br Modulation of the Gut Microbiome Using Stool

Modulation of the Gut Microbiome Using Stool-based Therapeutics In Table 2, we list representative examples of live microbial preparations and microbial-based products that are currently being developed with therapeutic manipulation of the gut microbiome or its associated host interactions in mind. Fecal-microbiota derived products, probiotic, prebiotic and targeted molecule therapeutics have been developed for a variety of indications. In the following section, we specifically discuss the use of complex stool-based therapeutics as the most commonly used treatment modalities to date.
Regulation of Stool-based Therapeutics There is persuasive evidence for the use of FMT in rCDI, and perhaps also for a number of different diseases where the gut microbiota may play a pivotal role. FMT is cost effective and now recommended for treating rCDI nonresponsive to conventional antibiotic therapy (HQO, 2016; Lapointe-Shaw et al., 2016; Merlo et al., 2016). As such, two registered stool banks have emerged in the USA that screen and provide FMT products for use in the treatment of rCDI (Kazerouni et al., 2015; Advancing Bio, 2016) (Table 2). These organizations aim to facilitate and expand FMT access, nonetheless, the FMT regulatory landscape poses one of the biggest obstacles to efficient delivery of FMT to rCDI patients, as well as to the exploration of potential uses of FMT for other diseases. In many countries that recommend FMT for rCDI (e.g. England, Austria, Australia), FMT is not considered a drug by regulatory bodies (GESA, 2015; Kump et al., 2014; NICE, 2014). In contrast, Health Canada, the Federal Drug Administration, (FDA, USA), and the Agence nationale de sécurité du médicament, (ANSM, France) all classify FMT as a drug (ANSM, 2014; FDA, 2013; Health Canada, 2015). Because fecal material is extremely complex containing living microbes, microbial metabolites, host cells, and food particles; it ampk inhibitor is not inert and thus cannot be standardized as a drug in terms of pharmacokinetics, pharmacodynamics, or consistency of chemical composition. Labeled as a drug, storage of FMT falls under the jurisdiction of the pharmacist, which has caused problems for implementing FMT in North America but perhaps more so in France, where the preparation and documentation of FMT material is the responsibility of the pharmacist (Kump et al., 2014). Pharmacies not equipped for preparation of FMT material must coordinate with a microbiology laboratory, adding an additional layer of complexity. In addition, for tracking purposes donor fecal samples must be stored for a minimum of two years. Across regulatory bodies, there is also no clear consensus on donor screening tests. The ANSM is the most specific, requiring a two-step screening process and indicates which types of culture media and PCR tests should be employed (ANSM, 2014). Health Canada provides less specific recommendations, suggesting a list of potential pathogens for testing at the discretion of the treating physician (Health Canada, 2015). Currently the FDA will allow FMT for the treatment of rCDI without the need for an Investigational New Drug (IND) application, provided the donor and donor stool are adequately screened, and the health care provider obtains adequate consent from the patient after discussion of risks (FDA, 2013). An IND is required if the above conditions are not met, and for FMT for any indication other than rCDI. Health Canada has released similar restrictions (Health Canada, 2015). In March 2016, the FDA proposed an additional “enforcement discretion” clause that requires the donor be “known” to the treating physician, i.e. that the FMT product used is not obtained from a stool bank (IDSA, 2016). These restrictions, while aimed at improving safety, create delays, as healthy donors need to be sourced and screened. The FDA currently continues to exercise “enforcement discretion”, however, the Infectious Disease Society of America (IDSA) has recently requested that IND regulations for using FMT from stool banks to treat rCDI be waived, as they may cause potentially fatal delays in providing treatment for rCDI (IDSA, 2016). IDSA also pointed out that stool banks very comprehensively screen their donors. Indeed, the development of centralized, registered stool banks, with rigorous donor screening and FMT processing protocols in place, would be more efficient overall.