Adapting Drug Approval Pathways for Bacteriophage-Based Therapeutics

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.

Keywords: adaptive pathways; alternative licensing; bacteriophage; phage therapy; pharmaceutical regulation.

Figure 1

FDA Novel Drug Approval 2011–2015. Data obtained from (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm430302.htm). , Total; , anti-infective; , anti-bacterial.

Figure 2

Schematic representation of current FDA approval procedures for anti-infective drugs.

Figure 3

Proposed submission of whole phage based products under an adaptive licensing framework. ^aCharacterization to be based on genotypic analysis and lytic activity. ^bImprovement to be characterized on the basis of classical and surrogate endpoints.