Fecal Microbiota Transplantation: FDA Announces Limited Enforcement Discretion

By Alexander J. Varond –

Undoubtedly, most microbes in humans are nonpathogenic, if not beneficial (a.k.a., “good bacteria”).  But, since at least the advent of the microscope, humans have shown great hostility toward pathogenic microbes, and relatively little regard for those that are nonpathogenic.  Antibiotics are routinely prescribed, sometimes with little understanding of the effect such drugs might have on bacterial ecosystems.  For some patients, treatment with antibiotic courses kills normal gut flora and can contribute to severe complications, such as Clostridium difficile (“C. diff.”) infections.  These C. diff. infections can be persistent and life threatening.  Traditional treatment involves administering still more antibiotics, and prognosis for some C. diff. patients can be poor.  This is particularly concerning given the marked increase in the virulence of C. diff. in the last decade.

In the presence of such unmet need, a promising therapy has emerged: fecal microbiota transplantation (“FMT”).  The therapy, also known as a stool transplant, involves the transplantation of fecal bacteria, via enema, colonoscopy, or other method, from a healthy individual to a recipient.  By introducing donor stool into the stomach or small intestine of a patient, FMT introduces beneficial flora into the colon to, in theory, overtake harmful bacteria in the gut.  And, while the therapy is relatively rare in humans, it is commonly used in animal husbandry to treat digestive ailments.

A 1958 paper documented four instances in which FMT was used to treat life-threatening digestive infections.  Since then, however, the treatment has only rarely been used and scientific evidence was lacking.  Then, in January 2013, the New England Journal of Medicine published the results of a 52-patient study that compared the efficacy of treatment with vancomycin, an antibiotic, and FMT in patients who suffered from C. diff. and had at least one relapse after antibiotics.  The results of the study overwhelmingly supported the use of FMT.

The practice then gained much wider recognition, and in February 2013, FDA announced that it would hold a public workshop “to exchange information with the medical and scientific community about the regulatory and scientific issues associated with . . . FMT.”  After the two-day public workshop on May 2-3, FDA stated that it would require FMT products to be administered under an Investigational New Drug Application (“IND”).  FDA reasoned that FMT was a biologic and that requiring INDs would help to protect patients by standardizing therapy, adding oversight, and encouraging the development of reliable products.

Advocates of FMT reacted to FDA’s new requirements by highlighting the time and cost of submitting an IND.  Moreover, they emphasized that requiring INDs could lead patients to resort to do-it-yourself procedures.  Only a month later, FDA made an informal statement that it would exercise enforcement discretion and allow practitioners to conduct FMT procedures without INDs.

Last week, FDA took an unusual step and issued a guidance entitled, “Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies.”  The guidance only applies to the use of FMT to treat C. diff. not responding to standard therapies and requires that doctors obtain informed consent from patients or their authorized representatives before performing FMT.  Interestingly, while FDA remarked that informed consent should include a discussion of risks, the agency did not say what those risks are.  The guidance also stated that sponsors could continue to submit INDs on a voluntary basis.  FDA was careful to note that its enforcement direction was only on an interim basis, while the agency further considered the matter, and only applied to C. diff. and not other diseases or conditions.

With the Human Biome Project reporting initial results last year and the considerable growth of the market for probiotic products, it is clear that we are at the forefront of a new and exciting branch of health science.  Where FMT will fit in is not yet clear.  One can imagine a day when patients routinely store autologous fecal samples as a hedge against developing C. diff. infection.  If projects such as the Human Biome Project yield discoveries that common diseases such as obesity, diabetes, and asthma may be linked to imbalances or a lack of certain bacteria, there could be interest in the use of FMT to address such conditions. 

Because there is the potential for FMTs to be performed outside of the clinic and without doctor supervision, it is virtually guaranteed that complex regulatory and public health questions will continue to arise.  This is a fascinating subject, and we’ll be watching closely.