Capsule

What’s new, what’s hot, what’s timely? If you don’t have time to search the Internet for the latest developments that might affect your work environment, you just might find some of that information in this Capsule column. Please e-mail any comments, suggestions, or insights to Robert A. Rasmussen at [e-mail].

Regulating Fecal Microbiota Transplants: Balancing Risk with Supply Demands

Fecal microbiota transplants (FMT), the transfer of stool from human donors to human recipients, have proven to be an effective treatment against recurrent cases of pathogenic Clostridium difficile gut infection (CDI). Indeed, this is now the prescribed treatment for CDI where antibiotics have proven either ineffective or even detrimental (by diminishing the biodiversity of the gut microbiome, resulting in a more homogeneous microbial environment that supports CDI). The potential for transfer of infectious pathogens from an FMT is obvious, yet there are inconsistent practices and regulations regarding the screening of donor stool for pathogens. To address this, the NIH Microbiota Transplantation Project—a panel of clinicians, human microbiome researchers, patient advocates, bioethicists, regulators, and legal scholars—convened a number of times over the past 2 years with the goal of establishing a workable policy for the Federal Drug Agency, and possibly other countries, to use to establish a set of pragmatic and consistent regulations for microbiota transplantations (MT). ¹

Because sources of donor material include stool banks (prescreened for infectious pathogens), hospital laboratories (may or may not prescreen donor material), or friends known to the physician or patient (usually not prescreened), the US Food and Drug Administration (FDA) has had difficulty in offering clear regulatory guidance. Challenges include the fact that FMT is not a drug per se but a community of live, dynamic microorganisms and that each “product” used to treat an individual patient is different. In 2013, the FDA labeled any FMT a biological product requiring investigational new drug (IND) review. However, with such high demand for donor stool because FMT was proving to be so effective, the FDA decided later that year that if FMT was used to treat CDI, then no IND review was required. In 2016 however, the FDA published draft guidance requiring all stool banks to submit an IND to obtain and distribute stool to doctors no matter the disease being treated by FMT; in contrast, no IND is needed for stool samples prepared at hospital laboratories or obtained directly by the physician. In theory, this was set up to both ensure that there would be no limit on the availability of samples for FMTs while also equalizing the playing field to properly compare efficacy results between FMT and IND review-subjected drugs for treating CDI.

The framework proposed by the NIH Microbiota Transplantation Project would require that the FDA treat unmodified stool microbiota as a tissue and not a biological product or drug. Through this, the group hopes to offer a framework that would “ensure the safety and effectiveness of the transferred material, provide adequate information to patients about benefits and risks, ensure access for patients who need the procedure, encourage research and development of microbiota-based therapies, and support public health objectives to reduce the burden of antibiotic resistance.” They proposed a 3-track regulatory scheme summarized as follows: (1) FMT performed with stool from someone known to the patient or physician would be state regulated as a “practice of medicine” procedure; (2) FMT performed with material from an FDA-regulated stool bank would be regulated as human cell tissue establishments currently are, including donor screening for underlying GI disease and the required reporting of adverse events from donor stool to the FDA; and (3) FMT performed with “modified stool-based products,” for example, defined microbial populations originally cultured from stool, would be regulated in a manner similar to that currently in place for biological products or drugs.

So how might these proposals affect biosafety professionals? If put in place, the proposed framework for regulating unmodified and modified donor stool will make it important that IBCs are clear about the source of any donor material as this will define how it has been screened. Knowing the type of source facility will also be important for biosafety officers concerned about the risk to workers handling fecal samples for basic research and animal work. The safest default risk assessment, however, is to assume samples contain Risk Group 2 organisms and should be handled using biosafety level 2 recommendations.