The ladder of regulatory stringency and balance: an application to the US FDA's regulation of bacterial live therapeutics.

Abstract

The three main types of live bacterial therapies - probiotics, fecal/microbiome transplants, and engineered bacterial therapies - hold immense potential to revolutionize medicine. While offering targeted and personalized treatments for various diseases, these therapies also carry risks such as adverse immune reactions, antibiotic resistance, and the potential for unintended consequences. Therefore, developing and deploying these therapies necessitates a robust regulatory framework to protect public health while fostering innovation. In this paper, we propose a novel conceptual tool - the Ladder of Regulatory Stringency and Balance-which can assist in the design of robust regulatory regimes which encompass medicine practices based not only on definitive Randomized Controlled Trials (RCTs), but also on meta-analyses, observational studies, and clinicians experience. Regulatory stringency refers to the strictness of regulations, while regulatory balance concerns the degree of alignment between the regulatory framework governing a technology and the actual risks posed by specific products within that technology. Focusing on the US regulatory environment, we subsequently position the three types of live bacterial therapies on the Ladder. The insight gained from this exercise demonstrates that probiotics are generally positioned at the bottom of the Ladder, corresponding to low-stringency regulation, with a proportionate regulatory balance. However, probiotics intended for high-risk populations are currently subject to low-stringency regulations, resulting in under-regulation. Our analysis also supports the conclusion that fecal microbiota transplants (FMT) for recurrent Clostridium difficile infection should be positioned close to but below the threshold for under regulation by the U.S. Food and Drug Administration (FDA), and we recommend improved donor screening procedures, preservation and processing, storage, and distribution. Our framework can serve as a scale to assess regulatory gaps for live bacterial therapies and to identify potential solutions where such gaps exist.