The phage community has an awful lot to be happy about right now. Thanks to the hard work of dedicated scientists, physicians, and advocates, phage therapy is increasing in popularity and prominence. These experts are on the front lines in the fight against the dramatically increasing incidence of multi-drug-resistant (MDR), extensively-drug-resistant (XDR), and even pan-drug-resistant (PDR) bacterial pathogens.
The nature of the rise of these pathogens—namely, the evolving failure of conventionally developed small-molecule drugs—has taken modern phage therapy on an unorthodox ride through a rugged regulatory landscape that was not designed to accommodate its unique qualities. High-profile stories like the world-famous “Perfect Predator” case and the genetic engineering of phages for personalized treatment have framed phage therapy in sharp relief, but medical regulations around the developed world have not yet kept pace with developments. This poses challenges to the short- and long-term evolution of phage therapy into a mainstream practice for the treatment of bacterial infections.
So how do we navigate this administrative quagmire to speed up and expand the delivery of phage therapy in the timeframe necessary to treat infected patients? In this piece, I will briefly discuss key parts of this infrastructure, how they help and hinder us, and a few tangible action items that we can support to benefit our field.
The Compassionate Spread of “Compassionate Use”
Many of the most high-profile cases of recent phage therapy have been enacted through “compassionate use”—the emergency review and approval to use unorthodox or unlicensed drugs or devices to treat patients for which conventional measures have failed. This reflects the contemporary state and purpose of phage therapy—a personalized, last-ditch effort to treat critically ill patients for whom antibiotics have failed or are failing fast.
The regulatory framework for compassionate use has been established in many countries. For example, the Food and Drug Administration (FDA) directly handles these cases in the United States, often hand-in-hand with emergency investigational new drug applications, tailored for specific patients. In contrast, the European Medicines Agency (EMA) delivers broad guidelines and regulations upon which member states of the European Union can craft their own specific policies. In recent years, the FDA has approved nearly all applications for compassionate use and has taken steps to streamline the process, but it still often takes a few weeks to file the necessary paperwork and wait for approval. As a result, the diligence, patience, and administrative support that this route requires likely puts large, wealthy teaching hospitals and clinical research centers at a substantial advantage over more rural, resource-stretched care centers that could benefit from greater access to alternative therapies.
We in the worldwide phage community, and the patients we serve, would benefit greatly if we worked together to share and expand the resources needed for compassionate use. Phage epicenters should share not just their phages, but also their legal and administrative resources, with clinical centers that are more hard-pressed to use this framework to their advantage. Doing so would let us connect with greater numbers of patients and bring phages to the attention of local government administrations whose cooperation is essential. It would also help us build the groundwork for long-term local and national policy changes in our respective home countries, thus compelling phage therapy into the fold of “conventional” modern medicine.
ACTION ITEM: Share our legal and logistical resources far and wide.
The Looming Legal Mess of Phage Clinical Trials
Much to our excitement, phage cocktails have been going through clinical trials all across the world, to assess their efficacy as prebiotics, antimicrobials, and immunogens. While clinical trials are intensive, time-consuming, and very, very expensive, they are the gold standard to which all new pharmaceuticals must be compared in order to be considered truly “adopted.” It is certainly good for our field that phages are running this gauntlet, but there are problems on the horizon that we can prevent with action now.
The most significant risk to the success of clinical trials of phages results from two key factors: their host specificity and their capacity to evolve. These introduce a bunch of variables that the contemporary regulatory infrastructure of clinical trials was not developed to address. Using heterogeneous cocktails addresses the host specificity issue (albeit to a more limited extent than most antibiotics), but it only amplifies the risk of fallout from the second factor: phages’ capacity to evolve. All kinds of messy legal arguments could ensue from the failure of a therapeutic that can mutate on its own, outside the explicit control of the clinician. And would a cocktail with 6 of the same 7 phages as a previously licensed one need to go through its own series of multi-million-dollar trials? Would all phages in a cocktail in clinical trials need to be rigorously screened for bacterial toxins that they may have picked up by transduction?
The existence of these variables foretells a new generation of medicine that much of our current regulatory systems are likely not prepared to face. We should also consider that compassionate use regulations could well become oversaturated if phage therapy really takes off around the world. For both these reasons, it is in our best interests to help shape the long-term future of this infrastructure, so that our work can be allowed to flourish while the patients we serve are still protected. Experts in the phage field should actively contribute their expertise to legal and political discussions that are necessary to enact these long-term changes. They could even team up with experts in oncolytic viral therapy and fecal microbiota transplant (FMT), whose fields are likely to face similar challenges.
ACTION ITEM: Advocate for structural updates to solve problems before they emerge.
New Systems Need New Connections
Perhaps the entirely unconventional nature of phage therapy requires some entirely new ideas for its regulation. This idea has already been embraced through different mechanisms in several countries, as has been beautifully summarized in a 2018 mini-review by Lucy Furfaro, Matthew Payne, and Barbara Chang. The unsung backbone of each of these profound policy developments has been effective science communication and outreach to public officials. To enact substantial changes in medical policy, we need to get the attention of policymakers and their constituents through enthusiastic engagement that emphasizes the purpose and urgency of new systems to manage phage therapy. The more that we take the initiative to explain the value of our work to the public and to public servants alike, the more likely it is that we will receive support for new methods to distribute phages.
ACTION ITEM: SciComm!
The sooner we start pursuing these concrete initiatives, the more robust the future of phage therapy will become.