Update on Fecal Microbiota Transplantation 2015

Indications, Methodologies, Mechanisms, and Outlook

Colleen R. Kelly; Stacy Kahn; Purna Kashyap; Loren Laine; David Rubin; Ashish Atreja; Thomas Moore; Gary Wu


Gastroenterology. 2015;149(1):223-237. 

In This Article

Regulatory Issues

Worldwide, regulation of FMT varies greatly between countries. The Therapeutic Goods Administration in Australia, where FMT is not considered a drug or regulated for any indication, has provided no communications regarding FMT. Although several trials of FMT are ongoing in China, there has been no indication that the Ministry of Health intends to exercise authority over the procedure. In Europe, the European Medicines Agency has not regulated FMT for CDI thus far.[111] However, Health Canada considers FMT and related synthetic stool therapies as a "New Biologic Drug" and requires that any clinical study go through the process of a clinical trial application to ensure that quality and safety standards are met.[112] The US Food and Drug Administration (FDA) has determined that administered stool constitutes a biological product and a drug in that it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or is intended to affect the structure or function of the body.[113] Although fundamentally different from existing drugs and biologics, the agency has maintained that, at this point, the process of donor eligibility determination and screening, stool processing, and infusion defines the FMT "product" and falls under FDA jurisdiction. As such, without large randomized controlled studies to support safety and efficacy, it is an unapproved product and an investigational new drug application (IND) is required to administer FMT.

The IND process is largely tailored to the pharmaceutical industry and regulatory experts. The time and administrative burden for any clinician wishing to sponsor an IND to treat his or her individual patients with FMT can be enormous. The initial application may take many weeks to prepare, and once an IND is active, follow-up documentation, such as required reporting of all serious adverse events (even if unrelated), institutional review board oversight, safety monitoring board meetings, and mandatory annual reports to the FDA are similarly time consuming and burdensome. Furthermore, it is not permissible to charge for products that are being administered under an IND. Requiring physicians to hold an IND to administer FMT would prevent many from offering this therapy and ensure that only commercial entities with the means to navigate the regulatory process and fund large clinical trials will control this effective therapy. The FDA announced the IND requirement in May 2013 at a public workshop to discuss the regulatory and scientific issues around FMT. Physicians, scientists, and patient stakeholders argued that the availability of FMT would be adversely affected by this requirement. The agency agreed and subsequently stated that it would exercise "enforcement discretion" around FMT when used by licensed physicians to treat patients with CDI that does not respond to standard therapies.[114] In other words, the FDA will not enforce its own requirement that FMT be performed under an IND as long as providers obtain informed consent, detail risks around the procedure, and explain that FMT is considered an investigational therapy. The enforcement discretion policy does not extend to other uses of FMT, such as IBD. Furthermore, clinical trials of FMT for CDI do not fall under enforcement discretion and require an IND.

This policy has enabled many patients with recurrent CDI to undergo FMT but is probably only temporary. The position of the FDA on this matter continues to evolve. Partially in response to stool banks, which were not operating under an IND and began shipping preparations of stool to providers across state lines, the FDA posted a draft guidance and solicited feedback in early 2014, proposing that the FMT product must be obtained from a donor known to either the patient or the licensed health care provider treating the patient and that the stool donor and stool are qualified by screening and testing performed under the direction of the licensed health care provider for the purpose of providing the FMT product to treat his or her patient. Although this policy has not been finalized, if fully implemented, such a policy would greatly limit FMT under the stool bank model, which uses volunteer donors who are not known to the patient or provider. Commercialized preparations of human stool are currently in clinical trials, and it is conceivable that the FDA might cease to offer enforcement discretion entirely once one or more of these products is approved and commercially available. It is clear that the regulatory landscape will continue to evolve as microbiota-based therapeutics emerge.