Although antibiotics are the standard-of-care treatment for Clostridioides difficile infection, they can cause further microbiota changes that predispose patients to recurrence.
Clostridioides difficile infection (CDI), the leading cause of antibiotic- and health care-associated infective diarrhea in the United States, is associated with almost half a million infections annually.1,2 Accumulating evidence suggests that dysbiosis, defined as a perturbation in the intestinal microbiota composition characterized by reduced richness and diversity, is implicated in development of and recovery from CDI.3-7
Although antibiotics are the standard-of-care treatment for CDI,8 they can cause further microbiota changes that predispose patients to recurrence. Approximately 20%-35% of patients experience recurrent CDI (rCDI), of whom up to 60% experience subsequent recurrences.9
As prevention and management of rCDI has continued to present a challenge, interest has been re-ignited throughout the past decade in the application of a microbiota-based therapeutic for CDI to aid in microbiome restoration. There is a strong historical basis for such methodologies, as fecally-originated products have been used since the fourth century when Ge Hong used “yellow soup” for diarrheal disease.10
Fecal microbiota transplantation (FMT) from healthy individuals to patients with CDI has been used increasingly over the past several decades to restore healthy flora in the gut, thus breaking the cycle of recurrent CDI.11 Indeed, FMT has emerged as a well-recognized strategy for rCDI management. Further, CDI treatment guidelines published by the Infectious Diseases Society of America and the American College of Gastroenterology now endorse FMT as a recommended therapy for rCDI unresponsive after 2 or more recurrences treated with antibiotics.12,13
However, FMT is a procedure that is not FDA-approved and has been performed under an investigational new drug (IND) application. Thus, FMT has been notoriously unstandardized with variability reported in fecal material screening and sources, collection procedures, preparation and storage processes, and routes of administration/delivery.14,15
Even the use of centralized manufacturing and storage banks has been noted to carry safety concerns related to the number of patients who may be exposed to a particular donor and particular manufacturing practices. These safety concerns include the transmission of infectious agents to at least 6 patients and ensuing death of 2, which prompted the FDA to issue a warning in 2020 regarding the potential risk of serious or life-threatening infections with the use of FMT.16 Therefore, at this time, the FDA no longer intends to extend enforcement discretion with respect to the IND requirements for distribution of FMT products obtained from stool banks.
The approval of live biotherapeutic products (LBPs) has been a much-needed development in microbiota-based therapies for CDI. Two LBPs are currently FDA-approved for the prevention of CDI recurrence in adults following antibiotic treatment for a rCDI episode: Rebyota (formerly RBX2660; RBL) and Vowst (formerly SER-109; VOS). A third, VE303, is in phase 3 trials. The designation of this new drug class has caused confusion in differentiating between what qualifies as FMT, an LBP, and even a probiotic. We aim here to clarify these differences.
The FDA has designated LBPs as a biological product meeting 3 criteria:17 contains live organisms, such as bacteria; is applicable to the prevention, treatment, or cure of a disease/condition of human beings; and is not a vaccine.
LBPs, such as RBL and VOS, are FDA-approved, manufactured under good manufacturing practice (GMP) methods, are screened thoroughly for pathogens as per the FDA, and both have undergone rigorous clinical trials. These serve as the major differentiating requirements between FMT and LBP.
Likewise, probiotics are considered dietary supplements and are regulated as such. However, each LBP meets the FDA qualifications differently. RBL and VOS are derived from human stool donors18,19 whereas VE303 is derived from clonal cell banks.20 Furthermore, VOS undergoes an ethanol purification step to ensure the final product contains only spores,21 whereas RBL is a whole-stool product.22
Both RBL and VOS are derived from qualified stool donors who undergo rigorous and continuous screening as part of the standardized manufacturing process. Additionally, donor samples are screened for at least 29 pathogens, as per the FDA requirements. Stool donations are collected at the manufacturing site, stored under controlled conditions, and can be traced back to a specific donor, date, and health status at the time of donation.
Clinicians should be aware of the major differences between FMT and LBPs, including RBL and VOS, and not consider them to be the same. FDA-approved LBPs may have differing compositions but are similar, to a large extent, in terms of rigor of manufacturing, safety, and efficacy.
About the Authors
Anne Gonzales-Luna, PharmD, research assistant professor, Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy.
Glenn S Tillotson PhD, FIDSA, FCCP, GST Micro LLC.
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17. FDA U. Early Clinical Trials with Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information 2016 [cited 2023 06 September]. Available from: https://www.fda.gov/files/vaccines,%20blood%20%26%20biologics/published/Early-Clinical-Trials-With-Live-Biotherapeutic-Products--Chemistry--Manufacturing--and-Control-Information--Guidance-for-Industry.pdf
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22. REBYOTA [package insert]. Parsippany, NJ: Ferring Pharmaceuticals Inc; 2022.