Phages, also known as Bacteriophages, are viruses that infect specific bacteria and provoke their death via lytic activity. They are one of the constituents of human microbiomes, which are the collection of microbial life, also including bacteria, yeasts, fungi, archaea, and other viruses, which inhabits a specific environment such as the gut, skin, and vagina. Phages are in particular highly abundant in the gut where they represent the vast majority of viruses, and where high bacterial concentration is favorable to their presence. [1] Phages total community is designated as the phageome. [2] Together with eukaryotic viruses, phages constitute the virome.
Links between virome alterations and diseases such as IBD, systemic lupus erythematosus (SLE), rheumatoid arthritis and ankylosing spondylitis have been reported. However understanding the link between the gut virome and disease remains challenging due notably to the compositional variability in individual viromes, to the many transient viruses in the gut, and to high fluctuation levels of resident gut viruses. [3]
While the microbiome science has generated a lot of interest over the past years for its high potential to provide innovative, efficient, and targeted solutions to critical health issues, most applications have been envisaged for bacteria-based solutions. Yet, phages too have been identified as a promising solution in health applications, in particular as an alternative to antibiotics for the treatment of resistant infections. Antimicrobial resistance is identified as one of the bigger global public health threats, estimated to have been linked to 1.2 million in 2019 and an increase to approximately 10 million deaths per year anticipated by 2050. [4] The ability that micro-organisms gain to survive and grow in spite of treatments with antimicrobial agents that normally inhibit or kill them over repeated exposure makes infections hard to treat. [5] Due to their narrow spectrum of activities, phages also present potential for applications in personalized health approaches, directing their activity against individual patients’ isolates.
The first phage-based preparation cleared by the FDA as a food additive was ListShieldTM, composed by a Listeria-specific phage cocktail. Presented as a spray-on disinfectant to be applied on foods, the product prevented Listeria growth on refrigerated food. The product is also Generally Recognized As Safe (GRAS) in the US. [6]
Phage-based products have also been investigated in clinical settings, with a significant portion of clinical trials involving phages based on single patient administration during investigator-initiated studies and part of compassionate use for treatment multidrug-resistant bacteria leading to severe infections.
Determining the Regulatory governance for Phage therapy medicinal products in the EU and the US
Over the past years regulators over the world have worked on establishing key principles on how the regulatory framework should apply to microbiome products. [7] Still, the regulatory environment remains scarce on the case of phages. The use of phages for health applications has been envisaged in very diverse forms and approaches, from single wildtype phages for eradication of a given pathogen, to cocktails specifically adapted based on a given patients’ clinical sample, to engineered phages for delivery of resistance inactivating construct to target bacteria, resulting in various regulatory pathways applying to these products.
In both the EU and the US, defined Phage therapy medicinal products (PTMPs) would fall under the overall framework of medicinal products/drugs, as substances used in human beings for treating diseases. More specifically phage-based medicines are biological drugs due to the nature of the substance. [8] Phages do not qualify as ‘Live Biotherapeutic Products’ since they are not considered as living organisms: they depend on other organisms to carry out their biological processes. The framework under which such phage products are regulated in the EU and in the US is highlighted below.
Phage therapy medicinal products are opposed to personalized, non-industrially produced phage-based preparations, which would fall under the framework pharmacy-prepared magistral formulas, and subject to specific national provisions. The case of such phage preparations is not discussed in the present blogpost.
To date, no phage-based medicinal product has been approved neither in the US nor on an EU-wide level. Still, specific compassionate use of certain phage-based medicinal products has been authorized on local levels for example in France. [9]
In the EU
Medicinal products are currently regulated as per Directive 2001/83/EC. New and innovative medicines are evaluated at the EMA level through the centralized authorization procedure. While wild-type bacteriophages are not gene therapy products, phages with recombinant nucleic acid sequences may qualify as advanced therapy medicinal products (ATMP) and fall under the remit of the Committee for Advanced Therapies (CAT). [10]
National agencies are at the forefront of interactions with developers in particular in the context of clinical trials and temporary authorizations. On the national level too, regulatory agencies are monitoring state of the art, reflect on recent experiences and consider perspectives for the use of phage therapies. For example the French Agency ANSM created on repeated occasion specialized scientific committees for phage therapies. [11]
Joint reflections between regulators and experts and stakeholders from the academic and industrial sectors have taken place to explore the use of bacteriophages in therapeutics applications. [12] While to date the EU regulatory framework is not specifically adapted to human phage therapies, two initiatives in view to explore new approaches in such an emerging area are worth noting. A new European Pharmacopoeia general chapter on Phage therapy medicinal products has been adopted in April 2024, providing framework of requirements for the production and control of phage therapy products. [13] Following this, the Bacteriophages Working Party (BACT WP) will focus on elaborating recommendations for bacteriophage potency determination.
In December 2023, an EMA Concept paper on the establishment of a Guideline on the development and manufacture of human medicinal products specifically designed for phage therapy has been opened for public consultation. [14]
In the US
Phages are regulated as biological products by the Center for Biologics Evaluation and Research at the Food and Drug Administration (FDA).
The US Agency has been at the forefront of phage-based drugs development, approving the first clinical trial assessing genetically modified phages. [15] In response to the critical issue of antibiotic-resistant infections, phage therapy has been granted emergency use authorization (EUA) by the FDA which allows for its compassionate use on a case-by-case basis. [16]
The FDA has also been exploring the case of phage–based therapies including through dedicated public workshops. [17] However, to date, the FDA has not emitted dedicated guidance for the development of phage-based therapies.
Of note, in both the EU and the US, certain phage medicinal products may be subject to complementary requirements, such as conducting an environmental risk assessment for phages produced by genetic engineering, for example for deletion of virulence, antibiotic resistance genes or for increasing infectivity. Certain phage medicinal products may also benefit from special incentives such as accelerated pathways where the product presents a major interest for public health and fulfills an unmet medical need in serious conditions.
The potential of phage products for therapeutic use has caught the eye of regulators, and we see emerging the premises for adaptations in the regulatory frameworks. Nevertheless, challenges in the development of such products remain, and identifying and anticipating these is critical for developers to optimize their development strategy.
Conclusion
The high potential of phage-based therapies in particular to tackle antimicrobial resistance issues aligns with the high priority national and international organizations to tackle this threat.
Looking towards the future, while initiatives are being launched in the EU to explore new approaches for phage therapies, the EU pharmaceutical legislation is also undergoing a reform process, with one of its priorities being to address the key health stake of antimicrobial resistance. This notably translates through proposed incentives to reward successful development and secure access to effective antimicrobials. [18]
Overall, the pressing need for solutions to address antimicrobial resistances and the on-going evolutions of the regulatory framework notably in the EU are opening perspective for a framework supportive of human phage therapies development, through technical guidance and incentives for developers.
In this context it is of the utmost importance for developers to be able to engage with regulators and define how to tackle the specific development challenges of their phage medicinal products. Groundbreaking health solutions with potential to address serious unmet needs and public health issues are the ones who may most strongly benefit from a collaborative dialogue between developers and regulatory bodies, in a view to streamline development and allow patients to access the most innovative solutions. Phage-based medicinal products are typically strong candidates for such approaches.
The next post of this Phage therapeutics series will explore the key hurdles that may arise in the development of Phage Medicinal Products and how developers can overcome these.
References:
[1] Townsend EM, Kelly L, Muscatt G, Box JD, Hargraves N, Lilley D and Jameson E (2021) The Human Gut Phageome: Origins and Roles in the Human Gut Microbiome. Front. Cell. Infect. Microbiol. 11:643214. doi: 10.3389/fcimb.2021.643214
Juntao Shen, Jieqiong Zhang, Luofei Mo, Yanchen Li, Yake Li, Cun Li, Xiaoxian Kuang, Zining Tao, Zepeng Qu, Lu Wu, Junyu Chen, Shiying Liu, Linfang Zeng, Zexi He, Zuohong Chen, Yu Deng, Tong Zhang, Bing Li, Lei Dai, Yingfei Ma, Large-scale phage cultivation for commensal human gut bacteria, Cell Host & Microbe, Volume 31, Issue 4, 2023, Pages 665-677.e7, ISSN 1931-3128, https://doi.org/10.1016/j.chom.2023.03.013.
[2] Townsend EM, Kelly L, Muscatt G, Box JD, Hargraves N, Lilley D and Jameson E (2021) The Human Gut Phageome: Origins and Roles in the Human Gut Microbiome. Front. Cell. Infect. Microbiol. 11:643214. doi: 10.3389/fcimb.2021.643214
[3] Microbiome Progress: A look at 2023 – Health For Life Capital Funds – Seventure Partners
[4] Tang KWK, Millar BC, Moore JE. Antimicrobial Resistance (AMR). Br J Biomed Sci. 2023 Jun 28;80:11387. doi: 10.3389/bjbs.2023.11387. PMID: 37448857; PMCID: PMC10336207.
[5] EU Action on Antimicrobial Resistance – European Commission (europa.eu)
[7] Live Biotherapeutic Products (LBPs): unprecedented quality requirements by the Ph. Eur. Commission (2028); FDA Guidance for Industry on Early Clinical Trials with Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information (2016)
[8] Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (2022); Definition of the Term “Biological Product” (2020)
[9] Agence nationale de sécurité du médicament et des produits de santé – ANSM (sante.fr, 2022)
[10] EMA CAT stakeholder meeting 2023, Considerations on regulatory aspects: Regulatory framework for medicinal products in the context of therapeutic use of bacteriophages (2015)
[12] Workshop on the therapeutic use of bacteriophages (2025)
[16] Hitchcock, Nicole Marie, Danielle Devequi Gomes Nunes, Job Shiach, Katharine Valeria Saraiva Hodel, Josiane Dantas Viana Barbosa, Leticia Alencar Pereira Rodrigues, Brahm Seymour Coler, Milena Botelho Pereira Soares, and Roberto Badaró. 2023. “Current Clinical Landscape and Global Potential of Bacteriophage Therapy” Viruses 15, no. 4: 1020. https://doi.org/10.3390/v15041020
[17] Science and Regulation of Bacteriophage Therapy (2021)
[18] Reform of the EU pharmaceutical legislation; Revision of EU pharmaceutical legislation (2024)
Published on: April 17, 2024
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