First Report - The antimicrobial potential of bacteriophages

The safety of phages has been well established mainly on the basis of observational evidence drawn from specific clinical interventions. However, as with all medicines, robust clinical trial data is important to provide and develop assurances around all aspects of patient safety, including the long-term impact of phages, especially their interaction with human immune systems, such as anaphylaxis and auto immune response.

Clinical data indicates that in many cases phages have been observed to reduce bacterial infections in patients. We also heard that their use in animals has also been shown to be effective. However, further clinical trials are required to prove the consistent effectiveness of phages. Such studies need to include analysis of the impact of different phage cocktails as well as phage/antibiotic combinations.

We recommend that the Department for Health and Social Care (DHSC), the Medicines and Healthcare products Regulatory Agency (MHRA), the National Institute for Health and Care Excellence (NICE) and National Institute for Health and Care Research (NIHR) should now consider what specific evidence, and to what standard, is needed to fully assess the safety and effectiveness of phages to allow them to be used more widely within the NHS and other UK healthcare settings, including over the long term. DHSC, MHRA, NICE and NIHR should engage with phage researchers to establish a dialogue on these issues. The Phage Knowledge Transfer Network established by Innovate UK to bring together phage stakeholders would be an appropriate forum for this dialogue.

Phages have been used as therapy for over a hundred years, and much of the fundamental science relating to phages is understood. However, there is still more that the global and UK research communities can learn. Further research will be able to establish key issues such as long-term interactions between phages and human hosts and how phages can be engineered to maximum effect, to work alone or in combination with antibiotics. Such research will help hone phage therapeutics and clinical practice. The UK is well placed to conduct this research as it has a number of leading phage research centres and academics, and access to world class genomic sequencing and bioinformatic resources and experts.

However, the apparent reticence of funders to commit to phages is despite a general acceptance in the evidence we took that phages show promise and need more research alongside clinical trials. It is important to understand and reflect on the reasons for this. The recently established Innovate UK Phage Knowledge Transfer Network may provide such a forum for funders and phage researchers to discuss these matters.

Because phages have had relatively limited recent research funding from public sources, we recommend that the Government reviews the status of phages within its plans to tackle AMR. We also recommend more specifically that the National Institute for Health and Care Research and the UK Health Security Agency engage with the phage The antimicrobial potential of bacteriophages 57 researchers to improve prospects for phage related applications for research funding. Without proper support, the full potential of phages will not be realised within the Government’s AMR strategy.

We were disappointed to hear that there is a translational phage research “gap” in the UK. We agree that funding, and especially public funding, should be awarded with care. However, we are concerned that, despite being included in the Government’s AMR strategy, if not properly supported, the potential of phages to deliver therapeutics and commercial outputs will remain untested and untapped. There is a particular danger that translational phage research will be trapped in an impasse where it will miss out on research funding because it has not been able to prove its credibility, because of a lack of previous funding.

We recommend that the Department of Health and Social Care (DHSC) reviews the current funding arrangements for phage translational research and identifies what are the bottlenecks for such research. A review should consider what specific assistance phage translational research requires to increase the prospects of success for funding bids. It should also consider whether specific funding is appropriate where it can deliver AMR priorities.

The Government, the World Health Organisation and a number of the witnesses we heard from have highlighted the importance of a “One Health” approach to tackling AMR across sectors including human and animal health, the food supply chain, and the environment. The Department of Health and Social Care (DHSC) and others told us that phages could play an important role in delivering this approach. However, the DHSC acknowledged that they were at an early stage of tracking progress on phages. We believe it is important that—if phages are to play a meaningful part in a ‘One Health’ approach to tackling AMR—progress is reported in a timely and comprehensive manner. We recommend that the DHSC, as the lead department on AMR, reports annually on the progress made on evaluating and developing all phage- related technologies and therapies that affect human, animal or environmental health (referred to as the ‘One Health’ approach). This should be a joined-up assessment bringing together analyses and data from all relevant departments, regulators, public bodies and funders who are in receipt of public funding for work on phages.

For the potential benefits of phages to be fully explored and, if possible, exploited in the UK, with competitive advantage, it is important that existing phage- related assets are properly aligned and integrated, connecting the various sectors, institutions, and actors so they can draw on shared resources, information, data, and expertise. This will also allow the development of additional shared assets, such as phage biobanks, as well as encouraging new relationships between universities, hospitals, the pharmaceutical industry, and other stakeholders. We were concerned to hear that the UK’s phage expertise and resources are ‘fragmented’. We therefore welcome Innovate UK’s Phage knowledge transfer initiative to bring phage stakeholders together to produce a roadmap to deliver a sustainable and integrated network for the transfer and sharing of phage-related knowledge for the benefit of all. (Paragraph 67) 58 The antimicrobial potential of bacteriophages

We recommend that the Department for Health and Social Care responds to the UK’s Phage Knowledge Transfer Network’s proposals within six months of their publication. The Department should set out how it will help develop a network for phage-related knowledge sharing and assets such as biobanks. The Department should also indicate how phage-related research and development across different sectors might be joined up as part of its overarching ‘One Health’ approach to tackling AMR.

If phages are to be used more widely within the UK’s healthcare system it is important that healthcare professionals are aware that they are an antimicrobial alternative, especially when antibiotics have failed or are failing. We recommend that information about the clinical use of phages is included within medical training courses and that information about how to access phages or phage expertise is readily available to clinicians and other healthcare staff within each hospital.

The public will need to be convinced that phages are safe and effective. This will be key if phages are to play a role in addressing AMR in healthcare and as part of a One Health approach to addressing AMR across various sectors, such as the food industry and the environment. Careful and transparent promotion of phages’ antimicrobial ability to reduce or eradicate bacterial pathogens and re-weaponise antibiotics, would help make their use more acceptable. (Paragraph 72) Manufacturing phages

The set of consensus high standards for pharmaceutical production, known as Good Manufacturing Practice (GMP), should continue to be required in the UK for high quality phages manufactured for generic products targeting the most common bacterial pathogens. It should also underpin the production of phage biobanks to be accessed at short notice by clinicians providing assurance to both clinicians and patients that phages from biobanks will be of the highest standard of safety and purity. Access to phages manufactured to GMP standards will also allow microbiology laboratories to deal with less common pathogens and tailor phages to be more effective for individual patients when a more agile precision medicine approach is required. However, there may still be a place for non-GMP phages in instances when non-banked phages are needed at short notice for compassionate use as a last resort and can be produced via collaboration between a physician and pharmacist—as in Belgium.

One of the main obstacles to establishing Good Manufacturing Practice (GMP) facilities in the UK is the cost and the reluctance of pharmaceutical firms to invest in phages and antimicrobials more generally because of an uncertain return on investment compared to other medicines and drugs. However, investing in a small, or shared multi-use, GMP facility is one possible solution to ensure that such capacity could be run cost effectively. The allocation of public funds to establish a GMP facility could be offset by savings delivered to the NHS, by avoiding wasted antibiotics and unnecessary surgery resulting from AMR. Such a facility could also supply phages to non-health sectors which could be used to cross-subsidise healthcare phages.

We recommend that the Department for Health and Social Care considers bringing together funders with relevant catapults and innovation centres, such as the Centre The antimicrobial potential of bacteriophages 59 for Process Innovation, to build a GMP facility that can be accessed and used by phage innovators, the NHS and those seeking to produce microbiome products. The Government should also consider investment in existing spare and disused laboratory space, such as the currently for sale Rosalind Franklin Laboratory, to develop a GMP facility for phage production. In addition, the Government should consider why there is a reluctance by pharmaceutical companies to invest in phages, and what steps it can take to address this.

We recommend that the MHRA provides guidance on how phage cocktails will be regulated. It should consider the case of influenza vaccines, and allow phage permutations to be assessed on the basis of their individual constituent ingredients meeting agreed purity and safety standards and not for each new combination of those ingredients.

For phages to be effective they will need to keep pace with bacterial resistance and be amenable to adaptation for individual patients. Genetically engineered (GE) phages may be one way of ensuring this. GE phages have already been used in the UK and elsewhere. However, if they are to be produced commercially, GE phages will need to be aligned with GMP. We recommend that the MHRA produces guidance on how GE phages will be regulated and how they will meet GMP. The MHRA should also provide guidance on how extracted phage enzymes will meet GMP requirements.

If the UK government supports the commercial production of genetically engineered (GE) phages, it will inevitably lead to regulatory divergence from the EU. However, we believe this divergence offers the UK an opportunity that should be pursued. This should be part of a clear regulatory and safety licensing regime for phages, if phages are to be exploited for competitive advantage.

We welcome the willingness of the MHRA to adopt a flexible approach to accelerating the authorisation of the use of phage therapies and its offer to work with phage innovators to support their development. However, the MHRA should provide clarity on how different pathways for developing phages, such as the Innovative Licensing and Access Pathway, and other flexible regulatory approaches will work in practice and how they will align with GMP and non-GMP phage for compassionate use in last resort cases. We recommend that the MHRA publishes guidance on how it intends to regulate phages if they are not produced using a GMP approach. This should include guidance on what developmental pathways are available to phage innovators. (Paragraph 94) Phage clinical trials

Our evidence suggests that current regulations for clinical trials and the manufacturing of medicines are unlikely to be effective for phages as they are for other drugs or antibiotics. This is because the current regulatory approach to testing and manufacturing medicines is based on a single consistent formulation being shown to have a demonstrable effect. This does not accord with the optimal use of phages which require considerable flexibility in terms of the specificity required for 60 The antimicrobial potential of bacteriophages individual patients. There are a number of different medical scenarios where the current regulations will struggle to cope with this need for specificity that mitigates against generic testing. These include: • the requirement for individual phage strains that are specific to the species and even strain genotype of the bacteria they seek to inhibit, which could be almost limitless and impossible to test in advance; • the need for multiple unique formulations of phages, often in conjunction with antibiotics and other drugs, to target infections in individual patients with specific microbiota, which might not be anticipated in traditional clinical trials; • in the future, pre-tested generic phages that have met regulatory standards may not be able to inhibit bacterial growth, necessitating adaptation which may be beyond inflexible regulations; • the specificity required to target a particular infection in a single human could require gene editing of phages, with current regulations implying that each new formulation would require full clinical trials each time, which would not be timely, cost effective, efficient or possible in terms of generating significant clinical data if each use is unique; • the use of double-blind clinical trials and control groups would be problematic if they related to a unique combination of phages produced for a single patient.

The MHRA should set out how they propose to regulate and ensure clinical safety for each of the scenarios set out above. This would allow for the narrowing of R&D and production work to prevent wasted effort and allow an agile approach, allowing non-generic phage production for specific patients but GMP production for phages to mitigate the most common bacterial pathogens causing AMR in humans, animals and the environment.

The MHRA should also set out more broadly how current clinical trial structures can support the development and regulation of new personalised medicines. This should include an outline of what changes may be required to underpin this emerging and promising area. This should include early and regular engagement by regulators with the sector and a transformative approach to the safety testing and licencing of these exciting products. It should publish this within a year of this report being published.

One of the major obstacles to phage clinical trials in the UK has been the requirement for GMP phages. However, regulators require that for phages to achieve GMP standards they must themselves have first been subject to clinical trials. This impasse is stalling the development of phages in the UK. The Department of Health and Social Care should consider investing in a small GMP facility which would solve one part of the problem. However, it would not solve the issue of UK GMP requiring clinical trials that in themselves had to use GMP phages. Clarity is needed on how this conundrum can be solved. (Paragraph 105) The antimicrobial potential of bacteriophages 61

We recommend that the MHRA sets out what standard of phages will be required for UK clinical trials and how GMP will be acquired by UK produced phages if they cannot be assessed by a clinical trial. This guidance should be published within six months of the publication of this report.

The funding of clinical trials, especially later trials, has proved an obstacle for phages. We were pleased to hear that the National Institute for Health and Care Research would welcome applications from phage researchers and companies to access public funding to conduct clinical trials. We recommend that DHSC and the National Institute for Health and Care Research follow up on this amenability to receive applications from phage researchers for clinical trials by engaging with them and supporting them in their applications. Similarly, we recommend that the Medicines and Healthcare Products Regulatory Agency offers tailored support for phage applications for clinical trials.

We are pleased that the MHRA is open to using phage data from a variety of sources as long as it is of sufficient quality. We recommend that the MHRA outlines how it will use clinical data from other countries and non-health evidence to inform its decision-making on regulating phages. (Paragraph 113) The Clinical use of phages in the UK

The current situation whereby in the absence of UK GMP facilities only phages imported from abroad can be used, which may themselves be non-GMP, is irrational and discriminatory. This is a costly approach based on a fragile supply chain, which is denying very ill patients rapid access to a therapy that is allowed in some other jurisdictions. It is also hindering the UK’s clinical development and evaluation of phages and holding back the strengthening of expertise across the UK’s health system. There is also a knock-on impact on the UK’s phage innovators. The greater compassionate use of phages in the UK in cases of last resort would be more likely to give the opportunity to demonstrate their potential, which could encourage more investment in clinical trials and GMP facilities, to drive forward the commercial use of phages in the UK and exports. We recommend that the Department of Health and Social Care and the Medical and Healthcare products Regulatory Agency reviews the current rules regarding the clinical use of phages in the UK. This should aim to ensure alignment between domestically produced and imported phages.

We believe that the UK should allow the compassionate use of non-GMP phages produced in the UK for last resort medical cases where other medical approaches have failed or are failing. This would bring the UK in line with several EU countries, and the USA and Australia. The UK can learn from these countries in ensuring that phages are produced to a high standard, albeit not to the exacting standard of GMP. Using monographs, as is the case in Belgium, that stipulate safety and purity standards, would be an ideal starting place. It could build upon existing guidance for the use of unlicensed specials (products that have not been assessed by the regulatory authority for safety, quality and efficacy in the same way as licensed products) within UK clinical settings and oversight procedures within hospitals. (Paragraph 128) 62 The antimicrobial potential of bacteriophages

We recommend that the Medicines and Healthcare products Regulatory Agency (MHRA) revisits the regulation of the clinical use of non-GMP phages produced in the UK for last resort compassionate cases where antibiotics or other antibacterial interventions have failed. The MHRA should review the use of non-GMP phages in such cases in other countries and produce a monograph to govern and ensure their safety and purity. The MHRA should publish its review and proposals for a non-GMP phage monograph and any changes that will be required to change necessary regulation to underpin this change. The Department for Health and Social Care should review and report on what changes, if any, will be required to ensure that current guidance and oversight procedures are sufficient for the preparation and use of UK produced non-GMP phages in UK healthcare settings.

We recommend that the MHRA reviews how current regulations would govern liability for clinicians and hospitals who used UK non-GMP phages, produced to a magistral monograph. It should consider what changes, if any, could be made to provide greater reassurance regarding liability, where appropriate safety and purity standards were met.

If the antimicrobial use of phages is to move beyond ad hoc compassionate cases, the Government and its agencies should reflect on what role they are to play in the fight against AMR. At the moment, phages are referred to in the AMR strategy, as one approach amongst others. However, we believe that the Government and its agencies should make a more definitive and positive statement on phages. Clarity is imperative for research funding decisions and for private investment in commercial phages.

We recommend that the Government produces a clear statement on its assessment of phages. If it concludes that phages are to play a significant role in fighting AMR, it should produce a comprehensive plan as to how they will be supported and how the necessary infrastructure and regulatory landscape will be created. (Paragraph 141) The antimicrobial potential of bacteriophages 63