Optimizing the European Regulatory Framework for Sustainable Bacteriophage Therapy in Human Medicine
Tóm tắt
For practitioners at hospitals seeking to use natural (not genetically modified, as appearing in nature) bacteriophages for treatment of antibiotic-resistant bacterial infections (bacteriophage therapy), Europe’s current regulatory framework for medicinal products hinders more than it facilitates. Although many experts consider bacteriophage therapy to be a promising complementary (or alternative) treatment to antibiotic therapy, no bacteriophage-specific framework for documentation exists to date. Decades worth of historical clinical data on bacteriophage therapy (from Eastern Europe, particularly Poland, and the former Soviet republics, particularly Georgia and Russia, as well as from today’s 27 EU member states and the US) have not been taken into account by European regulators because these data have not been validated under current Western regulatory standards. Consequently, applicants carrying out standard clinical trials on bacteriophages in Europe are obliged to initiate clinical work from scratch. This paper argues for a reduced documentation threshold for Phase 1 clinical trials of bacteriophages and maintains that bacteriophages should not be categorized as classical medicinal products for at least two reasons: (1) such a categorization is scientifically inappropriate for this specific therapy and (2) such a categorization limits the marketing authorization process to industry, the only stakeholder with sufficient financial resources to prepare a complete dossier for the competent authorities. This paper reflects on the current regulatory framework for medicines in Europe and assesses possible regulatory pathways for the (re-)introduction of bacteriophage therapy in a way that maintains its effectiveness and safety as well as its inherent characteristics of sustainability and in situ self-amplification and limitation.
Tài liệu tham khảo
Abedon ST, Thomas-Abedon C (2010) Phage therapy pharmacology. Curr Pharm Biotechnol 11:28–47
Abedon ST, Kuhl SJ, Blasdel BG et al (2011) Phage treatment of human infections. Bacteriophage 1:66–85
Bruynoghe R, Maisin J (1921) Essais de thérapeutique au moyen du bacteriophage du Staphyloccoque [therapeutic trials using bacteriophage of Staphylococcus]. CR Soc Biol 85:1120–1121
Bush K, Courvalin P, Dantas G et al (2011) Tackling antibiotic resistance. Nat Rev Microbiol 9:894–896
Caplin J (2009) Bacteriophage therapy: old treatment, new focus? Microbiologist 10:20–23
Dodds-Smith I, Valverde S (2009) The supply of unlicensed medicines for individual patient use. In: Griffin JP (ed) The textbook of pharmaceutical medicine, 6th edn. Wiley-Blackwell, West Sussex, pp 331–346
Fernebro J (2011) Fighting bacterial infections-future treatment options. Drug Resist Updat 14:125–139
Fortuna W, Miedzybrodzki R, Weber-Dabrowska B et al (2008) Bacteriophage therapy in children: facts and prospects. Med Sci Monit 14:RA126–RA132
Gill JJ, Hyman P (2010) Phage choice, isolation, and preparation for phage therapy. Curr Pharm Biotechnol 11:2–14
Górski A, Miedzybrodzki R, Borysowski J et al (2009a) Bacteriophage therapy for the treatment of infections. Curr Opin Investig Drugs 10:766–774
Górski A, Targońska M, Borysowski J et al (2009b) The potential of phage therapy in bacterial infections of the eye. Ophthalmologica 223:162–165
Housby JN, Mann NH (2009) Phage therapy. Drug Discov Today 14:536–540
Khawaldeh A, Morales S, Dillon B et al (2011) Bacteriophage therapy for refractory Pseudomonas aeruginosa urinary tract infection. J Med Microbiol 60(Pt 11):1697–1700
Kropinski A (2006) Phage therapy—everything old is new again. Can J Infect Dis Med Microbiol 17:297–306
Krylov V (2011) Use of live phages for therapy on a background of co-evolution on bacteria and phages. Int Res J Microbiol 2:315–332
Kutateladze M, Adamia R (2008) Phage therapy experience at the Eliava Institute. Med Mal Infect 38:426–430
Kutateladze M, Adamia R (2010) Bacteriophages as potential new therapeutics to replace or supplement antibiotics. Trends Biotechnol 28:591–595
Kutter E, De Vos D, Gvasalia G et al (2010) Phage therapy in clinical practice: treatment of human infections. Curr Pharm Biotechnol 11:69–86
Letkiewicz S, Międzybrodzki R, Kłak M et al (2010) The perspectives of the application of phage therapy in chronic bacterial prostatitis. FEMS Immunol Med Microbiol 60:99–112
Matinkhoo S, Lynch KH, Dennis JJ et al (2011) Spray-dried respirable powders containing bacteriophages for the treatment of pulmonary infections. J Pharm Sci 100:5197–5205
Maura D, Debarbieux L (2011) Bacteriophages as twenty-first century antibacterial tools for food and medicine. Appl Microbiol Biotechnol 90:851–859
Merabishvili M, Pirnay JP, Verbeken G et al (2009) Quality-controlled small-scale production of a well-defined bacteriophage cocktail for use in human clinical trials. PLoS One 4:e4944
Monk AB, Rees CD, Barrow P et al (2010) Bacteriophage applications: where are we now? Lett Appl Microbiol 51:363–369
Payne RJ, Jansen VA (2003) Pharmacokinetic principles of bacteriophage therapy. Clin Pharmacokinet 42:315–325
Pirnay JP, De Vos D, Verbeken G et al (2011) The phage therapy paradigm: prêt-à-porter or sur-mesure? Pharm Res 28:934–937
Puapermpoonsiri U, Ford S, van der Walle CF (2010) Stabilization of bacteriophage during freeze drying. Int J Pharm 389:168–175
Rhoads D, Wolcott R, Kuskowski MA et al (2009) Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial. J Wound Care 18(237–238):240–243
Ryan E, Gorman S, Donelly RF et al (2011) Recent advances in bacteriophage therapy: how delivery routes, formulation, concentration and timing influence the success of phage therapy. J Pharm Pharmacol 63:1253–1264
Shorthose S, Bird & Bird LLP (2010) Guide to EU pharmaceutical regulatory law. Wolters Kluwer, Alphen aan den Rijn
Skurnik M, Strauch E (2006) Phage therapy: facts and fiction. Int J Med Microbiol 296:5–14
Sulakvelidze A, Alavidze Z, Morris JG Jr (2001) Bacteriophage therapy. Antimicrob Agents Chemother 45:649–659
Thiel K (2004) Old dogma, new tricks—21st Century phage therapy. Nat Biotechnol 22:31–36
Trouet C, Gobert M et al (2007) Investigational medicinal products. In: Clinical trials in Belgium: the Belgian implementation of the European Clinical Trials Directives. An operational guidance, 2nd edn. Intersentia, Antwerp
Verbeken G, De Vos D, Vaneechoutte M et al (2007) European regulatory conundrum of phage therapy. Future Microbiol 2:485–491
Wright A, Hawkins CH, Anggard 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