State of the regulatory affair: Regulation of phage therapy in Australia

Phage therapy: a solution for antibiotic resistance?

Phage therapy is gaining traction in the age of rising antibiotic resistance. Historically, phages have been known to behave like antiseptics and antibiotics, but a crucial aspect of their applicability as antibacterials is their capacity to be applied directly to living tissues without causing harm. An additional attractive characteristic is their selective activity against specific microbes, leaving existing useful microbiota intact. This narrow spectrum of activity can be exploited in the clinic in a phage cocktail with a defined antibacterial spectrum, or as bespoke (personalised) therapy. We are now seeing the commercialisation of natural and synthetic phages for clinical and industrial applications.

Human phage therapy in Australia: safe and tolerable, but still experimental

Recent studies in Australian centres of both intranasal instillation and intravenous injection of high-purity preparations of anti-staphylococcal phage have demonstrated safety and tolerability. The treatment, however, is not readily available to the general public and is prescribed only by trained health practitioners under defined conditions and protocols.

Our study: 14 patients treated with IV phage

We recently completed the largest single, uncontrolled, open-label, interventional clinical study at Westmead, Australia (n=39 referred, n=14 treated) of intravenous (IV) phage therapy in severe sepsis, where fourteen patients with severe Staphylococcus aureus infections received a GMP (Good Manufacturing Practice)-quality 3-phage cocktail product (AB-SA01, Armata Pharmaceuticals) as adjunct to standard of care, delivered IV twice daily for two weeks.

How our study was regulated

The US Food and Drug Administration (FDA) and the Australian Therapeutic Good Administration (TGA) both considered phage as an investigational drug during this study.

We conducted our study according to two TGA pathways: the Special Access Scheme (SAS) and the Clinical Trial Notification (CTN) scheme.

Special Access Scheme

Critically-ill patients were treated with AB-SA01 under the auspices of the TGA’s Special Access Scheme (SAS). This pathway is for health practitioners who wish to access therapeutic goods that are not listed on the Australian Register of Therapeutic Goods (e.g. phages), and as such, cannot be used for the purposes of conducting a clinical trial.

Treatment under the SAS is provided under a compassionate basis. Accordingly, clinical data and sampling is expected to be consistent with standard of care (including informed consent) and to be directed toward monitoring of patient safety rather than research purposes.

Clinical Trial Notification (CTN)

CTN is a notification scheme to the TGA. The TGA relies on the research institution's Human Research Ethics Committee and research sponsor (Local Health District) to review and approve the research protocols. After approval of the research protocols, the TGA is notified about the trial.

This pathway allows patient sampling according to ethically approved research protocols, and permits relevant further scientific investigations (i.e., whole genome sequencing of gut microbiome, environmental swabs, gene expression profiling of blood and valve from patients, phage kinetics in vivo, etc) under informed consent.

A third pathway: Clinical Trial Exemption

There is also a third pathway by which phage therapy can theoretically be regulated in Australia: Clinical Trial Exemption (CTX). This pathway is generally designed for complex therapies such as cell- or tissue-based products or novel treatments. Under the CTX scheme, the data about the product is reviewed by the TGA before commencement of the clinical trial.

The main determining factor to proceed according to the CTN or CTX scheme is whether the local Human Research Ethics Committee has access to the scientific and technical expertise required to assess the safety of the product.

For example, if our lab were to generate our own phage and/or phage cocktail according to GMP standards, the CTX route would apply. In the trial we describe here, however, we were able to provide the Westmead Hospital's Human Research Ethics Committee with evidence of the safety of the phage cocktail we used. Therefore, we could proceed according to the CTN instead of the CTX pathway.

A place for therapeutic phages in Australia: not yet settled

The classification of phage under the TGA's Biological Framework is not entirely clear, and this has meant that the place of therapeutic phages is not yet fully settled within the Australian regulatory framework.

At present, phage preparations are classified as investigational drugs. An application to use natural phages prepared in the laboratory to GMP standards, including exclusion of toxigenic impurities (e.g. FDA endotoxin limit for parenteral drug products is 175 EU/mL or 5 EU/kg), might therefore be allowed under the auspices of either the CTN or CTX (for research protocols) or SAS (for individual use on a compassionate basis) to treat patients in Australia.

Where to from here?

Ideally, randomised controlled trials using phages either as a cocktail preparation or through bespoke matching to a specific infection (magistral preparation route) would inform clinicians and scientists of how effective phage therapy is. From our initial experience, it is advisable that a multidisciplinary team should be engaged for such an approach.

Furthermore, advancement in synthetic biology opens up the application of synthetic phage in the clinical space, and this adds another level of complexity for regulatory bodies worldwide. The biological framework to classify such will need further discussion. For now, phage therapy has at least captured the imagination of the medical community.

References

1. Gilbey, T, Ho, J, Cooley, L, Petrovic-Fabijan, A, Iredell, J. Adjunctive bacteriophage therapy for prosthetic valve endocarditis due to Staphylococcus aureus. Medical Journal of Australia 2019; https://doi.org/10.5694/mja2.50274
2. Petrovic Fabijan, A, Ben Zakour, NL, Ho, J, Lin, RCY, Iredell, J. Polyclonal Staphylococcus aureus bacteremia. Annals of Internal Medicine 2019. In press.
3. Maddocks, S, Petrovic Fabijan, A, Ho, J, Lin, RCY, Ben Zakour, NL, Dugan, C, Kliman, I, Branston, S, Morales, S, Iredell, JR. Bacteriophage therapy of ventilator-associated pneumonia and empyema caused by Pseudomonas aeruginosa. American Journal of Respiratory and Critical Care Medicine 2019. Provisionally accepted.
4. Petrovic Fabijan, A. P., Lin, R. C., Ho, J., Maddocks, S., & Iredell, J. R. (2019). Safety and Tolerability of Bacteriophage Therapy in Severe Staphylococcus aureus Infection. bioRxiv, 619999. https://www.biorxiv.org/content/10.1101/619999v1.full
5. Pirnay, JP, Verbeken, G, Ceyssens, PJ, Huys, I, De Vos, D, Ameloot, C, Fauconnier, A. The Magistral Phage. Viruses. 2018;10(2):64. doi:10.3390/v10020064
6. Dedrick, RM, Guerrero-Bustamante, CA, Garlena, RA, Russell, DA, Ford, K, Harris, K, Glimour KC, Soothill, J, Jacobs-Sera, D, Schooley, RT, Hatfull, GF, Spencer, H. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nature Medicine 2019; https://doi.org/10.1038/s41591-019-0437-z