What regulation for fecal transplantations?

A year ago, I wrote about the first randomized controlled trial investigating the medical use of human feces. The trial evaluated the efficacy of fecal transplantations to treat recurrent infections with Clostridium difficile. The results revealed a success rate of 94% for fecal transplantations, by contrast to a 27% success rate for a conventional antibiotics treatment.

Interest in the potential benefits of manipulating the gut microbe population (microbiota) has increased a lot over the past 5 years, as more and more research has shown how the bacteria living in the human gut can affect their host physiology (for example, by participating in the “education” of the immune system). However, transplanting fecal material from one individual to another as a way to transplant gut bacteria may carry risks as well as benefits. An adequate regulatory frame is therefore needed to ensure that the therapeutic potential of fecal transplants can be investigated and such procedures achieved in the safest conditions possible.

In an article published in Nature on February 19th, 2014, three researchers from the Massachusetts Institute of Technology and Brown University comment on the current regulatory issues surrounding the use of fecal transplantations and suggest that human feces should be classified as a human tissue, not a drug, by the Food and Drug Administration (FDA) in order to facilitate both research and therapeutic applications while ensuring patient safety.

Fecal microbiota transplantation, potential benefits and risks

Fecal microbiota transplantation (FMT) consists in processing the stools from a healthy person to make a solution that is then delivered directly to the gut of another individual (via enema, colonoscopy, or in the case of the clinical trial mentioned previously, via a tube threaded through the nose and reaching down to the small intestine). Such FMTs have been used to treat C. difficile infections with a high success rate (80-90%). The idea is that transplanting fecal material from a healthy person to a patient, thereby transplanting the gut bacteria, helps restore a population of normal gut bacteria that competes out the pathogenic microbes in the patient.

Many studies in mice and in humans have shown that the gut microbiota affects the host physiology. To give only a few examples, an abnormal microbiota has been linked to obesity and malnourishment in humans, and many studies done in mice have shown that the gut microbiota influences the development of the immune system and the subsequent susceptibility to immune-related disorders (for example, a study showed that gut bacteria influenced susceptibility to disease in a mouse model of type 1 diabetes).

The hope is to use the increasing knowledge of the human microbiome and how it affects physiological and pathological states in humans to design microbiota-based therapies for a range of diseases. Although a few clinical trials are already ongoing to evaluate the efficacy of FMTs to treat inflammatory bowel disease, the hopes to treat other diseases are still highly speculative. More research is required to better understand the role of bacteria in human health and disease before treatments can be designed and implemented.

Meanwhile, it is important to also recognize the potential risks associated with FMTs and to find ways to address them adequately. For a start, there is as yet no large prospective study investigating the long-term safety of fecal transplants. Potential unintended consequences of modifying someone’s gut microbiota, such as increasing susceptibility to chronic conditions like obesity or autoimmune disorders, have to be considered (however, this also applies to the use of antibiotics). The risk of spreading infectious diseases (e.g. hepatitis) also exists, and proper screening of stool donors is of paramount importance.

In view of the potential benefits but also risks associated with FMTs, it is important that regulatory authorities provide an adequate frame that would ensure patient safety while allowing enough flexibility to perform FMTs for therapeutic applications and clinical research. The authors of the Nature article point out that such a regulatory frame is also important to facilitate patients’ access to FMTs and thus ensure that unsafe “at-home” treatments will not spread.

The regulatory issue

Until last year, FMTs were classified as a drug by the FDA, meaning that physicians had to file an Investigational New Drug (IND) application to be legally allowed to perform them (and filling out an IND is no trifle). The idea was that categorizing FMTs as a drug would encourage the development of standardized commercial products that would allow easy access to such a treatment, while also ensuring adequate control of safety issues. A few companies are indeed developing feces-derived products that would fit the FDA’s drug classification, however the conventional path for drug development is long and costly, and the authors of the Nature article argue that such a drug classification slows down research on the risks and benefits of FMTs.

Hearing the concerns of the scientific and medical community about the limited access to FMTs for people suffering from C. difficile infections and the resulting risk of “at-home” treatments spreading, the FDA decided in June 2013 to make an exception for the use of FMTs in the case of C. difficile infections (compassionate use). However, that decision may not have improved things much: IND filing is still required for any other use, and at the same time, no mandatory screening of stool donors is required for C. difficile treatment by FMTs.

Fecal transplants are actually rather ill-fitted to make it as a drug as defined by the FDA: the primary material is stools – a mix of microbes, metabolites, and human cells, and is therefore highly variable from one donor to the other; by contrast, the ingredients of conventional drugs are precisely defined and drugs are produced under highly controlled conditions, two characteristics that would be hard to achieve for FMTs. All things considered, FMTs are more amenable to a classification as human tissue. Other human products (e.g. cartilage, skin, bone, etc.) are classified as such or have their own statute (e.g. blood or semen): transplantations of these tissues/cells require a tight control of the tissue’s life from donor to patient and thorough screening for communicable diseases, characteristics that are also needed in the case of FMTs.

The authors of the Nature article argue that a drug classification for FMTs is too limiting and advocate for a classification as a tissue product (or for its own classification, as is the case for blood). According to them, this would still ensure safety for patients, but would facilitate use and research.

Stool banks

Two of the Nature article authors participated in the creation of a “stool bank” in 2012 (OpenBiome, a non-profit), which has since functioned to deliver stool material for treatment of C. difficile infections under the “compassionate use” legal terms.

Just like blood banks have improved the safety, availability and access to blood transfusions, stool banks can make FMT-based treatments safer, easier, and cheaper by providing a source of standardized material collected from stringently screened donors. For example, OpenBiome screens donors for infectious agents and for chronic conditions such as metabolic syndrome, autoimmune disorders or digestive problems. Such a centralized source of material for FMTs also allows for better tracking of potential adverse events, increased standardization of the treatments provided, and better control over what FMTs are used for. The Nature article authors thus suggest that stool banks could require approval from a clinic’s institutional review board before releasing material for FMT in order to limit inappropriate use.

Beyond FMTs

The raw material for FMTs is currently made of minimally processed stools collected from healthy donors, meaning that FMTs deliver a bunch of uncharacterized gut microbes to the patients. Beyond the “icky factor”, receiving stool material from someone else may also be a bit scary considering all the unknown. After all, each of us harbors their own specific mix of gut microbes, and what works great for your friend, sister, or neighbor, may not work that well for you.

Ideally, it would be better if it were possible to identify the “active ingredients” of FMTs, namely the bacterial species that provide the actual benefits. This could lead to the development of well-characterized bacterial cultures, allowing for a better control of what is actually transferred to patients and circumventing the risks inherently associated with having to transfer material from one human being to another.

Such bacterial cultures would be well-defined and possible to manufacture under controlled conditions, making them amenable to being regulated as a drug. Companies are already working on such an approach, however these treatments are still a long way down the road. Meanwhile, it is important to provide an adequate regulatory frame for FMTs to ensure a safe and easy access for patients needing them.


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