Abstract
The global rise of multi-drug resistant bacteria has resulted in the notion that an “antibiotic apocalypse” is fast approaching. This has led to a number of well publicized calls for global funding initiatives to develop new antibacterial agents. The long clinical history of phage therapy in Eastern Europe, combined with more recent in vitro and in vivo success, demonstrates the potential for whole phage or phage based antibacterial agents. To date, no whole phage or phage derived products are approved for human therapeutic use in the EU or USA. There are at least three reasons for this: (i) phages possess different biological, physical, and pharmacological properties compared to conventional antibiotics. Phages need to replicate in order to achieve a viable antibacterial effect, resulting in complex pharmacodynamics/pharmacokinetics. (ii) The specificity of individual phages requires multiple phages to treat single species infections, often as part of complex cocktails. (iii) The current approval process for antibacterial agents has evolved with the development of chemically based drugs at its core, and is not suitable for phages. Due to similarities with conventional antibiotics, phage derived products such as endolysins are suitable for approval under current processes as biological therapeutic proteins. These criteria render the approval of phages for clinical use theoretically possible but not economically viable. In this review, pitfalls of the current approval process will be discussed for whole phage and phage derived products, in addition to the utilization of alternative approval pathways including adaptive licensing and “Right to try” legislation.
Highlights
The discovery of penicillin in 1928 heralded a dynamic shift in modern medicine with antibiotics quickly becoming one of the linchpins of modern medicine (Zaffiri et al, 2012)
As with all phage trials there are arguments that the overall number of participants in custom cocktail trials would be limited to just one (Eichler et al, 2015) as infecting strains, and cocktail composition, would vary on a patient to patient basis. As such it may be advantageous to inform AL trials based on a pre-characterized library of phages against a defined pathogen in a defined condition (e.g., Ps. aeruginosa burn infections), this would require a significant redesign of approvals processes
Despite the pressing need to develop new antibacterial agents, the approval rate of anti-bacterial drugs remains low when compared to other forms of drug due in part to both economic and scientific issues
Summary
The discovery of penicillin in 1928 heralded a dynamic shift in modern medicine with antibiotics quickly becoming one of the linchpins of modern medicine (Zaffiri et al, 2012). Both whole phages and their derived products will be subjected to the same rigorous clinical trials process as antibiotics They are classified as “Therapeutic biological products” and subject to the Food, Drug, and Cosmetic Act (http://www.fda.gov/RegulatoryInformation/ Legislation/FederalFoodDrugandCosmeticActFDCAct/FDCAct ChapterVDrugsandDevices/default.htm#Part_A; accessed 13th June 2016) and the Public Health Service Act (http://www.fda.gov/RegulatoryInformation/Legislation/ucm148 717.htm; accessed 13th June 2016) and under EU Directive 2001/83/EC (Rose et al, 2014; Pelfrene et al, 2016) and would require additional controls over the manufacturing process. Should any changes be made to the manufacturing process, extensive comparability testing would be required to confirm the consistency of the product (Chirino and Mire-Sluis, 2004) Regulators, such as the EMA, are aware of the additional issues faced by phage therapeutics and believe that dialogue with developers will contribute toward a solution (Kingwell, 2015). A single strictly virulent phage or phage derived product (e.g., endolysin) is selected from pre-clinical studies which produces a suitable level of bacterial reduction for the intended application
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