Naar een aangepast regelgevend kader voor bacteriofaag therapie

Summary The worldwide emergence of antibiotic resistant bacteria and constraints to investment in potential solutions may eventually lead to a return to the pre-antibiotic era. As industries’ antibiotic pipeline is virtually dry and infectious diseases are steadily on the increase, the use of bacteriophages (bacteriophages are bacterio-specific viruses) to kill bacteria can be considered as a valuable option. Bacteriophages (meaning “bacteria-eaters”) are the bacteria’s natural enemies. In combination with or as substitute for antibiotics, bacteriophage therapy could be a therapeutic option in the eradication or control of bacterial colonization/infections. Bacteriophages can be considered as self-amplifying therapeutic products. By setting up a screening system for the circulating noxious bacteria and their respective bacteriophages it will be possible to obtain the right bacteriophage against any emerging pathogen. Bacteriophages were discovered independently during World War I by the French-Canadian biologist Felix d’Herelle and by the English microbiologist Frederick Twort. d’Herelle developed a commercial laboratory in Paris that produced and distributed bacteriophage preparations against various bacterial infections. In the 1930s, therapeutic bacteriophages were also marketed in the United States by major pharmaceutical companies. The advent of antibiotics relegated bacteriophage therapy to complete obscurity in most of the Western world. This PhD project aims at contributing to the creation of a dedicated European regulatory framework that makes the smooth re-introduction of bacteriophage therapy in the European Union possible. The research hypothesis is that final reflections and proposals, specifically designed in relation to bacteriophage therapy, will offer new and usable insights to all stakeholders involved. This research (11 studies) resulted in 14 international scientific publications that form the core of this thesis manuscript. Chapter 1 of this manuscript is written as a general introduction and describes the natural bacteriophage, the problem of bacterial resistance development to antibiotics, the potential of natural bacteriophages in tackling this problem, the history of bacteriophage therapy and the actual European medicinal product regulatory setting relevant to the therapeutic use of bacteriophages. This chapter also contains an overview of the PhD project, including the research objectives. Chapter 2 investigates the actual European regulatory and intellectual property hurdles relevant to the re-introduction of bacteriophage therapy into the European Union. This chapter also describes what a small-scale production of a qualitative bacteriophage cocktail, meant for use in e.g. a clinical trial, could look like. These investigations (and their results) intrigued regulators, politicians and medical ethical committees. The regulatory discussion on the subject of “bacteriophage therapy” was opened. Chapter 3 explains what an optimal regulatory pathway, tailored to bacteriophage therapy, could look like. It explains why bacteriophage therapy is probably best served by a tailor-made and sustainable bacteriophage therapy concept. Chapter 4 compares the bacteriophage therapy concept (explained in Chapter 3) with other medicinal products and assesses the compatibility of this bacteriophage therapy concept with current attitudes of national and European regulatory agencies towards bacteriophage products. Chapter 4 also analyses if the European Advanced Therapy Medicinal Products (ATMPs) Regulation, an example of an existing adapted medicinal product legislative framework, could be tailored to also cater for flexible bacteriophage therapy concepts. Chapter 5 proposes a dedicated European regulatory frame for bacteriophage therapy, including quality and safety requirements for sustainable bacteriophage therapy products. These requirements are consensus-requirements defined by 33 bacteriophage experts from 11 different countries. The proposed regulatory framework was validated during an international workshop that took place at the Belgian Royal Military Academy (Viruses of Microbes II, Brussels, Belgium). Chapter 6 investigates all stakeholders’ moral responsibility in relation to the large-scale re-introduction of bacteriophage therapy into the European Union. Moral principles are investigated and moral arguments are formulated in an effort to motivate all stakeholders to take bacteriophage therapy seriously. Although the efficacy of bacteriophage therapy has not been proven according to the actual standards of the European Union, bacteriophage therapy can be considered to be an Ethically Justified Medical Therapy (EJMT) within the European Union. Chapter 7 is written in the format of a concluding discussion summarizing legislative proposals that could work for the conceptual re-introduction of natural bacteriophage therapy into the European Union.

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