Bacteriophages are usually described as precision therapeutics due to their targeted mechanism of action. As a therapeutic, bacteriophages meet the definition of drugs or medicines under most regulatory frameworks. This means product regulation is focused on the assessment of safety, demonstrated efficacy compared to other treatments (e.g., antibiotics), and quality control data. Such frameworks also inherently involve the application of process controlled good manufacturing practices standards, which is seen by many as an expensive undue path for a biological product whose composition can be at times specific to an individual patient. GMP manufacturing is indeed an expensive process, but from a regulator’s point of view, quality by design is in place to protect the safety of the public, and high costs is not a justifiable reason to compromise safety.

The same regulatory agencies also have approved pathways (e.g., Expanded Access in the US, Special Access Scheme in Australia, Compassionate Use in Europe) that allow the administration of unapproved medicines to ill patients for whom registered approved medicines are no longer effective. Such pathways are less onerous on development and production methods of the unapproved medicine.  In countries like the Republic of Georgia, and other former Soviet Union countries, where bacteriophages have been long approved and used as biological medicines, there is a regulatory process overseen by the Ministry of Health, which hasn’t required production under modern GMP standards, but has implemented clear guidelines nonetheless to assure safety and activity of the products, which are widely used.

Due to the antimicrobial resistance crisis, the clinical demand for compassionate treatments has significantly increased around the world, and as a result, the number of clinicians treating patients under this pathway has increased as well. Primarily, their goal is to help patients in need but along the way some are actively trying to document evidence of safety and effectiveness of phage therapy. The challenge for the clinicians has been sourcing well-characterized and purified therapeutic phages that are accepted by the local ethics committees and/or regulatory agencies in a timely manner. In response to this challenge (and many others not yet described here), a self-described pragmatic regulatory framework for tailored phage products, also known as the magistral phage approach, has been established in Belgium. While this arrangement seems to have resolved, at least locally, the issue of product quality controls, the users still report a backlog on the number of patients that can be treated especially due to logistical problems. The data collected suggest the treatments are safe, but no evidence of efficacy has been concretely acquired because nearly every case is a unique phage-pathogen combination.

In parallel, industry has continued the development of fixed-composition bacteriophage products carefully characterized and methodically developed to be active against a particular species of pathogen. These products are typically being used in clinical trials following the traditional medicines regulatory framework. Progress has similarly been slow, and no efficacy data has yet been generated for any indication, i.e. there are no approved products yet.

Regardless of the approach taken to help patients in need, everyone agrees randomized controlled trials are required to move the field forward.

While these regulatory challenges may be difficulty to overcome, they are certainly not insurmountable.  Phage products for treating plant diseases (e.g., Agriphage™), and controlling animal-borne diseases (e.g., PhageGuard products; ListShield™) have been successfully commercialized and are currently marketed.  While these followed different regulatory pathways than human treatment products, similar issues of safety, efficacy, and quality control needed to be demonstrated.

Long-term which of these regulatory approaches might prove more effective in taking phage therapy from experimental treatment to approval by modern regulatory agencies? Should the approaches be combined in some way?  We invite the phage community to participate in a discussion with us – either in person or via an on-line survey – about this.