Abstract
Interest in phage therapy continues to intensify, driven in part by the threat of global antimicrobial multidrug resistance. However, there is uncertainty whether the phage therapy approaches – mainly, industrial fixed cocktails or, alternatively, personalized tailor-made phage products – can be clinically safe and efficacious. The adoption of separate regulatory protocols in EU Member States, with subsequent treatment experience gained in selected patients, supports the need for collecting high-standard clinical trial data. Since regulatory oversight will be a crucial determinant for successful introduction of bacteriophages into clinical practice, the main regulatory prerequisites for phage therapeutic development are highlighted.
This is a preview of subscription content, log in via an institution to check access.
References
Abedon ST, Thomas-Abedon C (2010) Phage therapy pharmacology. Curr Pharm Biotechnol 11(1):28–47
Abedon ST, Kuhl SJ, Blasdel BG et al (2011) Phage treatment of human infections. Bacteriophage 1(2):66–85
Borysowski J, Ehni H-J, Gorski A (2017) Ethics review in compassionate use. BMC Med 15:136
Breederveld RS (2019) Phage therapy 2.0. Where do we stand? Lancet Infect Dis 19(1):2–3
Castillo DE, Nanda S, Keri JE (2019) Propionibacterium (Cutibacterium) acnes bacteriophage therapy in acne: current evidence and future perspectives. Dermatol Ther (Heidelberg) 9(1):19–31
Chan BK, Abedon ST (2015) Bacteriophages and their enzymes in biofilm control. Curr Pharm Des 21:85–99
Chan BK, Turner PE, Kim S et al (2018) Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evol Med Public Health 1:60–66. https://doi.org/10.1093/emph/eoy005
d’Herelle F (1919) Sur le rôle du microbe bactériophage dans la typhose aviaire. C R Acad Sci 169:932–934
Dąbrowska K (2019) Phage therapy: what factors shape phage pharmacokinetics and bioavailability? Systematic and critical review. Med Res Rev 39:2000–2025
Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA et al (2019) Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med 25:730–733
Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex%3A32001L0018. Accessed 07 Jan 2020
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. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_83_cons2009/2001_83_cons2009_en.pdf. Accessed 07 Jan 2020
European Commission (2008) Annex 1: manufacture of sterile medicinal products. In: EudraLex – the rules governing medicinal products in the European Union, Volume 4: EU guidelines to good manufacturing practice, medicinal products for human and veterinary use. http://www.ec.europa.eu/health/files/eudralex/vol-4/2008_11_25_gmp-an1_en.pdf. Accessed 07 Jan 2020
European Medicines Agency (1998) International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Committee for Proprietary Medicinal Products (1998). CHMP/ICH Q5D note for guidance on quality of biotechnology products: derivation and characterisation of cell substrates used for production of biotechnological/biological products (CPMP/ICH/294/95). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003280.pdf. Accessed 07 Jan 2020
European Medicines Agency (2020) Human regulatory/research and development/scientific guidelines. https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines. Accessed 07 Jan 2020
European Union (2004) Regulation (EC) No 726/2004 of the European Parliament and Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2004_726/reg_2004_726_en.pdf. Accessed 07 Jan 2020
European Union (2007) Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2007:324:0121:0137:en:PDF. Accessed 07 Jan 2020
European Union (2008) 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. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2008_1234_cons_2012-11-02/reg_2008_1234_cons_2012-11-02_en.pdf. Accessed 07 Jan 2020
European Union (2014) Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf. Accessed 07 Jan 2020
Fauconnier A (2017) Regulating phage therapy: the biological master file concept could help to overcome regulatory challenge of personalized medicines. EMBO Rep 18:198–200. https://doi.org/10.15252/embr.201643250
Fischetti VA (2018) Development of phage lysins as novel therapeutics: a historical perspective. Viruses 10:310. https://doi.org/10.3390/v10060310
Fischetti VA (2019) Lysin therapy offers new hope for fighting drug-resistant bacteria. Science News, February 1. https://www.rockefeller.edu/news/24920-lysin-therapy-offers-new-hope-fighting-drug-resistant-bacteria/. Accessed 07 Jan 2020
Gordillo Altamirano F, Barr JJ (2019) Phage therapy in the postantibiotic era. Clin Microbiol Rev 32:e00066–e00018
Górski A, Międzybrodzki R, Łobocka M et al (2018) Phage therapy: what have we learned ? Viruses 10(6):288. https://doi.org/10.3390/v10060288
Harper DR (2018) Criteria for selecting suitable infectious diseases for phage therapy. Viruses 10(4):177. https://doi.org/10.3390/v10040177
Harper DR, Parracho HMRT, Walker J et al (2014) Bacteriophages and biofilms. Antibiotics 3:270–284. https://doi.org/10.3390/antibiotics3030270
Hodyra-Stefaniak K, Miernikiewicz P, Drapała J et al (2015) Mammalian host-versus-phage immune response determines phage fate in vivo. Sci Rep 5:14802. https://doi.org/10.1038/srep14802
Imanishi I, Uchiyama J, Tsukui T et al (2019) Therapeutic potential of an endolysin derived from Kayvirus S25-3 for Staphyloccocal impetigo. Viruses 11(9):76
Jault P, Leclerc T, Jennes S et al (2019) Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (Phagoburn): a randomised, controlled, double-blind phase 1/2 trial. Lancet Infect Dis 19(1):35–45
Jennes S, Merabishvili M, Soentjens P (2017) Use of bacteriophages in the treatment of colistin-only-sensitive Pseudomonas aeruginosa septicaemia in a patient with acute kidney injury – a case report. Crit Care 21:129. https://doi.org/10.1186/s13054-017-1709-y
Kutateladze M (2015) Experience of the Eliava institute in bacteriophage therapy. Virol Sin 30(1):80–81
Lehman SM, Mearns G, Rankin D et al (2019) Design and preclinical development for the treatment of antibiotic-resistant Staphylococcus aureus infections. Viruses 11(1):88
Leitner L, Sybesma W, Chanishvili N et al (2017) Bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomized, placebo-controlled, double-blind clinical trial. BMC Urol 17:90. https://doi.org/10.1186/s12894-017-0283-6
Łusiak-Szelachowska M, Żaczek M, Weber-Dąbrowska B et al (2017) Antiphage activity of sera in patients during phage therapy in relation to its outcome. Future Microbiol 12:109–117
Marza JA, Soothill JS, Boydell P et al (2006) Multiplication of therapeutically administered bacteriophages in Pseudomonas aeruginosa infected patients. Burns 32:644–646
McCallin S, Sacher JC, Zheng J et al (2019) Current state of compassionate phage therapy. Viruses 11(4):343
Międzybrodzki R, Borysowski J, Weber-Dąbrowska B et al (2012) Clinical aspects of phage therapy. Adv Virus Res 83:73–121
Nir-Paz R, Gelman D, Khouri A et al (2019) Successful treatment of antibiotic-resistant, polymicrobial bone infection with bacteriophages and antibiotics combination. Clin Infect Dis 69(11):2015–2018
Oechslin F (2018) Resistance development to bacteriophages occurring during bacteriophage therapy. Viruses 10(7):351
Parfitt T (2005) Georgia: an unlikely stronghold for bacteriophage therapy. Lancet 365(9478):2166–2167
Parracho HM, Burrowes BH, Enright MC et al (2012) The role of regulated clinical trials in the development of bacteriophage therapeutics. J Mol Genet Med 6:279–286
Patey O, McCallin S, Mazure H et al (2019) Clinical indications and compassionate use of phage therapy: personal experience and literature review with a focus on osteoarticular infections. Viruses 11(1):18
Pelfrene E, Willebrand E, Cavaleiro Sanches A et al (2016) Bacteriophage therapy: a regulatory perspective. J Antimicrob Chemother 71:2071–2074. https://doi.org/10.1093/jac/dkw083
Pires DP, Cleto S, Sillankorva S et al (2016) Genetically engineered phages: a review of advances over the last decade. Microbiol Mol Biol Rev 80(3):523–543
Pirnay J-P, De Vos D, Verbeken G et al (2011) The phage therapy paradigm: Prêt-à-Porter or Sur-mesure? Pharm Res 28:934–937
Pirnay J-P, Verbeken G, Ceyssens PJ et al (2018) The magistral phage. Viruses 10:64. https://doi.org/10.3390/v10020064
Principi N, Silvestri E, Esposito S (2019) Advantages and limitations of bacteriophages for the treatment of bacterial infections. Front Pharmacol 10:513. https://doi.org/10.3389/fphar.2019.00513
Regnstrom J, Koenig F, Aronsson B et al (2010) Factors associated with success of market authorisation applications for pharmaceutical drugs submitted to the European Medicines Agency. Eur J Clin Pharmacol 66:39–48
Reindel R, Fiore CR (2017) Phage therapy: considerations and challenges for development. Clin Infect Dis 64:1589–1590
Roach DR, Debarbieux L (2017) Phage therapy: awakening of a sleeping giant. Emerg Top Life Sci 1(1):93–103
Rodríguez-Rubio L, Jofre J, Muniesa M (2017) Is genetic mobilization considered when using bacteriophages in antimicrobial therapy? Antibiotics 6:32. https://doi.org/10.3390/antibiotics6040032
Sarker SA, Sultana S, Reuteler G et al (2016) Oral phage therapy of acute bacterial diarrhea with two coliphages preparations: a randomized trial in children from Bangladesh. eBioMedicine 4:124–137. https://doi.org/10.1016/j.ebiom.2015.12.023
Schooley RT, Biswas B, Gill JJ et al (2017) Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrob Agents Chemother 61(10):e00954–e00917. https://doi.org/10.1128/AAC.00954-17
Speck P, Smithyman A (2016) Safety and efficacy of phage therapy via the intravenous route. FEMS Microbiol Lett 363:fnv242. https://doi.org/10.1093/femsle/fnv242
Sulakvelidze A, Alavidze Z, Morris JG Jr (2001) Bacteriophage therapy. Antimicrob Agents Chemother 45:649–659. https://doi.org/10.1128/AAC.45.3.649-659.2001
Tan SY, Tatsumura Y (2015) Alexander Fleming: discoverer of penicillin. Singap Med J 56(7):366–367
Torres-Barceló C, Hochberg ME (2016) Evolutionary rationale for phages as complements of antibiotics. Trends Microbiol 24(4):249–256
Totté J, de Wit J, Pardo L et al (2017) Targeted anti-staphylococcal therapy with endolysins in atopic dermatitis and the effect on steroid use, disease severity and the microbiome: study protocol for a randomized controlled trial (MAAS trial). Trials 18:404. https://doi.org/10.1186/s13063-017-2118-x
Vandenheuvel D, Singh A, Vandersteegen K et al (2013) Feasibility of spray drying bacteriophages into respirable powders to combat pulmonary bacterial infections. Eur J Biopharm 84:578–582
Wienhold S-M, Lienau J, Witzenrath M (2019) Towards inhaled phage therapy in Western Europe. Viruses 11(3):295
Wittebole X, De Roock S, Opal SM (2014) A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens. Virulence 5:226–235
Wright A, Hawkins CH, Anggård EE et al (2009) A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin Otolaryngol 34:349–357
Disclaimer
The views expressed in this paper are the personal views of the authors and must not be understood or quoted as being made on behalf of or representing the position of the European Medicines Agency or one of its committees or working parties.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Switzerland AG
About this entry
Cite this entry
Pelfrene, E., Sebris, Z., Cavaleri, M. (2020). Regulatory Aspects of the Therapeutic Use of Bacteriophages: Europe. In: Harper, D., Abedon, S., Burrowes, B., McConville, M. (eds) Bacteriophages. Springer, Cham. https://doi.org/10.1007/978-3-319-40598-8_51-1
Download citation
DOI: https://doi.org/10.1007/978-3-319-40598-8_51-1
Received:
Accepted:
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-40598-8
Online ISBN: 978-3-319-40598-8
eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences