The fragmentation of existing approaches to phage therapy regulation signals a growing need for adaptive regulatory mechanisms to improve patient access. Regulatory sandboxes represent one such approach. A sandbox is a controlled testing environment established and overseen by a regulatory authority. Within this defined ‘safe space’, innovators have the opportunity to test novel products or services that may not conform to existing regulatory requirements [24]. This aspect acknowledges that strict adherence to regulations can create structural obstacles in areas where established rules are not well suited to the characteristics of a new technology or process. Sandboxes provide reduced or bespoke regulatory requirements, limited waivers or derogations from specific rules, which would otherwise impede testing and development [25].

Sandboxes have been successfully explored and implemented in fast-moving fields such as financial technology [26], artificial intelligence, food [27] and Australian border control [28]. Sandboxes are also gaining traction in health [29, 30], and particularly in frontier innovation fields such as neurotechnology [31], orphan drugs [31, 32] and data science in medicine [33]. By facilitating the collection of experiential data, sandboxes enable the evaluation of effectiveness, safety and practical feasibility of interventions in actual clinical settings, while contemporaneously gauging appropriate guardrails.

A sandbox is typically structured in four phases [34], each designed to enable structured experimentation while ensuring oversight and accountability. In the health context, this would manifest as follows:

(i)

an initial application stage where innovators propose their therapeutic product or service and outline the intended use and rationale for participation to the sandbox. Regulators assess whether the proposed innovation falls outside existing regulatory pathways and presents potential public health value. Crucially, scrutiny at the entry level is particularly stringent, and should encompass assessment of: novelty; prospected public benefit; planned risk management; and readiness and feasibility;

(ii)

a preparation phase to set up the testing environment, where sandbox participants collaborate with regulators to co-design the testing parameters. This includes defining safety and data reporting requirements, identifying specific regulatory flexibilities to be granted, and establishing clear timelines and oversight mechanisms;

(iii)

an experimentation phase where the product is tested under the agreed conditions. This may involve limited-scale clinical use, iterative product refinement, and ongoing engagement with regulators to resolve emerging challenges in safety, efficacy or manufacturing;

(iv)

a final evaluation phase where regulators and sandbox participants conduct a joint review of outcomes, including safety and performance data, regulatory lessons learned and implications for broader policy. This stage informs decisions not only about potential product authorisation outside the sandbox, but also potential broader regulatory changes. Indeed, the key outcome of a sandbox is the development of the evidence that may support reform to facilitate access to innovative products or processes.

By observing innovation within a controlled setting, regulators gain valuable insights through ‘regulatory learning’ [35, 36], which can inform adjustments to the framework. The aim is to develop proportionate and evidence-based regulatory responses to emerging technologies through a proactive and iterative approach to regulation, rather than a reactive approach. This process also aligns with broader calls to shift the paradigm in the regulation of medical products towards regulators performing a facilitative function rather than a unilaterally directive function [32, 37]. For example, the European Union has included provisions for regulatory sandboxes as regulatory experimentation tools in its proposed new pharmaceutical legislation, signalling a move towards the adoption of this approach within health regulation at a transnational level [38].

3.1 Significance of the Sandbox Approach for Phage Therapy Regulation in Australia

A sandbox approach would give the opportunity to the Australian Therapeutic Goods Administration (TGA) to develop in-depth understanding of practical implications and risks associated with bespoke manufacturing processes involved in phage therapy, and evaluate different approaches to phage production, quality-control standards, and models for clinical deployment, from personalised phage selection to evolving broad-spectrum cocktails. Phage therapy does not fit neatly within existing TGA definitions of ‘therapeutic goods’, and presents challenges in aligning with standard GMP requirements designed for chemically defined products [39]. While GMP-compliant phage manufacturing is feasible, including in dedicated facilities such as Phage WA, it may be prohibitively expensive and difficult to replicate at scale. Laboratory-scale purification often relies on polyethylene glycol precipitation and caesium chloride density-gradient ultracentrifugation, yet caesium chloride is toxic to humans and must be fully removed before clinical use. The process is poorly suited to large-scale production [40, 41]. For this reason, rather than requiring full GMP compliance, jurisdictions with experience in bespoke phage therapy regulation have generally adopted risk-adapted quality frameworks, particularly in the context of compassionate use or personalised treatment settings [42].

A sandbox approach offers opportunities for regulatory learnings on several complementary fronts:

1.

Regulatory flexibility for a biologically tailored assessment:

Phage therapy requires evaluation tailored to its biological and clinical characteristics, without compromising core principles of patient safety and therapeutic efficacy. Experimental evidence would be drawn from complex clinical settings, whether involving patients with severe drug-resistant infections or those for whom phage therapy may offer a microbiome-sparing alternative to antibiotics. This type of evidence is critical for evaluating the therapy’s real-world effectiveness, safety profile, and logistical feasibility within Australia’s healthcare system. For example, it would allow assessment of the viability of N-of-1 or N-of-few clinical trials as alternative methods to large-scale controlled trials, which is particularly valuable in highly individualised therapeutics [43, 44].

2.

Adaptability for evolving bacterial resistance and regulatory models:

The dynamic nature of bacterial epidemiology and resistance patterns requires phage preparations to be frequently updated to remain effective. This calls for adaptive and modular regulatory pathways, with processes enabling the pre-approval of well-characterised phage biobanks, predefined manufacturing processes and purity levels, and implementation of streamlined procedures for updating phage cocktails based on evolving bacterial resistance patterns. Analogous frameworks exist for annual influenza vaccines, which are treated as platform technologies. Influenza vaccines receive a first approval based on a standard process involving pre-clinical and clinical data analysis of safety and efficacy. Subsequently, new strains can be added on a yearly or seasonal basis without having to undergo further clinical testing [45, 46]. These strain updates are not new products but minor variations to a well-established and previously authorised platform [47]. As such, lifecycle monitoring replaces repetitive trials and approvals. Notably, both the Food and Drug Administration and the UK Medicines and Healthcare products Regulatory Agency are moving towards similarly flexible baseline approvals for rare disease therapies, reflecting a global trend towards adaptive regulation [48, 49]. A sandbox would be the ideal setting to trial the viability of platform approvals for phage therapy — in Australia specifically, but with a potential broader transnational impact.

3.

Cross-sectoral integration via the One Health strategy:

A sandbox approach could also support alignment with Australia’s National Health and Medical Research Council One Health strategy, which promotes an integrated approach to tackling AMR across human, animal and environmental health [50]. Phages are inherently pathogen specific, thereby offering a precision-based method of AMR mitigation. Specificity also means that efficacy data collected from veterinary, agricultural and environmental contexts can be relevant for informing human use, particularly when pathogens cross species boundaries. A sandbox may enable a structured exploration of how cross-sector data may be ethically and scientifically integrated into human regulatory assessments, paving the way for a versatile translational oversight of future biologics.

While offering regulatory flexibility, sandboxes are designed with robust and carefully embedded mechanisms ensuring protection of public health and effective risk mitigation [51]. For phage therapy, this would include establishing carefully defined eligibility criteria, for both the phage products to be tested within the sandbox and the patient populations enrolled in trials. The inherently collaborative nature of a sandbox would facilitate the TGA working with sandbox participants to develop and implement clear and comprehensive risk mitigation strategies, while rigorously monitoring patient outcomes throughout the process.

3.2 Filling a Regulatory Gap

Currently in Australia, the Standardised Treatment and Monitoring Protocol for Adults and Paediatric Patients (STAMP) provides an avenue for the compassionate use of phage therapy [52]. STAMP facilitates access to phage products not included in the Australian Register of Therapeutic Goods on a case-by-case basis for patients with severe treatment-resistant infections. STAMP is designed to address immediate clinical needs and enable valuable safety and efficacy data collection of eligible individual cases. It is not however designed to support iterative testing of manufacturing models, scalable clinical deployment strategies or longitudinal data collection beyond individual outcomes. As such, while STAMP represents an important first step in enabling access to phage therapy in Australia, a regulatory sandbox model would complement it by providing a framework for controlled system-level innovation in phage development, regulation and delivery.

3.3 Conceptual Implementation: A Regulatory Sandbox for Phage Therapy

The ultimate goal is to transition phage therapy from its current niche and last resort use to an integrated and adaptable component of Australia’s antimicrobial arsenal. However, rather than proposing immediate legislative change to integrate sandboxes into the Therapeutic Goods Act 1989, one approach is to conduct a conceptual implementation through a regulatory sandbox project focused on phage therapy. This would allow the TGA to evaluate the feasibility of flexible regulatory mechanisms applied to emerging health technologies.

Essential features that underpin such a project in the Australian context are as follows:

1.

structured phases to provide clear processes for stakeholders;

2.

stringent eligibility criteria for phage products and patient populations to ensure appropriate selection and risk stratification;

3.

rigorous oversight and risk mitigation strategies, developed collaboratively between the TGA and participants to the sandbox;

4.

access to necessary expertise and resources (e.g. collaborating with research and innovation hubs);

5.

independent evaluation of the sandbox results to enhance credibility; and

6.

clear exit strategies from the sandbox to outline pathways for potential broader authorisation, standardisation or regulatory guidance based on the results.

The sandbox should entail a TGA-established, time-limited, and scope-defined programme targeting both a compassionate use and an early-stage clinical evaluation of phage products. Operationally, the project should rely on a close collaboration between the TGA and selected university hospitals, phage biobanks and manufacturers, relevant patient representative bodies, biotechnology companies and microbiology laboratories, functioning as a learning ecosystem to evaluate experiential workflows.

Specific features of a TGA-led conceptual implementation of a regulatory sandbox for phage therapy ought to include:

1.

the creation of an Approved Phage Repository — a curated and TGA-recognised collection of bacteriophages pre-vetted for quality, safety and suitability for clinical use (Table 1);

2.

the development of modular approval pathways, where pre-qualified phages from the Approved Phage Repository can be integrated in a therapeutic intervention (e.g. to substitute no longer effective ones due to bacterial mutation) without reinitiating a full regulatory review, thereby trialling the viability of platform approvals in this space;

3.

the development of adaptive quality-control standards, tailored to the biological variability of phages rather than rigid manufacturing templates (Table 2); and

4.

the adoption of streamlined documentation requirements for N-of-1 and N-of-few trials, or small-batch use cases.

Table 1 Proposed approved phage repository phage entry requirementsTable 2 Functional assay prioritisation in QC, standard versus adaptive models for phage therapy