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Today, there is a huge problem of antibiotic resistance. A lot of bacteria are developing resistance against multiple antibiotics, and the developing of new antibiotics is slowing down. Because these multidrug resistant bacteria are forming a threat to public health (they can cause infections, which even could lead to the death of patients), there has to be a search for alternatives. One such alternative could be phage therapy. Because there are some problems with authorising phages on the market, there also has to be searched for alternatives to treat patients with these phages. Some experts are proposing to prepare magisterial preparations with phages. Phages are not mentioned in the list of resources for magisterial compounding, which means that there has to be set up a document by the pharmacist. The safety and quality of phages has to be documented: for magisterial preparations, this needs to be done by the pharmacist by a certificate of analysis. For other uses, the quality and safety manners could be documented in the same way like allergens, or as Advanced Therapy Medicinal Products. This paper will be about natural phages used in human therapy. Bacteriofagen werden een honderdtal jaren geleden ontdekt maar zijn door de opkomst van de antibiotica verdrongen op de achtergrond voor de behandeling van infectieuze ziektes. Door de opkomst van resistentie is het noodzakelijk dat men opnieuw op zoek gaat naar alternatieve therapieën, hierdoor is de interesse in bacteriofagen opnieuw opgeflakkerd. Momenteel zijn verschillende onderzoeksgroepen en bedrijven die bacteriofagen voor verschillende doeleinden toepassen, maar deze zijn schaars en geïsoleerd. Wat staat de herintroductie van bacteriofaagtherapie precies in de weg? Aan de hand van een vragenlijst en interviews met contacten uit de industrie, gezondheidszorg en overheid werd er een beeld geschetst van het voornaamste obstakels die bacteriofaagtherapie in de weg stonden. Door een analyse met NVivo werden centrale onderwerpen geïdentificeerd en werden antwoorden onderling vergeleken. De onderzoeker kwamen tot de conclusie dat een gebrek aan interesse vanuit de industrie en de overheid door een gebrek aan absolute noodzaak gezien de efficiëntie waarmee antibiotica voorlopig nog worden ingezet. Daarnaast bleken bacteriofagen niet te passen binnen een duidelijk wetgevend kader en is er een dringende nood aan een duidelijke wetgeving op zowel nationaal als Europees niveau om investeringen te stimuleren. De onderzoekers zijn van mening dat de investering naar onderzoek van de overheid moet komen, te beginnen met de oprichting van een nationaal faagtherapiecentrum.

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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.