Abstract
Bacteriophages (phages for short) are increasingly put forward as potential (additional) tools in the fight against the worldwide antibiotic crisis. However, the setup of clinical trials, which are necessary to demonstrate the efficacy of phages and to optimize their clinical application protocols, and consequently to their implementation in the clinic is still hindered by the lack of an adapted regulatory framework. Although some (local) progresses have been made in recent years, no real paradigm shift has occurred. This chapter discusses the current status in Europe with regard to the two most pertinent barriers to phage therapy: the regulatory and intellectual property protection issues.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abedon ST (2014) Phage therapy: eco-physiological pharmacology. Scientifica 2014:581639
Abedon ST, Thomas-Abedon C (2010) Phage therapy pharmacology. Curr Pharm Biotechnol 11:28–47
Aiello AE, King NB, Foxman B (2006) Ethical conflicts in public health research and practice. Am J Public Health 96:1910–1914
Allen HK, Donato J, Wang HH, Cloud-Hansen KA, Davies J, Handelsman J (2010) Call of the wild: antibiotic resistance genes in natural environments. Nat Rev Microbiol 8:251–259
Atlas RA, Maloy SED (2014) One health, people, animals, and the environment. ASM Press, Washington, DC
Baquero F, Coque TM, Canton R (2003) Antibiotics, complexity and evolution. ASM News 69:547–552
Benner SA (2010) Defining life. Astrobiology 10:1021–1030
Britton RA, Cani PD (2018) Bugs as drugs. ASM Press, Washington, DC
Brower V (2012) US court reverses gene patent ruling for BRCA1 and BRC2. Lancet Oncol 12:835
Brüssow H (2009) The not so universal tree of life or the place of viruses in the living world. Phil Trans R Soc B 364:2263–2274
Brüssow H (2012) What is needed for phage therapy to become a reality in Western medicine? Virology 434:138–142
Brzuszkiewicz E, Thurmer A, Schuldes J, Leinbach A, Lieregang H, Meyer FD, Boelter J, Petersen H, Gottschalk G, Daniel R (2011) Genome sequence analyses of two isolates from the recent Eschericha coli outbreak in Germany reveal the emergence of a new pathogen type Entero-aggregative-Haemorhagic-Escherichia coli (EAHEC). Arch Microbiol 193:883–891
Buckling A, Rainey PB (2002) Antagonistic coevolution between a bacterium and a bacteriophage. Proc Biol Sci 269:931–936
Bush K, Courvalin P, Dantas G, Davies J, Eisenstein B, Huovinen P, Jacoby GA, Kishony R, Kreiswirth BN, Kutter E, Lerner SA, Levy S, Lewis K, Lomovskaya O, Miller JH, Mobashery S, Piddock LJV, Projan S, Thomas CM, Tomasz A, Tulkens PM, Walsh TR, Watson JD, Witkowski J, Witte W, Wright G, Yeh P, Zgurskaya HI (2011) Tackling antibiotic resistance. Nat Rev Microbiol 9:894–896
Cassini A, Högberg LD, Plachouras D, Quattrocchi A, Hoxha A, Simonsen GS, Colomb-Cotinat M, Kretzschmar ME, Devleesschauwer B, Cecchini M, Ouakrim DA, Oliveira TC, Struelens MJ, Suetens C, Monnet DL, Burden of AMR Collaborative Group (2019) Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European economic area in 2015: a population-level modelling analysis. Lancet Infect Dis 19:56–66
Chanishvili N (2009) A literature review of the practical application of bacteriophage research. UK HPA, Eliava Institute of Bacteriophage, Microbiology and Virology, Tbilisi, Georgia
Cleland CE (2007) Epistemological issues in the study of microbial life: alternative terran biospheres? Stud Hist Phil Biol Biomed Sci 38:847–861
Conlon-Bingham GM, Aldeyab M, Scott M, Kearney MP, Farren D, Gilmore F, McElnay J (2019) Effects of antibiotic cycling policy on incidence of healthcare-associated MRSA and Clostridioides difficile infection in secondary healthcare settings. Emerg Infect Dis 25:52–62
Cooper MA, Shlaes D (2011) Fix the antibiotics pipeline. Nature 472:32
Corbellini G (2008) Evolution based medicine (EBM), an epistemological framework for thinking of, and dealing with the so called “crisis of medicine”. J Hist Med 20:115–139
Danner M-C, Robertson A, Behrends V, Reiss J (2019) Antibiotic pollution in surface fresh waters: occurrence and effects. Sci Total Environ 664:793–804
Darwin C (1968) The origin of species. Penguin Classics, Penguin Group, London, UK
De Vos D, Verbeken G, Ceulemans C, Huys I, Pirnay J-P (2014) Reintroducing phage therapy in modern medicine: the regulatory and intellectual property hurdles, Ch. 12. In: Borysowski J, Miedzybrodski R, Gorski A (eds) Phage therapy, current research and applications. Caister Academic Press, New York
Djebara S, Maussen C, De Vos D, Merabishvili M, Damanet B, Pang KW, De Leenheer P, Strachinaru I, Soentjens P, Pirnay J-P (2019) Processing phage therapy requests in a Brussels Military Hospital: lessons identified. Viruses 11:265
European Parliament (2003) Commission Directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and the council of the Community code relating to medicinal products for human use. Official Journal of the European Union (translated into Belgian Law by Royal decree of 04.03.2004, published in the Belgian Official Journal on 10.03.2004)
European Parliament (2004) 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 (translated into Belgian Law by Royal Decree of 04.03.2004, published in the Belgian Official Journal on 10.03.2004)
Faruque SM, Naser IB, Islam MJ, Faruque ASG, Ghosh AN, Nair GB, Sack DA, Mekalanos JJ (2005a) Seasonal epidemics of cholera inversely correlate with the prevalence of environmental cholera phages. Proc Natl Acad Sci USA 102:1701–1707
Faruque SM, Islam MJ, Ahmad QS, Faruque ASG, Sack DA, Nair GB, Mekalanos JJ (2005b) Self-limiting nature of seasonal cholera epidemics: role of host-mediated amplification of phage. Proc Natl Acad Sci USA 102:6119–6124
Fauconnier A (2019) Phage therapy regulation: from night to down. Viruses 11:352–360
Forterre P (2001) Genomics and early cellular evolution, the origin of the DNA world. Life Sci 324:1067–1076
Forterre P (2006) The origin of viruses and their possible role in major evolutionary transitions. Virus Res 117:5–16
Gilmore BF (2012) Bacteriophages as anti-infective agents: recent developments and regulatory challenges. Expert Rev Anti Infect Ther 10:533–535
Gold ER, Kaplan W, Orbinski J, Harland-Logan S, N-Marandi S (2009) Are patents impeding medical care and innovation? PLoS Med 7:e1000208
Honigsbaum M (2018) Superbugs and us. Lancet 319:420
Human D, Fluss SS (2001) The World Medical Association’s declaration of Helsinki: historical and contemporary perspectives. http://www.wma.net
Jault P, Leclerc T, Jennes S, Pirnay J-P, Que Y, Resh G, Rousseau AF, Ravat F, Carsin H, Le Floch R, Schaal JV, Soler C, Fevre C, Arnaud I, Bretaudeau L, Gabard J (2019) Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (Phagoburn): a randomised, controlled, double-blind phase ½ trial. Lancet Infect Dis 19:35–45
Jennes S, Merabishvili M, Soentjens P, Pang KW, Rose T, Keersebilck E, Soete O, François P-M, Teodorescu S, Verween G, Verbeken G, De Vos D, Pirnay J-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
Jernberg C, Löfmark S, Edlund C, Jansson JK (2010) Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology 156:3216–3223
Kapczynski A (2009) Innovation policy for a new era. J Law Med Ethics 37:264–268
Karkey A, Thwaites GE, Baker S (2018) The evolution of antimicrobial resistance in Salmonella typhi. Curr Opin Gastroenterol 34:25–30
Kesselheim AS (2010) Using market-exclusivity incentives to promote pharmaceutical innovation. N Engl J Med 363:1855–1862
Khawaldeh A, Morales S, Dillon B, Alavidze Z, Ginn AN, Thomas L, Chapman SJ, Dublanchet A, Smithyman A, Iredell JR (2011) Bacteriophage therapy for refractory Pseudomonas aeruginosa urinary tract infection. J Med Microbiol 60:1697–1700
Kittler S, Wittmann J, Mengden RALP, Klein G, Rohde C, Lehnherr H (2017) The use of bacteriophages as one-health approach to reduce multidrug-resistant bacteria. Sustain Chem Pharm. https://doi.org/10.1016/j.scp.2016.06.001
Koonin EV, Starokadomsky P (2017) Are viruses alive? The replicator paradigm sheds decisive light on an old but misguided question. Stud Hist Philos Biomed Sci 59:125–134
Kumarasamy K, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, Chaudhary U, Doumith M, Giske CG, Irfan S, Krishnan P, Kumar AV, Maharjan S, Mushtaq S, Noorie T, Paterson DL, Pearson A, Perry C, Pike R, Rao B, Ray U, Sarma JB, Sharma M, Sheridan E, Thirunarayan MA, Turton J, Upadhyay S, Warner M, Welfare W, Livermore DM, Woodford N (2010) Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis 10:597–602
Kutateladze M, Adamia R (2010) Bacteriophages as potential new therapeutics to replace or supplement antibiotics. Trends Biotechnol 28:591–595
Leibovici L, Paul M, Ezra O (2012) Ethical dilemmas in antibiotic treatment. J Antimicrob Chemother 67:12–16
Levy SB, Marshal B (2004) Antibacterial resistance worldwide: causes, challenges and responses. Nat Med 10:S122–S129
Li R, Jay JA, Stenstrom MK (2019) Fate of antibiotic resistance genes and antibiotic-resistance bacteria in water resource recovery facilities. Water Environ Res 91:5–20
Ma W (2016) The essence of life. Biol Direct 11:49. https://doi.org/10.1186/s13062-016-0150-5
Martinez JL, Baquero F (2002) Interactions among strategies associated with bacterial infection: pathogenicity, epidemicity, and antibiotic resistance. Clin Microbiol Rev 15:647–679
Mayr E (2004) What makes biology unique? Considerations on the autonomy of a discipline. Cambridge University Press, Cambridge
Mi S, Lee X, Li X-P, Veldman G, Finnerty H, Racie L, LaVilie E, Tang X-Y, Edouard P, Howes S, Keith JC, McCoy JM (2000) Syncitin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403:785–789
Möller-Gundersen K, Nygaard Jensen J, Bjerrum L, Plejdrup Hansen M (2019) Short-course vs long course antibiotic treatment for community-acquired pneumonia: a literature review. Basic Clin Pharmacol Toxicol 124:550–559
Parracho HM, Burrowes BH, Enright MC, McConville ML, Harper DR (2012) The role of regulated clinical trials in the development of bacteriophage therapeutics. J Mol Genet Med 6:279–286
Paterson IK, Hoyle A, Ochoa G, Baker-Austin C, Taylor NGH (2016) Optimizing antibiotic usage to treat bacterial infections. Sci Rep 6:37853
Patey O, McCallin S, Mazure H, Liddle M, Smithyman A, Dublanchet A (2018) Clinical indications and compassionate use of phage therapy: personal experience and literature review with a focus on osteoarticular infections. Viruses 11:11
Peek and Reddy (2006) https://www.federalregister.gov/documents/2006/08/18/E6-13621/food-additives-permitted-for-direct-addition-to-food-for-human-consumption-bacteriophage-preparation
Phoba MF, Barbé B, Lunguya O, Masendu L, Lulengwa D, Dougan G, Wong VK, Bertrand S, Ceyssens PJ, Jacobs J ea (2017) Salmonella enterica serovar Typhi producing CTX-M-15 extended spectrum beta-lactamase in the Democratic Republic of the Congo. Clin Infect Dis 65:1229–1231
Pirnay J-P, Verbeken G, Ceyssens P-J, Huys I, De Vos D, Ameloot C, fauconnier A (2018) The magistral phage. Viruses 10. https://doi.org/10.3390/v10020064
Podolski SH (2018) The evolving response to antibiotic resistance (1945–2018). Palgrave Commun 4:124
Raoult D, Forterre P (2008) Redefining viruses: lessons from the mimivirus. Nat Rev Microbiol 6:315–319
Renjie L, Jay JA, Stenstrom MK (2019) Fate of antibiotic resistance genes and antibiotic-resistant bacteria in water resource recovery facilities. Water Environ Res 91:5–20
Selgelid MJ (2007) Ethics and drug resistance. Bioethics 21:218–229
Servick K (2016) DRUG DEVELOPMENT. Beleaguered phage therapy trial presses on. Science 352:1506
Shanks N, Pyles RA (2007) Evolution and medicine: the long reach of “Dr. Darwin”. Philos Ethics Humanit Med 24. https://doi.org/10.1186/1747-5341-2-4
Spellberg B, Tyalor-Blake B (2013) On the exoneration of Dr. William H. Stuart: debunking an urban legend. Infect Dis Poverty 2:3
Taubman A (2008) The international patent system and biomedical research: reconciling aspiration, policy and practice. AAPS J 10:526–536
Thiel K (2004) Old dogma, new tricks – 21st century phage therapy. Nat Biotechnol 22:31–36
Tirard S, Morange M, Lazcano A (2010) The definition of life: a brief history of an elusive scientific endeavor. Astrobiology 10:1003–1009
Torres-Barcello C (2018) The disparate effects of bacteriophages on antibiotic-resistant bacteria. Emerg Microbes Infect 7:168
Torres-Barcello C, Hochberg ME (2016) Evolutionary rationale for phages as complements of antibiotics. Trends Microbiol 24:249–256
Valenti R (2012) Time, evolution and physical reductionism. EMBO Rep 13:181–185
Van Overwalle G (2009) Gene patents and collaborative licensing models, patent pools, clearing houses, open source models and liability regimes. Cambridge University Press, Cambridge
Van Overwalle G (2010) Turning patent swords into shares. Science 230:1630–1631
Verbeken G, De Vos D, Vaneechoutte M, Merabishvili M, Zizi M, Pirnay J-P (2007) European regulatory conundrum of phage therapy. Future Microbiol 2:485–491
Verbeken G, Pirnay J-P, De Vos D, Jennes S, Zizi M, Lavigne R, Casteels M, Huys I (2012) Optimizing the European regulatory framework for sustainable bacteriophage therapy in human medicine. Arch Immunol Ther Exp 60:161–172
Ward P (2005) Life as we do not know it. Viking Penguin, New York
Websites https://www.nobelprize.org/uploads/2018/06/fleming-lecture.pdf; https://www.reactgroup.org/antibiotic-resistance/course-antibiotic-resistance-the-silent-tsunami/part-1/the-discovery-of-antibiotics/
WHO Policy package to combat antimicrobial resistance. www.who.int/world-health-day/2011/presskit/WHDIntroductotobriefs.pdf?bcsi_scan_3c79e7817cdc4fd7=0&cbcsi_scan_filename=WHDInterntrototobriefs.pdf. Accessed Jan 2012
Williams PD (2010) Darwinian interventions: taming pathogens through evolutionary ecology. Trends Parasitol 26:83–92
World Medical Association (2008) Declaration of Helsinki. Ethical principles for medical research involving human subjects. http://www.wma.net/en/30publications/10policies/b3/index.html. Accessed Jan 2012
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
De Vos, D., Verbeken, G., Quintens, J., Pirnay, JP. (2019). Phage Therapy in Europe: Regulatory and Intellectual Property Protection Issues. In: Górski, A., Międzybrodzki, R., Borysowski, J. (eds) Phage Therapy: A Practical Approach. Springer, Cham. https://doi.org/10.1007/978-3-030-26736-0_15
Download citation
DOI: https://doi.org/10.1007/978-3-030-26736-0_15
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-26735-3
Online ISBN: 978-3-030-26736-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)