Optimizing the European Regulatory Framework for Sustainable Bacteriophage Therapy in Human Medicine

Abstract

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.

Appendix

Box 1 Innovation Task Force (ITF)

The “Innovation Task Force” of the European Medicines Agency (EMA)²³ is a multidisciplinary group of scientific, regulatory and legal experts set up at the EMA to provide a forum for early dialogue in the form of “briefing meetings”. The scope of the briefing meetings covers regulatory, technical and scientific issues arising from innovative medicines development, new technologies and borderline products. Within 60 days of receipt of a valid request, the ITF arranges free-of-charge briefing meetings to facilitate the informal exchange of information and the provision of guidance early in a development process. The scientific discussions are led by experts from the European Medicines Agency network, working parties and committees, where the best available scientific expertise is represented. Briefing meetings are meant to complement and reinforce existing formal regulatory procedures (e.g., ATMP classification, ATMP certification, designation of orphan medicinal products, etc.).

Box 2 Quality and safety evaluation criteria bacteriophage cocktail BFC1 (Merabishvili et al. 2009)

Characterization of the bacteriophages:

• Determination of the morphotype

• Complete DNA and proteome analysis (confirm absence of lysogeny and toxin genes)

• Testing host bacteria used in production for absence of (lysogenic) phage (mitomycin test)

QC tests performed by qualified accredited laboratories:

• Phage titer (agar overlay method)

• pH (according to EP)

• Cytotoxicity (ISO10993-5)

• Pyrogenicity (10 ml/kg rabbit, according to USP)

• Sterility (according to EP)

• Confirm morphology and activity towards targeted bacteria (transmission electron microscopy)

Box 3 Bacteriophages introduced into the food chain: some reflections

As a regulatory pathway, legislation for food supplements was investigated. In the US, the Food and Drug Administration (FDA) approved the use of Listex natural bacteriophages for the decontamination of foods.²⁴ Additionally, in the Netherlands and Switzerland anti listeria bacteriophages are in use for food products.²⁵ Current practice in the US for bacteriophage-based products is that such products are evaluated ‘case-by-case’ and finally approved (or not) under the US GRAS regulation (Federal Regulation of Substances Generally Recognized As Safe). In the US, foods and drugs are administered by one competent authority, the FDA, which is a federal structure without an equivalent in Europe. In Europe, the European Medicines Agency (EMA) and the European Food Safety Authority (EFSA) are two separate structures, probably explaining why it is a bigger step from food to medicinal products in Europe than it is in the US. However, in 2008 the European Commission (DG Health and Consumers) asked the EFSA to provide technical assistance in relation to the use and mode of action of bacteriophages on food of animal origin (Question No EFSA-Q-2008-400²⁶). The scientific opinion of the EFSA panel on biological hazards was endorsed on 22 April 2009. The EFSA panel concluded that some bacteriophages, under specific conditions, have been demonstrated to be very effective in the targeted elimination of specific pathogens present on meat, milk and products thereof. The panel, however, could not conclusively find that bacteriophages could protect such products when re-contamination of the decontaminated products occurs. The panel also proposed that a “case-by-case” evaluation of presented phage products is necessary. This European approach is comparable to the US (GRAS) approach, which is in fact a positive evolution.

Surprisingly, however, some (pro-biotic) food-products define health claims in their dossier without being registered as medicinal products (for example, Actimel²⁷ and Yakult²⁸). These types of products, by definition, also contain natural bacteriophages. It is questionable whether these health claims are evidence-based. In any case, the issue is hot in Europe, especially because Europe recently refused to accept some of the health claims related to specific products based on lack of evidence.²⁹ ,³⁰ Recently, an international workshop on the topic was organized in Brussels³¹ entitled “how to design studies to prove the claimed health effects of these food products”. Obviously, this field is moving quickly as well.