As interest in phage therapy continues to grow, various regulatory approaches may be used in different regions around the world. In the following sections, we summarise the regulatory frameworks related to the approval and to the unlicensed use of phage therapy within four TATFAR regions. This includes the legal definition of phage-containing medicinal products, the regulatory expectations for approval, specific considerations for personalised phage products, and access to unlicensed products. A summary that may be valuable for researchers, healthcare providers, and industry professionals engaged in phage research and development is outlined in Table 1.

European Union (European Medicines Agency)

In the EU, phages used for treatment of infections are classified as biological substances, and phage-containing medicines are considered as biological medicinal products under the existing EU pharmaceutical legislation (Directive 2001/83/EC)⁴⁸. The manufacturer must characterise the biological properties of each phage, including its lytic activity. For phages, the centralised authorisation procedure is generally used⁴⁹. Developers submit a single marketing authorisation application to the European Medicines Agency (EMA). This is evaluated by the EMA’s Committee for Medicinal Products for Human Use (CHMP). Based on a positive CHMP recommendation, the European Commission (EC) issues a legally binding decision to authorise the phage-containing medicinal products. Once granted, this marketing authorisation is valid in all EU and European Economic Area (EEA) countries.

Developers are advised to consult all relevant EMA guidelines aimed at developing medicines for the prevention and treatment of bacterial infections^50,51. As with every biological product seeking approval, phage therapy medicinal products need to adhere to specific quality parameters. Both individual phages and the final preparation (as drug substance and drug product, respectively) should follow a standardised manufacturing process that includes a clear description, validation, and control. Phage banks need to be established in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) quality guideline Q5D, which covers the derivation and characterisation of cell substrates used for the production of biotechnological/biological products (ICHQ5D)⁵². Phages should be properly identified, and their purity, potency, and viability must be maintained. In addition, a host bacterial cell bank must be established, ensuring that hosts are screened for the absence of resistance to antibiotics, virulence factors, and prophages. The manufacturing of the final drug product should comply with GMP^23,53.

Nonclinical studies should gather proof-of-concept data on the intended use of the medicine, determining whether the medicine will be used in conjunction with the best available therapy (BAT) with antibiotics or as a stand-alone therapy. These studies should also inform pharmacokinetics (PK) of the disposition of phages inside the body and support the chosen dosage regimen (in vivo Pharmacodynamics [PD]). It may be beneficial to investigate the potential emergence of resistance and its impact on gut microbiota. Nonclinical development discussions with EU regulators via scientific advice are recommended, although toxicological requirements might be abbreviated when relevant animal models are utilised. Typically, genotoxicity, carcinogenicity, and reproductive toxicity studies may not be required. As previously emphasised, it is crucial to obtain evidence of efficacy and safety through well-designed RCTs. Most of these trials will likely compare the candidate phage medicinal product in combination with the BAT against BAT alone. In this case, the EMA may require demonstrating the superiority of the combination therapy over the BAT for approval. However, alternative study designs for certain types of infection could be discussed with EMA. This primarily applies to pre-established combinations of phages administered topically or systemically in the form of a “phage cocktail.” Relevant clinical endpoints, such as time to cure or relapse rates, and other clinical benefits, should be agreed upon upfront with the EU regulators. To maintain therapeutic efficacy, these products will likely require periodical updates. Existing regulatory tools may need to be refined to facilitate the timely adjustment of the phage therapy medicinal products. In addition to efficacy data, safety data need to be collected to reassure European regulators of the safety of these products. Potential risks, such as endotoxemia from bacterial lysis, anaphylactic shock, and transduction of antibiotic resistance genes by phages, cannot be excluded a priori.

Candidate medicines based on engineered phages could be classified as advanced therapy medicinal products (ATMPs). The extent of data on quality, safety, and efficacy will be determined based on a risk-based approach, in accordance with existing EU legislation. In certain situations, such medicines also need to comply with the Directive regulating the release of genetically modified organisms^53,54.

The EU has been implementing various initiatives to clarify the regulatory framework for phage therapy, particularly pertaining to the development and manufacturing of phage products⁵⁵. In March 2024, the European Pharmacopoeia Commission (EPC) adopted a new general chapter on Phage therapy Medicinal Products (5.31)⁵⁶, which outlines the requirements for the production and control of these products. This chapter allows for a degree of flexibility that corresponds to the complex approaches currently employed in this rapidly evolving field. In addition, in December 2023, EMA released a concept Paper addressing ‘the Establishment of a Guideline on the Development and Manufacture of Human Medicinal Products Specifically Designed for Phage Therapy,’ which underscores the existing gap in appropriate regulatory guidance for phage medicinal products intended for human use in the EU²³.

The development of personalised phage products involves a more complex scenario. In these cases, it is essential to establish the combination of phages, either trained on the actual bacteria causing the infection or taken from a phage bank, through a process known as phagogram analysis. The advantage of this approach lies in its ability to rapidly adjust the composition of the medicinal product. However, such flexibility may raise concerns among regulators regarding both quality and clinical aspects of the product, as the drug product may require a variable composition. Several solutions have been proposed to address these challenges, but it is likely that the existing legislative and regulatory framework in the EU will need to be revised to better accommodate this scenario. Notably, the EU institutions are engaged in a substantial revision of the EU pharma legislation⁵⁶, which recognises that certain new categories of medicinal products may require adapted regulations to address their specific characteristics. The EU Commission, the EU Parliament and the Council of the EU have now published their proposals for a Directive of the EU Parliament and of the Council on the Union code pertaining to medicinal products for human use^57,58,59, which include provisions to establish an “adapted framework” for “phage-containing medicinal products,” particularly in instance where the composition of the medical product varies based on specific clinical contexts (see Article 28 and Annex VII of the proposals). This proposed framework would entail targeted technical adaptations to the requirements necessary for market authorisation, contingent upon stringent criteria and guided by the scientific input from EMA. As of now, this legislative act remains under discussion and has not yet been adopted.

In some of the EU Member States, there are established pathways for administering experimental phage therapy to patients with no viable treatment options. These pathways may include compassionate use or participation in clinical trials. In addition, unlicensed medicines may be dispensed to individual patients based on a prescription from a healthcare practitioner. In this case, a pharmacy prepares the medicine according to the applicable pharmacopeia, and it is directly dispensed to the subject (known as the officinal formula route). Another option, known as the named subject use route, allows a medicinal product to be formulated under the prescriber’s responsibility and used directly by the patients. Member States can also temporarily authorise certain medicines under special conditions, which adds to the regulatory complexity. As previously noted, in Belgium, phage preparations must comply with phage monographs for active pharmaceutical ingredients.

While these frameworks enable patients with limited treatment options to access phage therapy, they do not contribute to assessing the efficacy of the treatment. Consequently, such pathways cannot be recognised by the EU regulator for medicine approval. The EMA recommends that all developers engage with the EU regulatory network as early as possible so that the respective programmes can be thoroughly discussed, and advice can be provided.

Canada (Health Canada)

Addressing the rising threat of AMR is a top health priority for Canada. Guided by the Pan-Canadian Action Plan on AMR (2023–2027) (PCAP), Canada is advancing a One Health, multi-sectoral approach to combat AMR⁶⁰. The PCAP Year 1 Progress Report, published in September 2024, highlights early milestones and ongoing activities across five pillars, including research and innovation⁶¹. Health Canada’s specific AMR priorities focus on preserving the effectiveness of existing antimicrobials while facilitating access to new treatment⁶². In parallel, Health Canada is modernising its regulatory framework to support innovation within the healthcare system, as outlined in its Regulatory Innovation Agenda⁶³. Recognising the importance of international collaboration, Health Canada actively participates in global partnerships to advance both domestic and international AMR objectives, including the International Coalition of Medicines Regulatory Authorities (ICMRA) and the Regulatory Agencies Global Network against AMR (RAGNA).

Health Canada classifies both natural and recombinant phages as biological medicinal products (i.e., drugs) when they are used to treat, mitigate, or prevent disease in humans or animals, as per the Food and Drugs Act⁶⁴, Schedule D⁶⁵, and the Food and Drug Regulations, Part C, Division 4⁶⁶. Currently, no phage products have received market authorisation in Canada. Therefore, phage therapy is considered an experimental drug in Canada and is only available through a clinical trial that has been reviewed and authorised by Health Canada as per the Food and Drug Regulations, Part C, Division 5:“Drugs for Clinical Trials Involving Human Subjects.⁶⁷”

Sponsors wishing to conduct a clinical trial in Canada can submit a clinical trial application (CTA) to Health Canada, who will review the application within 30 days. Health Canada can object to the trial if the requirements in the Regulations are not met. Alternatively, if the application meets all standards, a No Objection Letter to the sponsor will be issued, allowing the trial to proceed. Sponsors are encouraged to contact Health Canada’s Biologic and Radiopharmaceutical Drugs Directorate (BRDD)⁶⁸ for specific guidance related to their proposed single-patient or larger phage therapy clinical trials. In addition, it may be beneficial for sponsors to request a meeting with Health Canada when planning their clinical trial application (CTA) in order to ask questions, as needed. Notably, there is no cost to sponsors for these preparatory meetings.

To date, Health Canada has authorised several single-patient clinical trials focused on studying phage therapy for various infections, including recurrent urinary tract infections, cystic fibrosis lung infection, and periprosthetic joint infections that have not responded to traditional antibiotic treatments (unpublished data; see clinicaltrials.gov). It is encouraging to see an increasing interest in the clinical application of phage therapy in Canada. However, Health Canada recognises that more clinical data is required in needed to further demonstrate the efficacy of phage therapy. Clinical trial sponsors, including those from industry, academic hospitals, or other research institutions, are encouraged to consider phage therapy in larger-scale clinical trial settings to advance our understanding of phage biology.

Since Health Canada has not yet received clinical trial applications for phage therapy involving more than a single patient, sponsors are strongly encouraged to arrange a pre-CTA meeting with Health Canada as early as possible during the development process. This meeting should focus on discussing clinical, non-clinical, and quality data requirements. Given the extremely diverse nature of phage biology, regulatory requirements may evolve in a risk-based manner, building on what was required in single-patient trials as clinical development progresses. Sponsors can refer to existing Health Canada guidance⁶⁹ for clinical trial sponsors for additional information. Although GMP compliance is not required for RCTs, the expectation for “GMP-like” conditions will increase throughout clinical development. This is essential to ensure consistency in phage manufacturing, quality control, product safety, and robustness of clinical trial results. However, given the innovative and unique nature of phage therapy, regulatory requirements may vary according to the proposed phage product, indication, route of administration, patient population, and trial design.

Single-patient clinical trials are regulated under the same authority as larger clinical trials, specifically under Part C, Division 5 of the Food and Drug Regulations. When submitting a CTA for a single-patient study, the sponsor should provide a rationale and supporting information (e.g., literature and clinical data) demonstrating that the patient meets at least one of the following criteria: (1) they have a serious, life-threatening condition, (2) they are not eligible for or exhausted all other treatment options, and (3) there is no other way to access treatment. In addition, the CTA must include information about the investigational product, which should cover dosage form, strength, rationale for dose selection, route of administration, frequency of re-administration, and duration of therapy. It should also include available safety data, potential for efficacy in the patient considered, and identified potential risks. Furthermore, the CTA should contain a detailed treatment and follow-up plan, safety monitoring and risk mitigation measures, evidence of Research Ethics Board approval, and a plan for reporting study outcomes, including safety and efficacy.

In terms of quality data requirements, Health Canada has developed draft guidance (unpublished; available upon request) on key quality attributes that need to be included in the CTA. In urgent situations, such as when a patient has a serious, life-threatening infection, Health Canada will require essential information related to the phage history, lytic activity, potency, impurities, sterility, and endotoxin level, as well as critical manufacturing processes and controls, and storage and transportation. In less urgent situations, Health Canada will require this same information, along with additional phage characterisation and details about manufacturing processes and controls. This additional characterisation should include phage genomic sequencing (for identity), assessment of temperate life-cycle properties (such as integrases, recombinases, transposases), resistance and toxin genes, and stability. This information should be provided for Clinical Trial Material intended for subjects, or for a product derived from the same starting materials (e.g., phage stocks) and manufactured by comparable processes.

While phages used in single-patient trials can be sourced from existing phage banks inside or outside of Canada from well-established research institutions, the Canadian government is currently developing guidelines and phage sharing agreements with various industry and academic partners. The goal is to establish a Canadian government-run phage collection and phage susceptibility testing service⁶¹.

There is currently no specific regulatory framework in Canada tailored to phage therapy or personalised phage products. However, the Advanced Therapeutic Products Pathway (ATPathway)⁷⁰ is an agile licensing framework established in 2019 through legislative amendments to Canada’s Food and Drugs Act. This framework allows for flexible regulation of innovative health products. ATPs may include drugs, devices, or combinations thereof that do not fit into Canada’s existing Food and Drug Regulations due to their complexity or uniqueness. ATPs could encompass innovative products like personalised phage therapies, which are developed at the point of care and/or manufactured and administered in ways that differ significantly from traditional health products. This framework could enable Health Canada to customise regulatory requirements for phage therapy in the future, ensuring appropriate yet flexible regulatory oversight, while ensuring appropriate standards for safety, efficacy, and product quality. Finally, the ATPathway could facilitate improved access to potentially transformative treatments for Canadian patients, advancing Canada’s priority to combat AMR.

In Canada, patients may access unlicensed phage products through Open Label Single-Patient Clinical Trials, as detailed in the section above.

United Kingdom (The medicines and healthcare products regulatory agency)

The UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) is actively working to address the threat of AMR through both national and international efforts. This includes the 5-year AMR National Action Plan, participation in regulatory network AMR activities and initiatives, such as the International Coalition of Medicines Regulatory Authorities (ICMRA) and the Regulatory Agencies Global Network against AMR (RAGNA). The MHRA is also involved in the development and production of reference materials and World Health Organisation (WHO) international standards that are essential for assuring the quality, safety, and efficacy of biological medicines; at the time of writing, there are three phage reference materials/methods in development. The MHRA also has external funding for regulatory science research that supports research and innovation focused on AMR.

UK researchers are significantly interested in the use of phages across the One Health spectrum, and there is an established and well-connected community. In 2023, the UK House of Commons Science, Innovation and Technology Committee (SITC) launched a public enquiry titled ‘The antimicrobial potential of bacteriophages’ following a successful pitch by Professor James Ebdon, Professor of Environmental Microbiology at the University of Brighton, UK, on behalf of Applied Microbiology International⁷¹. This enquiry considered “over 40 pieces of written evidence and held three oral evidence sessions [hearing from] academic experts and clinicians from the UK and from around the world, funders, Small and Medium-sized enterprises (SMEs), regulators and government officials.” The SITC published the enquiry report in January 2024, which contained several recommendations, to which the government published its response on March 1^st,2024⁷². The recommendations and responses highlight that although regulatory frameworks for using phage therapy are defined and in place in the UK, successful implementation and adoption require coordinated activities across the entire healthcare ecosystem and clear communication of the relevant processes.

This section covers the legal definition, pathway(s) for authorisation, and regulatory recommendations pertinent to phage medicinal products in the UK. The MHRA published ‘Regulatory considerations for therapeutic use of bacteriophages in the UK’ on the 4^th June 2025⁷³, which provides comprehensive regulatory information pertaining to the development and use of phages to patients, via both licensed and unlicensed routes, including ‘specials’ clinical trials and imports.

In the UK, phages that are isolated or manufactured with the intention of treating a medical condition are classified as biological medicinal products. Consequently, they are subject to the Human Medicines Regulations 2012 (HMRs, as amended). Broadly, phages are classed as biological medicines. If a phage is genetically modified, it may, in certain instances, also be classified as an advanced therapy medicinal product (ATMP), contingent upon the nature of the modification. ATMP is a class of biological medicines subject to both HMRs and separate legislative requirements. For licensed medicinal products, the HMRs outline the criteria for assessing safety, quality, and efficacy to grant a marketing authorisation (license). Currently, there are no licensed phage medicines available in the UK.

For unlicensed medicines, often referred to as “Specials”, Regulation 167 of the HMRs permits the supply of medicines without a marketing authorisation (license) under certain circumstances. This exemption is narrowly defined in the interest of public health since unlicensed medicines have not been evaluated by the licensing authority against the criteria of safety, quality, and efficacy. An unlicensed medicinal product, a “special,” can only be supplied to meet the special clinical needs of individual patients when no available licensed medicinal products can fulfil those needs. Determining whether an individual patient has unique needs that cannot be addressed by a suitably licensed product is a matter for the prescriber responsible for the patient’s care. The prescriber holds the responsibility for the use of unlicensed. An unlicensed medicine may be supplied following a bona fide unsolicited order and is formulated in accordance with the specific requirements of the prescriber.

An unlicensed medicine can either be manufactured in the UK or imported. Manufacturing in the UK must be conducted by the holder of a Manufacturer’s “Specials” license in appropriate facilities, subject to GMP inspection by the MHRA. Importers of unlicensed medicinal products into the UK must hold appropriate licences for such imports. Prior to importing, the importer must notify the MHRA of their intent to import the unlicensed medicine and provide a set of supportive documentation, which will be assessed by the MHRA. The MHRA retains the authority to object to the importation of unlicensed medicine if significant risks are identified that could negatively impact patients. Each import request is assessed on a case-by-case basis, considering both the product and the special clinical needs identified by the prescriber. Medicines imported into the UK as unlicensed medicines are usually required to comply with similar GMP expectations as those manufactured domestically.

Section 10 of the Medicines Act 1968 and Regulation 4 of the HMRs provide an exemption from the restrictions imposed by regulations 17(1) (manufacturing of medicinal products) and 46 (requirement for authorisation) of the HMRs for “anything which is done in a registered pharmacy, a hospital, a care home service or a health centre and is done there by or under the supervision of a pharmacist and consists of preparing or dispensing a medicinal product in accordance with a prescription given by an appropriate practitioner, or assembling a medicinal product.”⁷⁴ The conditions for extemporaneous preparations are not determined by the MHRA, so consultation with appropriate experts is recommended. The General Pharmaceutical Council regulates pharmacists, pharmacy technicians, and pharmacies in Great Britain.

The composition of phage ‘cocktail’ products may require adjustment or updating over time to maintain their effectiveness against circulating strains. Such product variations may be a suitable route to making these changes. Evidence will need to be provided to the competent authority to demonstrate that replacing one phage with another in a given cocktail product retains host range and efficacy for the indication for which the product is licensed without additional risk to the product’s quality or safety. Whether a new clinical trial is necessary will depend on the scientific data accompanying the change, and it is advisable to engage in discussion with the regulator. Developers can seek advice from the MHRA⁷⁵, which is currently revising its clinical trial approval process⁷⁶ following the Lord O’Shaughnessy review⁷⁷, employing a risk-proportionate approach. Engaging with the MHRA through its Innovation Office⁷⁸ for advice is highly advisable.

Regulatory oversight for genetically modified organisms, including genetically modified phages, is administered by either the Health and Safety Executive (HSE) or the Department for Environment, Food & Rural Affairs (Defra), depending on the nature of their release. It is also crucial for product developers intending to introduce products to markets to engage with procurers and/or health technology assessment (HTA) bodies. In the UK, the National Institute for Health and Care Excellence (NICE) and NHS England launched a new subscription model. This model acknowledges that investing in antimicrobials is often not commercially attractive due to cost expectations and limited usage; it decouples the value added from the number of prescriptions sold. Currently, the subscription model⁷⁹ only encompasses traditional (small molecule) antimicrobials, but eligibility criteria are expected to expand to include non-traditional therapies, such as phage and microbiome treatment, which is reviewed regularly.

For product developers seeking licensure in the UK, it is advisable to understand evidence requirements and evaluation processes. NICE offers a specific service called NICE Advice⁸⁰ to support companies seeking to enter the NHS market.

Personalised phage therapies may be classified as either licensed or unlicensed medicinal products. Other types of licensed personalised therapies include engineered cell therapies and mRNA cancer immunotherapies. It is envisaged that personalised phage therapy could follow a similar licensing route, and, like cell and mRNA therapies, be subject to GMP. Although the ‘complexity’ of phages is often cited as a barrier to GMP compliance, it is important to note that individualised cell and gene therapies, which are prepared and administered under GMP, have been adopted by the NHS and are recommended by NICE for several adult and paediatric indications. Guidance on pharmacy institutional readiness for these products⁸¹ has been developed to facilitate adoption across the NHS.

Beyond the role of MHRA in regulating unlicensed medicinal products, governance for the use of unlicensed medicines is the responsibility of individual NHS Trusts. It is imperative for individuals seeking to utilise therapeutic phages to recognise that decisions regarding the use of unlicensed medicines are determined based on local unlicensed medicines policies within NHS Trusts, not by the MHRA.

Unlicensed medicines manufactured in the UK must adhere to GMP standards. Unlicensed medicinal products imported for use in the UK undergo quality evaluation by the MHRA Imports Office to ensure they meet UK quality requirements. To date, imported phages have been used in the UK on an unlicensed basis, with some cases included among the 100 reported cases from Belgium in 2024⁸.

United States (food and drug administration)

Phages proposed for the treatment of infectious diseases in humans are regulated as biological drug products by the Office of Vaccines Research & Review (OVRR) at the Centre for Biologics Evaluation and Research (CBER), within the United States Food and Drug Administration (US FDA). Clinical investigations of unlicensed products or unapproved uses of licensed products intended to cure, mitigate, treat, or prevent a disease require an Investigational New Drug (IND) application. This requirement applies regardless of whether the product is intended for commercial development or for expanded access (compassionate use).

For considerations of when to approach the FDA for potential use of phage in the clinic, sponsors should first identify a specific, attainable investigational product and develop a draft clinical plan or synopsis. At that point, it is appropriate to request a pre-IND meeting with OVRR to obtain input on the proposed development plan and other pertinent, product-specific regulatory questions. Guidance on this aspect of the product development process can be found in Formal Meetings with Sponsor and Industry⁴³. This formal feedback from the FDA should be carefully considered when a sponsor is preparing to submit the IND application.

The IND application should include product-specific information on chemistry, manufacturing, and controls (CMC), the clinical plan, and any non-clinical information such as proof-of-concept studies that may inform clinical development (21 CFR 312). The submission should articulate a rationale for the clinical studies and product development⁸². Generally, an Investigator’s Brochure should also be included⁸³. The information outlined below does not encompass a complete list of what may be required for an IND submission. Each file is reviewed on a case-by-case basis to enable the Agency to assess risk/benefit and help to ensure the safety of study participants.

It is essential to demonstrate that the investigational phage product is manufactured in a manner appropriate for the stage of clinical development. While phage preparations must be safe for human administration at all phases of development, full GMPs are generally not required for early phase studies^84,85. The phage product must be clearly defined. It can be a single phage or a combination of several phages, known as a ‘cocktail’ that targets one bacterial strain or multiple bacterial strains. In addition, it can be a fixed cocktail or a personalised product comprised of engineered or naturally occurring phage. The phage product and the propagating strain should be fully characterised, including identity (annotated sequencing and phenotyping), sterility, and characterisation of any deleterious genes, mobile elements, prophage, and exotoxins. The history and sourcing of the phage should be included. Plans for cell banking and relevant data should also be included. Data regarding the drug substance and drug product should be evaluated and provided. Proposed investigational product information on potency (Plaque Forming Units (PFU)/ml), transduction (based on the presence of 16S rDNA of the bacteria that is used to proliferate phages), demonstration of removal of residuals/contaminants, phenotyping, sterility, pH, appearance, endotoxin and exotoxin, and host cell proteins (HCP) should be included. In addition, information about any diluent and placebo should be provided. A stability plan with proposed expiry dating and any relevant supporting data should be included. If sponsors are planning a personalised/individualised approach to their phage therapy clinical trial, the same information must be submitted for each phage strain used (as well as propagating bacterial strain and history of phage) prior to treatment.

The FDA recommends providing a description of the manufacturing process, along with a flow diagram and accompanying narrative. Manufacturing facility information, including any other products handled or manufactured at the site, should be included⁸⁶. Information on dedicated or shared equipment used at the manufacturing site should be supplied. A complete list of raw materials and sources of each must also be included.

In the instance where the IND sponsor may not manufacture the product and therefore may not have access to CMC information, the sponsor must include a cross-reference to the manufacturing information of the product in a Type II CMC master file (MF). This allows for the submission of confidential information and data that is reviewed in the context of a specific IND. This MF must be submitted to CBER, and the MF holder must provide a Letter of Authorisation (LOA) to the IND sponsor to allow the IND to cross-reference the MF. An MF can be used to support multiple INDs. It is important to note that Type II MFs can only be used during the IND development stage⁸⁷.

The FDA’s OVRR/CBER reviews Phage INDs for infectious disease indications. For early clinical studies, the information discussed below is recommended to be included. The route of administration of the investigation product can include, but is not limited to, intravenous (IV), intraperitoneal (IP), nebulised, topical/direct, intravascular, and intraarticular. This may or may not involve the use of a device. If sponsors are using a device to administer the phage product, the device information should be submitted with the IND. It is also essential to provide details on where the clinical trials will be conducted, including other investigators and sub-investigators, as known and as appropriate (21 CFR 312).

• Design: The FDA has numerous disease-specific guidance documents pertaining to clinical trial design. It is recommended that sponsors refer to these Guidance Documents when designing their studies, as applicable and appropriate⁸⁸. It is also recommended that the clinical trial design build in testing and matching of the infecting bacterial strains of the trial participants against the investigational phage strain, including collecting data on any developed resistance of the bacteria to the phage. Collecting this information during development may inform future trial design.

• Collection of laboratory measurements: Baseline measurements and assessments at critical points during the trial are important. If the investigational phage product is administered via IV or other invasive means, liver function testing should be included. This information and scheduling of events can be presented in tabular format. Investigational product route of administration, frequency of dosing, and length of treatment must be prospectively defined, with proposed follow-up time. Study-wide and individual pausing rules must be proposed, with relevant toxicity grading scales provided. The safety and rights of the participants must be assured⁸⁹. The clinical study design should incorporate a prospectively defined decision tree if phage strains may be proposed to be switched out, including culture results that are critical for these decisions (such as for developed resistance or futility), or phage administration extended. It is noted that any modifications and changes to the phage strains used during a clinical trial or in development may confound data interpretation and affect clinical trial design.

• Objectives and endpoints: Primary objectives for early clinical development are generally safety and tolerability. Randomisation and blinding are not always mandatory in early (phase 1) development stages. Consult with the FDA if patient-reported outcomes are planned to be used in the clinical assessment⁹⁰. Determining an appropriate case definition is important for the disease studied.

• Participant screening: Defining the target population and establishing criteria for enrolling participants are crucial. In addition, the following factors should be considered: types of infections, locations of infections, whether there are single or multiple infecting bacterial strains, prior medical treatments, allowable use of concomitant use of medications, and recommended standard of care for the specific disease. A collection of relevant infection history (culture results) of the participant and treatments previously used is also recommended.

• Statistics: Statistical analyses used in early studies are generally descriptive rather than statistically powered. Information on methods to define and demonstrate safety and any preliminary efficacy must be included, along with measurable objectives. The protocol and a statistical plan (if included) should define the ‘intent to treat’ population and outline how missing data will be handled.

Information submitted to the IND should be focused specifically on the product proposed for clinical use. All information should be consistent and accurate throughout the IND, including the protocol (schedules, charts, narratives), Investigator Brochure (IB –ICH E6 (R2) Good Clinical Practice, part 7 or FDA publication), the general investigational plan, and the summaries of clinical, nonclinical, and product information⁸³.

Single-patient, Expanded Access (EA) Investigational New Drug applications (SPINDs), also known as Compassionate Use, may be requested for FDA review when a patient has a serious or immediately life-threatening disease with no other treatment options available. The SPIND should be directed to OVRR/CBER within the FDA. Specific criteria must be met for consideration of expanded access as described in INDs 21 CFR 312.305 (a) (1–3) and 21 CFR 312.310. In summary, they are:

• Patient has a serious or immediately life-threatening disease or condition.

• There is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition.

• Patient enrolment in a clinical trial is not possible.

• Potential patient benefit justifies the potential risks of treatment.

• Providing the investigational medical product will not interfere with investigational trials that could support a medical product’s development or marketing approval for the treatment indication.

Generally, the types of CMC and clinical information provided for controlled clinical trials can be applied to SPINDs, although the level of detail may be significantly reduced. In most cases, a treating physician submits the SPIND, which includes the treatment plan and patient history, while a phage manufacturer may supply the CMC information. This may also be provided from one source, but this information must be made available for review. The FDA has a comprehensive website that should be consulted^91,92