Fecal microbiota transplantation (FMT) has emerged as an increasingly common treatment for patients with refractory Clostridium difficile infection (CDI). Unlike standard antibiotic approaches, which only exacerbate dysbiosis and may perpetuate CDI recurrence, FMT restores normal gut microbial community structure and function of the gastrointestinal tract. However, a number of challenges need to be overcome before this procedure is widely accepted in mainstream clinical practice.

Before I jump into highlighting the number of practical barriers that are associated with FMT, I want to make clear that none of these issues represent insurmountable hurdles. The development of an efficient, safe and reliable transplant mechanism is certainly within technological reach.

Roadblock #1: Donor selection

Historically, an ideal FMT donor was considered a close family member, an intimate partner or a trusted friend; and patients were tasked with identifying their donor. However, there is no evidence that relatedness of a donor impacts the patient’s clinical outcome. Further, it is appropriate to consider the general health of the donor, which may be overlooked by a patient desperate to receive FMT.

The donor problem can be solved by the development of a dedicated, standardized donor program. In this ideal system, stool donors will be screened in a similar fashion to blood donors, with additional consideration of systemic problems, such as metabolic syndrome, diabetes, autoimmunity, inflammatory bowel disease, colon cancer risk,  irritable bowel syndrome, food intolerances, allergies, and neurologic and psychiatric problems. Further, potential donors cannot have a history of recent antibiotic exposure. While this would limit the number of eligible donors dramatically, the program is feasible because qualified donors can provide repeated donations, supplying sufficient material for an extensive FMT program. (While on this topic: you may have recently read that the nonprofit OpenBiome has created a stool bank for FMT, enticing healthy donors with up to $13,000 a year for their stool donations.)

Roadblock #2: Material processing

While FMT can be performed using whole stool, such a procedure can be very challenging esthetically. However, it is possible to separate the microbial portion from fecal material, and even more importantly, it is possible to freeze this microbial fraction while maintaining the viability of the different microbial taxa and clinical efficacy of the preparation.

There are several important advantages in using the frozen microbial fraction instead of the freshly prepared stool. First, the material is no longer esthetically challenging, having lost most of the potent pungent odor associated with stool. Second, the preparation can be quantified in terms of numbers and types of bacteria present rather than the crude measure of stool weight, which can vary in bacterial content between individual donations. Most importantly, the ability to bank the microbiota material before its use allows performance of rigorous testing and elimination of uncertainty associated with freshly prepared material.

Roadblock #3: Standardization

While there is currently no set standardization process in place, the entire process of producing fecal microbiota material can be standardized in accordance with the Current Good Manufacturing Practices (CGMPs), which is used and enforced by FDA to ensure proper design, monitoring and control of the manufacturing processes and facilities. Adherence to CGMPs is absolutely critical to large-scale manufacture of fecal microbiota preparation that may enter routine clinical practice. The ultimate purpose in the manufacture of a product as complex as fecal microbiota is not to obtain precise compositional consistency, which is impossible given that composition of every donation is somewhat different and gut microbiota is intrinsically dynamic. However, CGMPs do ensure that the manufacturing process is consistent between different batches, and any possibility of introducing risk is minimized.

Roadblock #4: Regulations on biotechs

The spectacular success of FMT in treating refractory CDI has provided a boost to various biotechnology start-up manufacturing companies that are attempting to harness the power of the microbiome for novel therapeutics development. Different companies are taking varying approaches to develop fecal microbiota–based products, including standardized whole donor-derived microbiota; highly simplified, defined microbial consortia; and hybrid products, such as SER-109, the lead spore-based compound from Seres Health (Cambridge, MA), which recently was reported to have promising early results in recurrent CDI. The pace of discovery and clinical validation is accelerating, and it appears very likely that a range of highly effective therapeutic options for CDI and perhaps other indications, soon will be introduced into mainstream medicine.

However, in addition to the many scientific and technical hurdles, developers also are challenged by the fluid regulatory framework and uncertainties in the intellectual property landscape. While FDA issued a policy of “enforcement discretion” for physicians using FMT on patients with refractory CDI not responding to standard therapies, these restrictions have been applied unevenly to commercial entities.

Functionally, gut microbiota fit the description of an organ and given its tight co-evolutionary linkage to its specific host species, it can be considered a human organ composed of microbial cells. Therefore, it may be more reasonable for FDA to borrow elements of regulation for microbiota products from those applied to tissue transplantation, rather than those applied to new drugs.

Moving forward

Most importantly, therapeutic development in this area should be guided by the best science. We have the medical community on our side, as the American Gastroenterological Association has developed the AGA Center for Gut Microbiome Research and Education to continue to advance research on the gut microbiome in human health and disease.

Ultimately, we all — physicians, scientists, developers and regulators — need to be informed by continued research, basic and clinical, to allow establishment of this promising new class of therapeutics into mainstream medicine.

Alexander Khoruts is a gastroenterologist.