European Regulatory Framework for Bacteriophage therapy:
Opportunities and limitations
This article analyzes the opportunities and limitations of the current European Regulatory Framework under which phage therapy operates. Despite of the fact that phage therapy is not yet authorised in Europe to be used in patients, Belgian authorities found a way to integrate this therapy in their national law. Dr. Jean-Paul Pirnay, member of the Ethics Advisory Board of CURE, explains how this happened and how phage therapy is used at the Queen Astrid Military Hospital in Brussels.
Antimicrobial resistance has become a global threat and alternatives to antibiotics are urgently needed. In this context, bacteriophage therapy has become a potential alternative in the treatment of multi-drug resistant bacterial infections.
Historical clinical data on the effective use of phages in patients exists, mostly from Eastern Europe, particularly Poland, and former Soviet Republics, concretely, Russia and Georgia. However, these data have not been validated under European Regulatory standards and no evidence exists under these standards, proving the safety and efficacy of this therapy. For this reason, the use of phage therapy on humans is not yet authorised in Europe.
Under what Regulatory Framework does phage therapy operate?
Natural bacteriophages used as therapeutics are considered by the European Medicines Agency (EMA) medicinal products , placing them under the Directive 2001/83/EC on the Community code relating to medicinal products for human use , under the category of biologicals.
Under this regulatory framework, bacteriophage therapy can be authorised for its use on humans after marketing authorisation approval (Article 6). A marketing authorisation can only be obtained after the quality, safety and effectiveness of the therapy is proven, through the application of Good Manufacturing Procedures (GMP) and the review of preclinical data, followed by Phase I, II and III clinical trials (Article 8).
Limitations for bacteriophage therapy under the Medicinal Products Directive
On March 2011, European authorities formally stated that the existing Regulatory Framework is adequate for the use of bacteriophage therapy on humans . However, a large part the scientific community disagrees and calls for an urgent adaptation of the current legislation .
A legislation for evolving bacteriophages is needed
Phage preparations become less effective with time and updates are needed. Bacteriophages and bacteria co-evolve in a dynamic system and, as with antibiotics, bacteria can develop resistance to phages during the course of the treatment to survive the phage intervention .
However, after the marketing approval of a phage preparation, any modification on its composition as an addition, removal or replacement of a phage strain, aiming at improving its effectiveness, could only be possible through the application of a new marketing authorisation , following Article 8 of the Directive 2001/83/EC.
The current licensing pathway for medicinal products is not suitable for evolving bacteriophages. A revision of the current legislation is crucial to allow rapid updates and licensing of bacteriophage preparations as it is the case with the influenza vaccine .
‘One size fits all’ or ‘personalised’ approach?
The provisions described in the Directive 2001/83/EC apply to industrially produced medicinal products for human use intended to be placed on the market in Member States (article 2).
The current legislation imposes many requirements and procedures for manufacturing and obtaining marketing authorisation for bacteriophage therapy. In this context, these requirements would not limit industry actors to produce and pursue uniform market placement of bacteriophage-based products, but the lack of strong intellectual property protection and bacteriophage-bacteria resistance issues discourage pharmaceutical companies to invest in bacteriophage therapy. Paradoxically, non-profit hospitals are willing to develop personalised bacteriophage preparations to treat patients but the provisions imposed by the Directive are too costly and time-consuming for them .
However, non-profit hospitals in a few European countries, such as Belgium, have sporadically applied bacteriophages to treat individual patients under very exceptional circumstances. This was only possible by exclusion from the provisions of the Directive 2001/83/EC, under two exemptions defined in the legislation: the magistral formula exemption (Article 3) and the “special needs” exemption (Article 5).
Phage therapy in Belgium
In Belgium the authorities developed a more suitable regulatory environment for phage therapy. Dr Jean-Paul Pirnay, member of the Ethics Advisory Board of CURE and head of the laboratory for molecular and cellular technology at the Queen Astrid Military Hospital in Brussels, Belgium, took part in the process of conforming phage therapy to the Belgian law.
The Queen Astrid Military Hospital is a non-profit hospital working independently from industry actors. In 2007, it was the first Belgian hospital to reinitiate a focus on phage therapy. Since then, phage therapy was applied to more than 60 patients, first under the umbrella of article 37 from the Declaration of Helsinki and later under the magistral preparation framework. According to Dr Pirnay, “we almost always had success and we could not see any adverse effects”.
Article 37 from the Declaration of Helsinki states that in the treatment of an individual patient, where proven interventions do not exist or other known interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorised representative, may use an unproven intervention if in the physician’s judgement it offers hope of saving life, re-establishing health or alleviating suffering. Dr Pirnay pointed out that “this umbrella only applies in very desperate cases. It is more like a guideline and not a law”.
In July 2016, Belgian authorities acknowledged that phage therapy had no specific Regulation in Europe . “We decided that we needed to have something stronger to give more protection to doctors to use phages. That is how, together with authorities we put the phages into an existing framework: the Magistral Preparations”, Dr Pirnay said.
In January 2018, a Belgian Magistral Phage Framework was created, allowing phages to be processed as active pharmaceutical ingredients of magistral formulations. Magistral preparations operate in accordance with Article 3 of the Directive 2001/83/EC defined as any medicinal product prepared in a pharmacy in accordance with a medical prescription for an individual patient. They are not subjected to constraints such as marketing authorisation and are a practical way for a medical doctor to personalise patient treatments to specific needs and to make medication available that do not exist commercially .
Active pharmaceutical ingredients (APIs) of magistral preparations (in this case the phages) must conform to the provisions of a monograph, an official document that defines the quality standards for the elaboration of medicines. Ideally, this monograph has to be integrated in the European Pharmacopeia, of the Belgian Pharmacopeia or of any official Pharmacopeia .
In Europe a phage monograph does not exist and therefore experts of the Queen Astrid Military Hospital together with the Belgian Authorities took the initiative to elaborate a generic monograph on how to safely prepare and test phages for use on patients. On 10 January 2018, version 1.0 of the monograph was deemed appropriate by the Belgian competent authorities for medicines . “The next step would be to have the Belgian monograph integrated into the European Pharmacopeia. If we succeed in this, then it will be easier for phage therapy in other European countries and for commercial stakeholders to bring phage APIs to the European market and to produce (outsourced by the pharmacist) magistral phage preparations”.
Watch here the full interview with Dr Jean-Paul Pirnay explaining more in detail the use of bacteriophage therapy in the Queen Astrid Military Hospital and how the Belgian law integrated bacteriophage therapy.
An adaptation of the current European legislation is needed for bacteriophage therapy
It is clear that the Medicinal Products Directive did not consider medicinal products with the characteristics that phages have and, thus, cannot be considered suitable for phage therapy.
The current provisions that apply to industrial processes of bacteriophage preparations contrast with the idea and practical aspects of bacteriophage therapy itself, based on a sustainable and tailor-made patient approach .
European Regulators should define a Regulatory Framework differentiating the industrial and personalised approaches and allowing rapid updates of phage preparations and licensing procedures. Overcoming the current limitations will strengthen a further development of phage therapy in Europe.
It is time to implement a broader phage therapy regulatory framework. Supranational medicine agencies, such as the European Medicines Agency (EMA) should build on the initiatives developed by some national regulatory authorities . Policymakers need to open the door for a broad and fast (possibly interim) solution with reduced stringency as compared to the current pharmaceutical requirements . Phage banks containing large amounts of characterized (e.g. host range, genomic passport,..) and safe therapeutic phages need to be set up. Medical Doctors need to be made aware of the existence and content of these banks.
 World Health Organization. (2019). Ten threats to global health. Link: https://www.who.int/news-room/feature-stories/ten-threats-to-global-health-in-2019
 Verbeken, G., Pirnay, J. P., De Vos, D., Jennes, S., Zizi, M., Lavigne, R., ... & Huys, I. (2012). Optimizing the European regulatory framework for sustainable bacteriophage therapy in human medicine. Archivum immunologiae et therapiae experimentalis, 60(3), 161-172. Available at:
 Fontaine, N., & Reynders, D. (2001). 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. Official Journal of the European Communities L, 311, 67-128. Available at: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32001L0083&from=en
 Dalli, J. (2011). Answer given by Mr Dalli on behalf of the Commission. Parliamentary questions, European Parliament, Brussels, 10. Available at: https://www.europarl.europa.eu/sides/getAllAnswers.do?reference=E-2011-001144&language=CS
 Pirnay, J. P., De Vos, D., Verbeken, G., Merabishvili, M., Chanishvili, N., Vaneechoutte, M., ... & Van den Mooter, G. (2011). The phage therapy paradigm: pret-a-porter or sur-mesure?. Pharmaceutical research, 28(4), 934-937. Available at: https://www.researchgate.net/publication/47730148_The_Phage_Therapy_Paradigm_Pret-a-Porter_or_Sur-mesure
 Annex I (1) (c) of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products. Available at: https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:334:0007:0024:en:PDF
 Wood JM, Levandowski RA. The influenza vaccine licensing process. Vaccine. 2003;21:1786–8.
 Pirnay, J. P., Verbeken, G., Ceyssens, P. J., Huys, I., De Vos, D., Ameloot, C., & Fauconnier, A. (2018). The magistral phage. Viruses, 10(2), 64. Available at: https://www.researchgate.net/publication/322968736_The_Magistral_Phage
 World Medical Association. (2001). World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Bulletin of the World Health Organization, 79(4), 373. Available at: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/
 Fauconnier, A. Guidelines for Bacteriophage Product Certification. Methods Mol. Biol. 2018, 1693, 253–268. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29119445
 Fauconnier A. Phage Therapy Regulation: From Night to Dawn. Viruses. 2019 Apr 17;11(4). pii: E352.
 Moelling K, Broecker F, Willy C. A Wake-Up Call: We Need Phage Therapy Now. Viruses. 2018 Dec 5;10(12). pii: E688.