Testing safety and efficacy of phage therapy for the treatment of antibiotic-resistant bacterial infections

Expected Outcome:

This topic aims at supporting activities that are enabling or contributing to one or several expected impacts of destination “Tackling diseases and reducing disease burden”. To that end, proposals under this topic should aim to deliver results that are directed, tailored towards and contributing to most of the following expected outcomes:

• Researchers and developers make the best use of the state-of-the-art knowledge and resources for an effective development of new treatment options for patients suffering from difficult-to-treat infections.
• Healthcare professionals and people living with difficult-to-treat infections are ultimately provided with the availability of clinically useful phage therapies.
• Regulators are provided with quantifiable, verifiable and replicable data on safety and efficacy of phage therapy for human use and move faster towards market approval of novel phage-based therapies against antimicrobial resistant infections.
• Citizens are engaged and informed on innovative phage-based treatments as alternative therapeutic options complementary to antibiotics.

Scope:

Antimicrobial resistance (AMR) has been identified by the United Nations (UN) General Assembly as a health Emergency in 2016. AMR is contributing to morbidity and mortality increasing the burden for society and healthcare costs. This is due to a worrying increase on the number of bacteria resistant to antibiotic treatment, causing chronic and often life-threatening infections such as wound and urinary tract infections. The World Health Organization (WHO) lists AMR among the top 10 threats for global health^[1]and recognises that a lack of innovation is set to undermine antibiotic performance and health gains, with a major gap in the discovery of innovative antibacterial treatments^[2].

Hence, there is an urgent need for the development of therapies to treat infections.

Bacteriophages (phages) represent a promising alternative or complement to antibiotics for the treatment of infections that do not respond to conventional treatment options. With the increase of AMR bacteria, both healthcare practitioners and innovators are expressing an increasing interest in the use of phages for the treatment of infections. As a result, the clinical use of phage therapy is expanding in the EU and beyond under different regulatory pathways, approaches and different conditions (e.g. magistral personalised phage preparations and fixed phage cocktails applied via compassionate use, named-patients based or expanded access programmes) despite a lack of large data on the efficacy of phage therapy for human use. So far, a few modest-sized randomised-controlled trials have been conducted providing indications for the safety and efficacy of the phage products, in agreement with preclinical animal studies. However, they could not always prove the efficacy of phage preparations.

Therefore, proposals should aim to develop phage-based therapies to treat bacterial infections that do not respond to conventional treatment options. For this, applicants should carry out multicenter, multinational randomised controlled clinical trial (RCT) to generate scientific evidence demonstrating safety and efficacy of phage-based therapy as stand-alone or in combination with standard-of-care (such as antibiotic or other innovative non-antibiotic-based treatment) for the treatment of difficult-to-treat bacterial infections.

Both approaches for phage therapy, personalised phage preparations or ready-to-use phage cocktails, are in scope with the call. Innovative study design, aiming at better capturing and evaluating the full potential of the benefit of personalised phage therapy, e.g. using regularly updated phage preparations, is welcome.

The topic is open to any pathogen causing difficult to treat infections mainly due to AMR or to biofilms, for any clinical indication and applying phage treatment in any route of administration. Applicants are encouraged to address pathogens listed in the WHO Bacterial Priority Pathogens List^[3].

Lessons learned from previous clinical trials that failed^[4] (e.g. PhagoBurn) should be considered for optimal study design, e.g. inclusions and logistics criteria, to favour success and conclusive results. The proposed trial should be designed with proper patient selection, diagnostic protocols (e.g. phagogram), production protocols (purification, stability, host selection, etc.) and treatment protocols (including dosage, repetition, duration, route of administration).

All available information about the characteristics of the phages to be used in the clinical trial should be provided (e.g. sequence, stability, targeted bacteria, registration in a phage bank or phage registry, etc.). Moreover, any additional indication of the use of phages for other applications than human use in the clinical trial (e.g. veterinary use, surface cleaning, food preservation) should be detailed in the proposal if available.

The use of computational modelling and/or artificial intelligence (AI) tools is encouraged to speed/optimise trial design, implementation and/or the analysis of large data. In the same way, the use of innovative in silico, in vitro or in vivo models to facilitate pre-clinical selection of phages to use in the clinical trial is welcome.

In their proposal applicants should describe how they take into account scientific advice or protocol assistance from the European Medicines Agency (EMA)^[5]. In addition, applicants should provide a sound timeline on the trial protocol in their proposal. Furthermore, in their proposal applicants should also provide a delivery date for approval of the RCT protocol from the regulatory body(ies), which should be within 12 months from the start of the project.

Applicants should propose a clear exploitation pathway through the different necessary steps (research, manufacturing, regulatory approvals and licensing, Intellectual Property management, etc.) in order to accelerate marketing authorisation and uptake by the health systems.

The participation of start-ups, micro, small and medium-sized enterprises (SMEs)^[6] is encouraged with the aim of strengthening their scientific and technological foundations, enhancing their innovation potential, and exploring possibilities for commercial exploitation.

Proposals should adhere to the FAIR^[7] data principles, adopt wherever relevant, data standards and data sharing/access good practices, and apply good practices for GDPR^[8] compliant personal data protection.

Sex and gender-related differences should be addressed, where relevant. To ensure that the needs of patients living with chronic infections are adequately addressed and that there is public acceptability and confidence on innovative phage-based therapies, the involvement of patient and/or civil society representatives in all phases of the research and development process is strongly encouraged. For this, the topic requires the effective contribution of social sciences and humanities (SSH) disciplines and the involvement of SSH experts, institutions as well as the inclusion of relevant SSH expertise, in order to produce meaningful and significant effects enhancing the societal impact of the related research activities.

Applicants should provide details of their clinical studies^[9] in the dedicated annex using the template provided in the submission system. As proposals under this topic are expected to include clinical studies, the use of the template is strongly encouraged.

[1] https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance

[2] https://www.who.int/news/item/22-06-2022-22-06-2022-lack-of-innovation-set-to-undermine-antibiotic-performance-and-health-gains

[3] https://iris.who.int/bitstream/handle/10665/376776/9789240093461-eng.pdf?sequence=1

[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598614

[5] https://www.ema.europa.eu/en/human-regulatory-overview/research-development/scientific-advice-protocol-assistance

[6] https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32003H0361

[7] See definition of FAIR data in the introduction to this work programme part.

[8] General Data Protection Regulation: https://commission.europa.eu/law/law-topic/data-protection_en

[9] Please note that the definition of clinical studies (see introduction to this work programme part) is broad and it is recommended that you review it thoroughly before submitting your application.