in clinical research on multidrug-resistant

countries with regards to EURECA’s progress. She is

bacteria. I facilitate the parti-

regularly in touch with her colleagues at CLIN-Net, STAT-Net, LAB-Net and EPI-Net as well.

EURECA, Belén does the same

cipation of Italian centers in for Spain. She is an outstanding researcher, to share data with her is an enjoyable experience.”

George DaikoS

National Coordinator, Greece

Tomislav Kostyanev LAB-Net, Antwerp

“Belén and I are in regular contact about the progress of the study. Five Greek

“LAB-Net assisted in the selection of

clinical sites are active in EURECA and have

EURECA labs and was in charge of evaluating

contributed with more than 250 patients.

their preparedness to detect carbapenem-

As the national coordinator, I am the linking

resistant Gram-negatives. The selected labs

pin to those sites. It is very exciting and

are required to send all collected strains back to

rewarding to work as one team in clinical

Antwerp for confirmation and further characte-

research on an international level.”

rization, which actually runs pretty smoothly.”

PUBLIC & PATIENT INVOLVEMENT

COMBACTE

IMPROVING

45

Use patientS' experiences For MORE successful trials The advantages of Patient and Public Involvement in antimicrobial studies

Putting the experiences and insights of former patients to use improving a clinical study’s chances of success – it sounds like a dream come true for the team behind any antimicrobial study. But how to make it a reality? The answer is Patient and Public Involvement (PPI). COMBACTE is developing a PPI toolkit.

Andy Gibson, Associate Professor of PPI: “By integrating PPI into your study, you are no longer working on patients, but together with patients. By intensively working with patients, former patients and the public in all aspects of the study, you turn them into research partners.

Finding the best way to conduct the study together.” Obviously this will cost time, effort and commitment. But this does not outweigh the fact that PPI helps to make research transparent, relevant, ethically sound and tailor made for patients. “PPI paves the way to recruit more patients more quickly, and with better retention rates. Thus improving the quality of research. Simply put, it yields faster studies that cost less.”

Incorporate patients and the public as research partners in order to improve your success

How PPI can contribute throughout the study -B efore: helps design the best research process and questions.

Finding the best way to word all patient-related documentation, like consent forms and information sheets.

-D uring: insights in how to recruit patients, how and when to approach them, if it is appropriate to approach family members.

-A fter: finding the best way to communicate study results. Which arguments yield the most impact?

PPI in antimicrobial research The benefits of PPI are clear, which makes the outcomes of a systematic review conducted by the COMBACTEMAGNET WP6i team that much more noteworthy. Sally Grier, WP6i program manager: “It turns out peer-reviewed literature contained only one mention of PPI in antimicrobial studies. It would seem there are many opportunities for COMBACTE to improve the success of its studies.”

Toolkit Sally: “The WP6i study team set up a panel of former study participants and family members. Our experience is that they genuinely want to help make things better.” Together with this panel, a PPI toolkit is developed. It teaches study teams how to incorporate PPI into their work, for example, how to set up a panel and to work with them throughout the study. The toolkit contains a guide with clear instructions for getting started, plus examples, tips and tricks. “These are of great use for the COMBACTE study teams, in order to optimize the study results and speeding up the process as well. Consequently, we will make sure – through website, newsletters, et cetera – every study team will hear about this PPI toolkit.”

Interested in a PPI workshop for your team?

Contact Sally Grier at sally.grier@nbt.nhs.uk

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NEXT STAGE TRIAL

COMBACTE-CARE

COMPLETED

Getting ready to fight carbapenem-resistant BACTERIA

REJUVENATE Unique trial completes recruitment ahead of schedule

There is a growing and urgent need for new options to treat carbapenem-resistant bacterial infections in hospitalized patients.

In COMBACTE-CARE’s REJUVENATE trial the optimal dosing and safety of a new combinational drug is being tested on a small number of European patients. Thanks to public-private teamwork, the trial completed recruitment ahead of schedule, and global Phase III efficacy trials are now being set-up.

At the end of 2017, REJUVENATE’s trial database was formally locked and final analysis of the data set began. The clinical study report summing up the trial’s results, is planned for delivery in July 2018.

According to Alison Luckey, Lead Study Clinician at Pfizer and COMBACTE-CARE trial co-leader, the network has performed well: “It has performed just as I had hoped it would. We have all learned from working together.” Luckey has been impressed by the work of her academic partners, particularly by the trial site network that was created in Spain.

“With his team, José Miguel Cisneros Herreros, the Spanish national coordinator and academic co-leader, really set an example for such a network.

We had the pleasure of visiting some of the 10 Spanish sites, and it was great to witness the motivation and enthusiasm maintained by the network.”

Carbapenem resistance Among the AMR threats, multi-drug resistant (MDR) Gram-negative bacteria are among the biggest concerns. Increasingly, patients who get infected by Enterobacteriaceae, Pseudomonas aeruginosa or Acinetobacter baumannii no longer respond to treatment with carbapenems, a beta-lactam drug seen as a key drug of last resort, often due to the production of betalactamases. Furthermore carbapenem-resistant Enterobacteriaceae (CRE) are frequently MDR to many other classes of antibiotics resulting in few available treatment options.

COMBACTE-CARE aims to meet this challenge, by supporting the development of ATM-AVI, a combination of aztreonam, an existing intravenous antibiotic, and avibactam, an inhibitor of beta-lactamases.

The last patient was completed a month ahead of schedule Clinicians from academia and industry experts, within COMBACTE-CARE, set up REJUVENATE, a prospective Phase II trial to find the optimal dose and check the safety of ATM-AVI in 40 Spanish, French and German patients with complicated intra-abdominal CRE infections. REJUVENATE is the precursor to Phase III trials of the same drug combination, which aims to investigate the efficacy and safety of ATM-AVI in appropriate patient populations.

47

Despite an unexpected challenge, we managed to meet the original timelines Real clinical needs “As a clinician, I like to be involved early in the design of clinical trials,” says Oliver Cornely, Director of Translational Research and the Clinical Trial Center of the University of Cologne and academic co-leader of REJUVENATE. “Sometimes, a new and wonderful drug is developed that doctors can only use in small groups of patients because the trial populations were too narrow. That should not happen.”

In REJUVENATE, infectious disease specialists, surgeons and academic pharmacologists worked with colleagues from industry to make sure that ATM-AVI, when approved, will address real clinical needs. “Clinicians who treat these infections daily immediately notice when inclusion or exclusion criteria would be too restrictive,” Cornely says.

From the long list of criteria, many were discussed for this reason. One example was age. Cornely: “Never before have I seen a trial protocol that says subjects could be up to 90 years old. It’s easier to set the upper limit at 60, because patients would be healthier and more homogenous. But doctors deal with aging hospital populations. Ever more 80-year olds are undergoing surgery. So that was a typical contribution from the academic side.” Including academics and clinicians this way is unique, says Cornely. “It’s not always done in infectious disease clinical trials, but it increases the likelihood that we will get useful results.”

Acquisition Halfway through the trial, in 2016, an unexpected challenge arose. Pharmaceutical company Pfizer acquired the late-stage small molecule antibiotics portfolio of AstraZeneca, until then a pivotal COMBACTE-CARE partner and the developer of ATM-AVI. Cornely: “It did halt the proceedings for a while, but it could have been much worse. All parties reached a consensus that we should not waste work or money. The fact that the key people from AstraZeneca remained involved, now at Pfizer, was crucial.”

However thanks to a huge amount of flexibility and commitment shown both by the academic partners and Pfizer, we managed to maintain momentum and keep recruitment on track.”

“An awful lot of unanticipated work landed on us in the middle of a study, but in the end we didn’t lose any time at all,” Pfizer’s Luckey adds. “The last patient was even completed a month ahead of schedule. I think we owed that to a very good network and a close collaboration between all COMBACTE partners and Pfizer.”

Sharing of research Both the study protocol and the results will be published – which is important, Cornely says. “Everyone will be able to see what we did. I really appreciate Pfizer’s openness to do that. They could have called the protocol proprietary, but that’s not their attitude.” Focus will now move to the Phase III trial, with the COMBACTE-CARE network responsible for 100 patients across Europe out of a total of 300. Cornely: “In the end, something really good will come out of this. I think this sharing of public and private research is a smart thing to do.”

For more information please contact

Guy Turner, formerly at AstraZeneca and now Clinical Operations Lead representative at Pfizer, agrees: “The transition was obviously unexpected and created a challenge for all of us.

Oliver Cornely at oliver.cornely@uk-koeln.de, Guy Turner at guy.turner@pfizer.com or Allison Luckey at alison.luckey@pfizer.com.

48

LINKING PIN

MIQUEL EKKELENKAMP, MIRANDA HOPMAN

EXPERIENCE

The backbone of CLIN-Net national coordinators CLIN-Net’s network of clinical sites is among the crown jewels of COMBACTE. Yet without the national coordinators, success would be unimaginable. To a large extent, they determine the vitality of their respective national networks. Many of these national coordinators are members of established cooperative networks of experienced centers specializing in infectious diseases and intensive care units (ICUs).

Setting up a network of national coordinators was no easy task. Not every country has an existing network of sites where a logical candidate for national coordinator exists. On the other hand, the differences between individual countries also make it quite evident why a national coordinator is so important: each country has its own idiosyncrasies and therefore requires a customized solution.

National coordinators in 27 countries Today, CLIN-Net has a team of national coordinators in 27 countries. In other countries, the search for suitable candidates continues: highly motivated specialists in the field who are actively involved and can motivate others. They also need to have an insight into the sites in their

country and be well versed in local legislation. They will need to maintain contact with new and existing sites and provide advice regarding suitable sites for trials, as well as on the alignment of the trial protocol to the specific local situation.

Paul Dark

National Coordinator, UK “The critical care national research network I run involves over 200

Working towards improvements Based on an exchange of experiences, the CLIN-Net team is currently working towards several improvements. For instance, the team of national coordinators hopes to provide a greater insight into the use of their network: which sites take part in trials and which are rejected? The team is also working to draft procedures that are better aligned to the individual countries, as this will make the process more efficient for the national coordinators.

Intensive Care Units (ICUs), in which over 60 trials are in progress. All the same, we’re still learning lessons that other countries around Europe are trying to learn as well: developing partnerships, maintaining connectivity and collaboration. Nevertheless, the UK has a very active and well-funded clinical trial network that is well positioned to collaborate and help COMBACTE, irrespective of what Brexit may bring.”

49

Each country has its own idiosyncrasies and therefore requires a customized solution Despoina Koulenti

National Coordinator, Greece

George Daikos National Coordinator, Greece “Since antimicrobial resistance is

high-quality clinical trials. As a

on the rise in Greece, our clinical

national coordinator, I ensure that

centers were eager to contribute

the collaboration among them as

to COMBACTE, being such a

well as with the consortium runs

large-scale and ambitious project

smoothly. Soon after we joined,

that will potentially change our

we realized how exciting and

clinical practice and save many

rewarding it is to work as one

lives. So far, 11 clinical centers

team in clinical research, both at

are interconnected, conducting

a national and international level.”

Biljana Carevic National Coordinator, Serbia

“Antibiotic resistance in Greek hospitals is high.

COMBACTE offered a great opportunity for building a network of Greek ICUs, and providing ICU staff the opportunity to take part in high-quality, large-scale scientific projects.

It came as no surprise that the GCP training COMBACTE offered was well attended by Greek intensivists. I’ve been national coordinator since 2013 and my focus is to continuously ensure that the ICUs maintain high engagement with COMBACTE, have good collaboration and timely communications. The next step is enhancing the ICU network’s research infrastructure and enabling more Greek ICUs to effectively participate in high quality interventional studies.”

“Antimicrobial resistance is a growing problem in the eastern-European region. I feel it’s my personal calling to improve the prevention and control of infectious diseases across all of former Yugoslavia. Since I began the mission as the first epidemiologist in Serbia in 1995, I have built up a record of valuable contacts in the region. Something that helped in that area is that I set up a nursing school, where I train nurses to be infectious controllers, all of whom are currently active in the field. My base of operations is the gigantic Clinical Centre of Serbia. As National Coordinator for COMBACTE, I have an opportunity to put my regional network to use for the purpose of conducting international, high-quality research, while expanding the knowledge of many of my contacts. This is extremely valuable for them, as well as a big step forward in terms of scientific advancement.”

Oliver A. Cornely National Coordinator, Germany “For over 25 years I’ve been

that they adhere to the concept

doing clinical research, and I’ve

of one national coordinator is

been national coordinator since

because they have much to gain

2012. Actually, my team brought

from it. We offer them partici-

the idea to COMBACTE, since we

pation in several clinical trials,

already coordinated for some

as well as additional support like

other German groups as well,

a feasibility service. In addition,

which worked smoothly. For

when you contact us, you receive

COMBACTE, we connected many

a same-day response. That contri-

infectious diseases clinical rese-

butes to the success as well.”

arch groups and sites. The fact

Jane Minton National Coordinator, UK

“In the UK, we benefit from an existing network of clinical investigation sites. That makes my job – selecting sites for ASPIRE-SSI – much easier.

For the near future, I would very much like to intensify our collaboration with COMBACTE. This would be in the interest of the UK’s Infectious Diseases investigators, who are champing at the bit to participate in a COMBACTE interventional study. It would be in my personal interest as well, as it would bring me into contact with other national coordinators across Europe, thereby enriching my network.”

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OUR CHOICE

DA VOLTERRA

CO-LEADERSHIP

DA VOLTERRA'S FLYING START IN COMBACTE

Da Volterra answered our open call and joined us in 2016, bringing along a promising candidate product against Clostridium difficile infections, ready for testing. It was a perfect match with COMBACTE’s network of validated clinical trial sites.

MarieNoëlle Bouverne Director, Clinical Operations Da Volterra Paris, France

Da Volterra is a Paris-based biopharmaceutical company focused on the discovery and development of innovative therapeutic and preventive strategies for life-threatening multi-resistant bacterial infections. Marie-Noëlle Bouverne: “One of our candidate products, DAV132, aims to prevent Clostridium difficile infections, which are often triggered by the use of antibiotics in vulnerable hospitalized patients.

Ultimately, we hope that the product will also keep those patients from shedding antibiotic-resistant bacteria.” Needless to say, this suited COMBACTE perfectly.

How DAV132 works In essence DAV132 adsorbs small molecules, including most antimicrobials. “The key is that we only deliver it to the very end of the gastrointestinal tract. When a patient receives DAV132 besides antimicrobial medicine, drug uptake in the upper gastrointestinal tract is not affected. By clearing just

We completed recruitment within 13 months

the final part of the gut – the colon – of antimicrobial residues, we hope less resistant bacteria will develop.”

Access to patients Exploring new avenues like these can make trials more challenging. MarieNoëlle Bouverne: “We needed to identify a patient group that is most at risk of developing Clostridium difficile infections. A challenging task. Through COMBACTE’s clinical network, we were able to recruit 1,000 high-risk patients.”

Data collection has now finished, and the ongoing analysis will help prepare the next stage: a Phase III trial with DAV132, also in collaboration with COMBACTE. Smooth collaboration Marie-Noëlle Bouverne: “COMBACTE opened the door to 86 validated clinical centers, out of which we selected 34.

It all went pretty smoothly and we completed recruitment within 13 months, which was a good outcome in itself.”

Da Volterra’s clinical team worked with the COMBACTE team on a daily basis, sharing insights and optimizing the study’s protocol and execution. Through its lab facilities, COMBACTE also assists with central sample analyses, which also will provide key trial endpoints. “The collaboration went way beyond us cofunding the work. We really enjoy a real strategic and operational co-leadership.”

MY NETWORK

COMBACTE

51

TOGETHER

My COMBACTE Community

Jessica Price

Project Manager MedImmune, Gaithersburg, MD (USA)

The network of one of our colleagues in COMBACTE

“Frank and I collaborate to ensure open communication between Academic and EFPIA partners, as well as coordinate assay technology transfer and data reporting to support ongoing clinical studies. Frank works to align everyone to the same end goals.”

Willem van Wamel

Biomarker Basal Researcher, Rotterdam “Frank supplies my team with serum samples received from various study locations, which we then analyze for biomarkers. Reliable distribution and clear

Frank Coenjaerts

communication are essential to our work; we have the utmost

to the progress of the various COMBACTE studies.”

LAB-Net, Antwerp “The Antwerp team

confidence in Frank’s efforts.

He also keeps me informed as

Leen Timbermont

Frank and his team set up the assays required for SAATELLITE, ASPIRE-ICU, ASPIRE-SSI and EVADE in the laboratory facilities at UMC Utrecht. Once satisfied that everything is in place and ready to go, he turns them

coordinates and carries out

over to the research team that will be conducting the study. Frank is the linking pin between the COMBACTE

serum samples. We regularly

Consortium, MedImmune, the gobal biologics research and development arm of AstraZeneca, and the Medical Microbiology department of UMC Utrecht, where samples are analyzed more closely in search of biomarkers.

Ruud Smolders

Data Manager, Utrecht

Gerard Lina Biomarker Basal Researcher, Lyon

“Together we have developed software to

“We interact a lot to synchronize all tasks in the

help laboratories keep track of samples and

biomarker research work package. Once the

measurements. The software also has the ability

COMBACTE samples are done at UMC Utrecht,

to incorporate analysis results, such as biomarkers,

Frank and his team make sure we receive them

to be used in further research. Frank’s insightful

to conduct biomarker research. His inexhaustible

comments have improved our tool greatly.”

energy makes this complicated project a success.”

the microbiological work on the collected samples and strains; Frank and his team do the same thing, but for the confer to coordinate the distribution of samples and to discuss the progress of biomarkers.”

52

COMMUNICATION

INFO@COMBACTE.COM

CLARITY

THE IMPORTANCE OF BEING TRANSPARENT

vents checkone line

53

It may not be the most obvious of partnerships: collaboration between academics and pharmaceutical companies. And for the outside world looking in, investing public funds in collaboration with a private partner remains a controversial endeavor. Yet our experience is that such a private-public partnership yields many unprecedented rewards. In the interest of our current and future partnerships, we must respond to any skepticism. The only way to do so is to ensure transparent communication each and every day: about how the collaboration is proceeding, our day-to-day-work and – most importantly – our results. It is our obligation!

www.combacte.com The most comprehensive information can be found online. This includes background information on all COMBACTE projects, along with an overview of all studies. Details for each project are provided: study set-up, a complete list of participants and individual study dashboards showing current up-to-date study progress. Noteworthy developments and interim results can be found in study-specific updates. Influencers and key people in our network are showcased in blogs and interviews. There is also an extensive publication library including all publications generated by our consortium, press releases, posters and presentations.

Newsletter To make sure you don’t miss a thing, we send out a monthly newsletter detailing the month’s most significant developments. This includes study updates, publications, upcoming events and messages from the management boards and top enrollers.

Social If you follow us on Twitter, you are guaranteed to stay up to the minute on the latest developments – not through hastily dashed-off tweets, but with highquality study news content. When a new study update has been published or an event has been announced, you will know about it instantly – no need to wait for the newsletter to be published. Stay up to date about COMBACTE and the field of AMR. Events In addition to all the online interaction that COMBACTE generates, face-to-face interaction is a powerful and valuable way to forge important relationships with our network. This means putting in an appearance at the annual European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) and at national conventions. We also organize country visits to generate interest among local clinics and experts, to consolidate our clinical and laboratory network (CLIN-Net & LAB-Net), and to

highlight our training sessions on good clinical practice (GCP) and good clinical lab practice (GCLP). These events allow us to engage with our network, while creating opportunities for future collaboration.

Showcase video It can be quite a challenge to explain a complex project such as COMBACTE, and all the studies, partners and activities it encompasses. To address this, there is a brief informational video available, in which COMBACTE is introduced: our origins, partnerships and funding, and the work that we do.

Magazine Our magazine offers a unique crosssection of the entire project, with in-depth interviews with new partners, progress reports on studies and candid testimonials from the field. It contains a rich selection of articles that provide a quick insight into various stakeholders, backgrounds and relevant developments.

Promoting the achievements of the project is crucial for our long-term future

54

THE ISSUE ANTIMICROBIAL RESISTANCE IN THE EU EVERY YEAR:

UNIQUE COLLABORATION

KILLS

25.000 People

COSTS THE ECONOMY € 1.5 Billion

IMI established an unprecedented partnership between industry, academia and biotech organizations to combat antibiotic resistance in Europe

CHALLENGES

In the development of new drugs 1

Scientific challenges

2

Regulatory challenges

3

Business challenges

ACTIONPLAN EUROPEAN COMMISSION issued in 2011

IMI NEW DRUGS 4 BAD BUGS PROGRAM issued in 2012

OBJECTIVES 1

A self-sustaining antibacterial development network Expanded research and laboratory networks Optimal alignment of clinical trials with investigator sites Clinical and epidemiological data

2

Increased efficiency of antimicrobial drug development Align clinical trials with cutting edge molecular methodologies and trial design Deliver clinical trials with various candidate compounds from MedImmune/AstraZeneca, Aicuris, AstraZeneca, Da Volterra, The Medicines Company

T1

T5

T6

T8

IMPROVING CLINICAL TRIALS FOR ANTIBIOTICS

COMBATTING CARBAPENEM RESISTANCE

COMBATTING RESISTANT GRAMNEGATIVE BACTERIA

COMBATTING RESISTANT CLOSTRIDIUM DIFFICILE BACTERIA

THE 4 PILLARS OF COMBACTE

CLIN-Net

LAB-Net

STAT-Net

High-quality clinical

High-quality laboratory

Network to improve

Network to identify and

research network in

network in Europe with

clinical trials delivery,

map existing surveillance

Europe with certification

assessment of existing

perform advanced

systems, to establish

criteria and GCP

laboratory methods,

biostatistical and PK/PD

frameworks for data

Training program

quality assessment

modelling studies, evaluate

collection to support

system, specimens and

novel clinical design

antibacterial drug

strains repository

strategies using modern

development

biostatistical concepts

EPI-Net

www.combacte.com - info@combacte.COM - @combacte

This Research project receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement nยบ 115523 | 115620 | 115737 | 777362 resources of which are composed of financial contribution from the European Union Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution.