Antimicrobial resistance (AMR) has become a serious global health problem contributing to morbidity and mortality from infectious diseases caused by bacteria, viruses and other agents in all countries. The number of patients dying or suffering long term from bacterial infections that cannot be treated continues to rise, as does the burden for society in terms of healthcare and other costs.
One tool that could potentially combat AMR is bacteriophages (aka phages) – viruses that target and can kill bacteria. These highly personalised therapies are matched to the specific bacterial strain (or strains) causing a patient’s infection.
Advances in genetics means that phages – their strengths and weaknesses – are now better understood. Their potential and importance, in terms of combating AMR infections, is being recognised by different organisations, including the UK government.
UK report gets government response
A report “The antimicrobial potential of bacteriophages” from the House of Commons Science, Innovation and Technology Committee was published in November 2023 and highlighted the exciting possibilities of using phages more widely to treat drug-resistant bacterial infections. The report recognised the barriers to implementation but argued that with new ways of thinking both on how to classify medicines and how to run clinical trials, these barriers could be overcome.
Experts have welcomed the report, saying that the recommendations are both wide ranging and practical. If they are implemented, they could pave the way for the UK to develop phage manufacturing capabilities and phage biobanks. A government response to the report was released on 1 March 2024. The response acknowledged the important role that phages could play in responding to the increasing crisis of AMR, as well as acknowledging the challenges and barriers to phage use.
Licensing and regulation of phages
One challenge is that phages are living organisms, meaning that they need to be grown. In addition, the phage that matches the infection causing bacteria will need to be identified correctly. This complicates requirements for regulation, manufacturing, and clinical trial pathways. Understandably, for phages to be used in healthcare, manufacturing processes would need to adhere to strict quality standards to ensure their quality, safety, and efficacy. How to ensure this through licensing and regulation is highly debated and no single regulatory solution for their use may be sufficient.
There are several important legal questions around the use of phages: Should phage therapeutics be classified as a distinct and specially regulated category of medicinal products? Which legal framework should govern the various techniques and methods by which phages can be manufactured and administered? Which legal framework is appropriate depends on whether phage therapeutics are produced in a standardised, patient-independent manner (i.e. off-the-shelf) or customised for individual patients.
Whatever framework is selected, production will always need to be in accordance with standards, the most likely being Good Manufacturing Practice (GMP). This is important to ensure consistent, high-quality, production that ultimately benefits patients.
There is also a legal distinction between phage therapeutics derived from phages which exist in nature (called wild-type phages) and those engineered using genetic modification techniques. Therefore, when it comes to the production of phages for clinical use, differential legal classification may be necessary for each.
The Government response noted that a non-binding advisory guidance for the licensing requirements for phage products development by the Medicines and Healthcare products Regulatory Agency (MHRA) is in development. The guidance will include the type of quality, safety and efficacy data needed to evaluate applications for phage products intended for proactive and reactive use in the NHS for common infections. Public consultation on the guidance is due this year.
Phages allowed for compassionate use
While the current legal and regulatory landscape around use of phages is complex, current rules around compassionate use do allow for their use. For example in February 2023 the Scottish Health Technology Group (SHTG) issued advice for clinicians that phage therapy may now be considered for use directly at the site of infection as an alternative treatment for life threatening so-called ‘superbug’ infections that have developed resistance to a range of antibiotics.
Looking ahead, phage production will need to increase if they are to be used on a large scale. However, the financial burden to establish phage manufacturing that would meet Good Manufacturing Practice standards is relatively high. The report notes that ideally a single facility that would enable production in bulk would be the best way to move forward. This would help ensure equity of access, something that is lacking with the ad hoc use of phages that is currently taking place under specific circumstances.
Interest in phages is spreading
Phages have been used in parts of Eastern Europe and Russia for decades and with increasing AMR rates it is now not only the UK that has an interest in the potential of phages to combat AMR. The European Medicines Agency (EMA) released a concept paper for consultation in December 2023 on establishing guidelines for the development and manufacture of phages to be used to prevent and/or treat specific bacterial infections or diseases in humans. Although an EMA guideline for such products exists for veterinary medicinal products, there is no appropriate regulatory guidance for medicinal products for human use in the EU.
Phage-based strategies can also be applied in the management of livestock, crops, and food for the control of infections and prevent disease transmission. A report, released this month and put together by Innovate UK as part of AgriFood Africa Connect project, outlines opportunities in the AgriFood sector in Africa.
Since we published an explainer in November 2021 on the potential of phages for combating AMR, interest in phage therapy has grown. In the past few years the UK has seen the establishment of the Phage Innovation Network, the official launch of the University of Leicester’s Centre for Phage Research and the establishment of the UKHSA’s National Collection of Type Cultures (NCTC) bacteriophage collection. It is encouraging to see these developments. Phages have great potential to be an important tool to combat AMR, and while there is still work to do, we look forward to seeing the progress that will be made in this critical area of healthcare.