Bacteriophage therapy
cells were also attached. 56 According to Bar et al., ‘the targeting of phage nanomedicines via specific antibodies to receptors on cancer cell membranes resulted in endocytosis, intracellular degradation, and drug release, causing significant growth inhibition of the target cells in vitro with a potentiation factor of >1000 over the corresponding free drugs’. As the systemic administration of chemotherapeutic agents gives rise to indiscriminate drug distribution and relatively more severe toxicity, phage-mediated chemotherapeutic drug delivery appears to be a more appealing future approach to chemotherapy. Certain engineered phages can also be used via phage display to introduce and modulate polypeptides (including antibodies) for anti-cancer purposes, along with mRNAs and microRNAs. 57 However, as observed from previous studies and research results, phage-based cancer therapy approaches remain experimental and have not been fully explored and clinically tested in RCTs, a factor that may largely determine the future of this revolutionary new field of cancer treatment therapy.
The regulatory dogma and conundrum
No specific regulations have been outlined regarding the therapeutic use of phages. The unconventional characteristics of phages, for example, the high specificity, amplification at the site of infection, and the variability of their qualitative and quantitative composition due to their co- evolutionary dynamic patterns with bacterial hosts pose a unique and previously unencountered challenge for Western regulatory agencies. 58 Despite the opposition from phage-related professionals, phages have been categorized as medicinal products (known as phage therapy medicinal products (PTMPs)) across the European Union (EU) or a drug in the United States. 59 As defined on the website of th e European Medicines Agency (EMA), ‘A medicinal product is a substance or combination of substances that is intended to treat, prevent or diagnose a disease. ’ A similar definition of drugs has also been given by the FDA of the United States. According to the European Directive 2001/83/EC, medicinal products for human use that are intended to be placed on the market in the member states should be either prepared industrially or manufactured by a method involving an industrial process. This legislation also applies to the United States and Japan based on the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), which, in other words, means that this set of definitive requirements has become internationally recognized as it is mutually adopted by three regulatory agencies of significant international status. Consequently, phages, as medicinal products (drugs), are required to be produced under the framework of good manufacturing practices (GMPs), tested for efficacy and safety in RCTs, and authorized in the form of marketing authorization (none obtained in the EU or the US as of 2020).
56 Bar et al. 2008. 57 Ibrahim et al. 2014. 58 Fauconnier 2019. 59 Debarbieux et al. 2015.
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