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Phage Therapy in Europe: Regulatory and Intellectual Property Protection Issues

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Phage Therapy: A Practical Approach

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.

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References

  • Abedon ST (2014) Phage therapy: eco-physiological pharmacology. Scientifica 2014:581639

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Abedon ST, Thomas-Abedon C (2010) Phage therapy pharmacology. Curr Pharm Biotechnol 11:28–47

    Article  CAS  PubMed  Google Scholar 

  • Aiello AE, King NB, Foxman B (2006) Ethical conflicts in public health research and practice. Am J Public Health 96:1910–1914

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Atlas RA, Maloy SED (2014) One health, people, animals, and the environment. ASM Press, Washington, DC

    Google Scholar 

  • Baquero F, Coque TM, Canton R (2003) Antibiotics, complexity and evolution. ASM News 69:547–552

    Google Scholar 

  • Benner SA (2010) Defining life. Astrobiology 10:1021–1030

    Article  PubMed  PubMed Central  Google Scholar 

  • Britton RA, Cani PD (2018) Bugs as drugs. ASM Press, Washington, DC

    Book  Google Scholar 

  • Brower V (2012) US court reverses gene patent ruling for BRCA1 and BRC2. Lancet Oncol 12:835

    Article  Google Scholar 

  • 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Brüssow H (2012) What is needed for phage therapy to become a reality in Western medicine? Virology 434:138–142

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buckling A, Rainey PB (2002) Antagonistic coevolution between a bacterium and a bacteriophage. Proc Biol Sci 269:931–936

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • Chanishvili N (2009) A literature review of the practical application of bacteriophage research. UK HPA, Eliava Institute of Bacteriophage, Microbiology and Virology, Tbilisi, Georgia

    Google Scholar 

  • Cleland CE (2007) Epistemological issues in the study of microbial life: alternative terran biospheres? Stud Hist Phil Biol Biomed Sci 38:847–861

    Article  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cooper MA, Shlaes D (2011) Fix the antibiotics pipeline. Nature 472:32

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Darwin C (1968) The origin of species. Penguin Classics, Penguin Group, London, UK

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  PubMed Central  Google Scholar 

  • 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)

    Google Scholar 

  • 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)

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fauconnier A (2019) Phage therapy regulation: from night to down. Viruses 11:352–360

    Article  PubMed Central  Google Scholar 

  • Forterre P (2001) Genomics and early cellular evolution, the origin of the DNA world. Life Sci 324:1067–1076

    CAS  Google Scholar 

  • Forterre P (2006) The origin of viruses and their possible role in major evolutionary transitions. Virus Res 117:5–16

    Article  CAS  PubMed  Google Scholar 

  • Gilmore BF (2012) Bacteriophages as anti-infective agents: recent developments and regulatory challenges. Expert Rev Anti Infect Ther 10:533–535

    Article  CAS  PubMed  Google Scholar 

  • Gold ER, Kaplan W, Orbinski J, Harland-Logan S, N-Marandi S (2009) Are patents impeding medical care and innovation? PLoS Med 7:e1000208

    Article  Google Scholar 

  • Honigsbaum M (2018) Superbugs and us. Lancet 319:420

    Article  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • Jernberg C, Löfmark S, Edlund C, Jansson JK (2010) Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology 156:3216–3223

    Article  CAS  PubMed  Google Scholar 

  • Kapczynski A (2009) Innovation policy for a new era. J Law Med Ethics 37:264–268

    Article  PubMed  Google Scholar 

  • Karkey A, Thwaites GE, Baker S (2018) The evolution of antimicrobial resistance in Salmonella typhi. Curr Opin Gastroenterol 34:25–30

    Article  CAS  PubMed  Google Scholar 

  • Kesselheim AS (2010) Using market-exclusivity incentives to promote pharmaceutical innovation. N Engl J Med 363:1855–1862

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kutateladze M, Adamia R (2010) Bacteriophages as potential new therapeutics to replace or supplement antibiotics. Trends Biotechnol 28:591–595

    Article  CAS  PubMed  Google Scholar 

  • Leibovici L, Paul M, Ezra O (2012) Ethical dilemmas in antibiotic treatment. J Antimicrob Chemother 67:12–16

    Article  CAS  PubMed  Google Scholar 

  • Levy SB, Marshal B (2004) Antibacterial resistance worldwide: causes, challenges and responses. Nat Med 10:S122–S129

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Ma W (2016) The essence of life. Biol Direct 11:49. https://doi.org/10.1186/s13062-016-0150-5

    Article  PubMed  PubMed Central  Google Scholar 

  • Martinez JL, Baquero F (2002) Interactions among strategies associated with bacterial infection: pathogenicity, epidemicity, and antibiotic resistance. Clin Microbiol Rev 15:647–679

    Article  PubMed  PubMed Central  Google Scholar 

  • Mayr E (2004) What makes biology unique? Considerations on the autonomy of a discipline. Cambridge University Press, Cambridge

    Book  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paterson IK, Hoyle A, Ochoa G, Baker-Austin C, Taylor NGH (2016) Optimizing antibiotic usage to treat bacterial infections. Sci Rep 6:37853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed Central  Google Scholar 

  • Podolski SH (2018) The evolving response to antibiotic resistance (1945–2018). Palgrave Commun 4:124

    Article  Google Scholar 

  • Raoult D, Forterre P (2008) Redefining viruses: lessons from the mimivirus. Nat Rev Microbiol 6:315–319

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • Selgelid MJ (2007) Ethics and drug resistance. Bioethics 21:218–229

    Article  PubMed  Google Scholar 

  • Servick K (2016) DRUG DEVELOPMENT. Beleaguered phage therapy trial presses on. Science 352:1506

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • Spellberg B, Tyalor-Blake B (2013) On the exoneration of Dr. William H. Stuart: debunking an urban legend. Infect Dis Poverty 2:3

    Article  PubMed  PubMed Central  Google Scholar 

  • Taubman A (2008) The international patent system and biomedical research: reconciling aspiration, policy and practice. AAPS J 10:526–536

    Article  PubMed  PubMed Central  Google Scholar 

  • Thiel K (2004) Old dogma, new tricks – 21st century phage therapy. Nat Biotechnol 22:31–36

    Article  CAS  PubMed  Google Scholar 

  • Tirard S, Morange M, Lazcano A (2010) The definition of life: a brief history of an elusive scientific endeavor. Astrobiology 10:1003–1009

    Article  PubMed  Google Scholar 

  • Torres-Barcello C (2018) The disparate effects of bacteriophages on antibiotic-resistant bacteria. Emerg Microbes Infect 7:168

    Article  CAS  Google Scholar 

  • Torres-Barcello C, Hochberg ME (2016) Evolutionary rationale for phages as complements of antibiotics. Trends Microbiol 24:249–256

    Article  CAS  Google Scholar 

  • Valenti R (2012) Time, evolution and physical reductionism. EMBO Rep 13:181–185

    Article  CAS  Google Scholar 

  • Van Overwalle G (2009) Gene patents and collaborative licensing models, patent pools, clearing houses, open source models and liability regimes. Cambridge University Press, Cambridge

    Book  Google Scholar 

  • Van Overwalle G (2010) Turning patent swords into shares. Science 230:1630–1631

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  Google Scholar 

  • Ward P (2005) Life as we do not know it. Viking Penguin, New York

    Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

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Authors and Affiliations

  1. Laboratory for Molecular and Cellular Technology (LabMCT), Queen Astrid Military Hospital, Brussels, Belgium

    Daniel De Vos, Gilbert Verbeken & Jean-Paul Pirnay

  2. QA/QC and regulatory affairs, Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, Belgium

    Gilbert Verbeken

  3. Vésale Bioscience, Noville sur Mehaigne, Belgium

    Johan Quintens

Authors
  1. Daniel De Vos
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  2. Gilbert Verbeken
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  3. Johan Quintens
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  4. Jean-Paul Pirnay
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Correspondence to Daniel De Vos .

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Editors and Affiliations

  1. Ludwik Hirszfeld Institute of Immunology, Polish Academy of Sciences, Wroclaw, Poland

    Andrzej Górski

  2. Ludwik Hirszfeld Institute of Immunology, Polish Academy of Sciences, Wroclaw, Poland

    Ryszard Międzybrodzki

  3. Department of Clinical Immunology, Medical University of Warsaw, Warsaw, Poland

    Jan Borysowski

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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

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