The Impact of Regulatory Policies on the Future of Fecal Microbiota Transplantation

Abstract

In this article, the authors explore the impact of a potential future regulatory decision by FDA whether or not to continue its enforcement discretion policy allowing physicians to perform, and stool banks to sell, stool product for fecal microbiota transplantation as a treatment for recurrent Clostridium Difficile infection without an Investigative New Drug (IND) application. The paper looks at the Agency's regulatory options in light of the current gut microbiota based products that are in the FDA pipeline for drug approval and the potential impact and repercussions of their approval on FDA action. In laying out FDA's options we consider the implications of market exclusivity and off-label use of newly approved drugs. Ultimately, we explore the potential impact of FDA's decision on patients, research, and innovation.

Vaginal Microbiota Transplantation: The Next Frontier

“…Although some of these challenges are addressed for biologics through the manufacturing process, obstacles still remain. 63 Another concern with the drug pathway is that because of the expense to the drug manufacturer/ sponsor of going through all of the required procedures and clinical trials, the price of the ultimate drug, if approved, is likely to be quite high. In addition, the approval process takes on average ten years.…”

“…This can reduce the burden of BV-associated bacteria prior to VMT, and is analogous to antibiotic use with FMT. 89 VMT should occur after an antibiotic "washout period" of a minimum of 24 hours. The placebo group should receive standard of care followed by a placebo treatment of a benign vehicle, such as normal saline.…”

Where Stool is a Drug: International Approaches to Regulating the use of Fecal Microbiota for Transplantation

“…Nevertheless, classifying stool as a biologic presents significant technical challenges and severely restricts patient access until market approval is granted. 24 In contrast to chemically synthesized drugs with well-defined structures, biologics are complex and often poorly characterized mixtures derived or isolated from living organisms. Because of this, biologics are often more sensitive to environmental factors during their manufacturing (e.g.…”

Batch Culture Formulation of Live Biotherapeutic Products

“…[3] Much like fecal microbiota transplants (FMT), these LBPs require human donor feces; as such, there is a constant need for fecal donations to provide the source material for these LBPs. [4] Recently, LBPs have achieved several milestones in clinical trials for DOI: 10.1002/adtp.202000226 treatment of Clostridium difficile infections, highlighting their therapeutic potential. [2a,4,5] Unlike small molecule drugs or biologics, LBPs are living organisms that sustainably interact with the existing microbiome through colonization to shift dysbiosis toward non-diseased, protective, states.…”

“…[2b,5b,6] LBPs that are derived from human donor feces must undergo multiple processing steps (e.g., filtering, biomass separation, pathogen neutralization, LBP isolation) prior to administration; [5a,7] when these LBP processing steps are applied to unique microbiota compositions of each fecal donor, variations in the composition of LBPs are possible. [4,8] A distinct subset of LBPs that can potentially standardize LBP composition are being developed as defined microbial consortiums of specific microbes that are individually cultured and specifically combined in LBP formulations. [9] These next-generation LBPs can potentially eliminate the repeated isolation and purification processes needed to manufacture LBPs from feces by introducing batch culture approaches.…”