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FDA IND Requirement for Fecal “Transplant”: Hitting the Fan

Recently the Food and Drug Administration announced its decision to require an Investigational New Drug application for fecal bacteriotherapy (aka fecal “transplants” or ) for the treatment of Clostridium difficile-associated Disease (CDAD), on the grounds that stool is being used as a probiotic agent, over which it has licensing jurisdiction. Fecal bacteriotherapy is an old fashioned remedy, and has increasingly been used to treat CDAD in recent years, because of increasing severity of CDAD and because of frequent failure and recurrence of CDAD with conventional, costly, and complex antibiotic treatments. In February 2013, a large trial comparing “fecal transplant” to conventional treatment was published in the respected New England Journal of Medicine. The trial was halted early due to significantly worse outcomes in the conventionally treated patients, in whom 31% were cured, in contrast to 94% by “fecal transplant”; conventially treated patients were offered “fecal transplant” because it was deemed unethical not to. It is a rarity in research that such significant differences are picked up before a study ends, and this finding has been received as validating the personal observations of many frustrated clinicians who treat these very ill patients: Healthy poop is far more effective than any probiotic or drug in restoring the balance of gut flora necessary to eliminate CDAD in most patients. The findings received wide press in respected lay publications from Nature to The New York Times.

In response to a potential groundswell of fecal bacteriotherapy by excited clinicians, the FDA held a  public workshop May 2-3, 2013 “To facilitate clinical development of FMT, … to provide a forum for the exchange of information, knowledge, and experience between CBER, NIAID, and the scientific-medical community.” Names of the panelists appear in the published transcripts for day 1 and day 2 (financial disclosure statements do not appear, nor do the numbers of participants from the scientific-medical community). Final rationale and review process for IND in FMT was outlined May 16th. FDA IND applications are reviewed as individual proposals for treatment, although the FDA site offers emergency approvals by phone.

Read an excellent review on fecal "transplant" therapy by Minnesota Public Radio here http://minnesota.publicradio.org/display/web/2012/12/10/health/fecal-transplants-colon-disease

Read an excellent review on fecal “transplant” therapy by Minnesota Public Radio here http://minnesota.publicradio.org/display/web/2012/12/10/health/fecal-transplants-colon-disease

No one can argue that we clearly need objective data on the short- and long-term effects of fecal bacteriotherapy.

First, the term “fecal transplant” is a misnomer, and the frequent use of FDA guidelines for organ/tissue transplantation as a template for screening stool  donors may be inadequate or inappropriate for something that is not a transplanted tissue.  Some are concerned about transmitting conditions we are not aware of and currently cannot screen for, such as cancer-causing biological materials or organisms.  Streptococcus bovis, for example, is not an organism screened for in organ/tissue transplant donors–and thus not included in most “fecal transplant” protocols published; this organism is suspected to cause or potentiate development of colon cancer in susceptible individuals, and may be used one day as a marker for colon cancer risk. Yet standard stool culture protocols in Microbiology laboratories are designed to screen for diarrhea-causing bacteria and antibiotic resistant organisms such as vancomycin-resistant Enterococcus, not usually-harmless gut organisms such as Streptococci. We need to study not only whether this is a real risk, but whether it’s an acceptable risk in the face of serious C. difficile infection or other serious conditions for which fecal bacteriotherapy is being considered. Certainly the very high risks of bone marrow transplants do not deter their use in the face of lifethreatening illness.

We do not know whether longterm survivors after fecal bacteriotherapy may develop other diseases related to it, or even derive new benefits. A 2012 survey, Long Term Follow Up of Colonoscopic Fecal Microbiota, following 75 patients who received stool for severe C. difficile for a mean of 17 months noted that 4 patients developed rheumatoid arthritis, idoepathic thrombocytopenic purpura, Sjögrens syndrome, and an undefined neuropathy inthat period; 2 patients noted improvement in allergic sinusitis and arthritis. Certainly any of these conditions may appear in populations prone to C. difficile, and in this particular study, the incidence of new conditions arising within 36 months of fecal bacteriotherapy is 0.05%; this survey is a snapshot of patients’ experiences; there is no control group to compare this incidence to untreated patients (if indeed such an ill comparator group would survive that long). These conditions are associations, and their relevance is unknown without further longterm studies.

Finally, there are other diseases besides CDAD in which fecal bacteriotherapy seems highly promising, such as inflammator bowel disease.

Requiring NDI will not significantly dampen study of these questions in academic settings with resources to apply. It’s the non-academic community, in which this procedure has been infrequently performed for years, that will be most affected in the near term, and will likely shut down the procedure as an option to seriously sick patients in many areas.

But besides reducing access to treatment,  I feel we have to be concerned with the “optics” and public perception of science and the federal agencies in 2013. As an example of the popular vibe on this, an interested layperson shared this negative blog post, Fecal Transplant Cures Antibiotic Resistant Infections – Will FDA Stop It?, on a well-trafficked website edited by the CEO of Tropical Traditions, a manufacturer of coconut oil products.  Physician and patient outcry has been prompt and vocal across many medical and nonmedical websites, with commenters on Fecal Transplants: FDA Wants Regulation already scrutinizing panelists’ financial interests in the decision, questioning lack of public comment solicitation before the decision, and some describing their own ordeals as patients and how the public could use DIY treatments to avoid similar experiences and drug expenses. This is not a “slippery slope” argument. This is the view on the ground, now.

Respectfully, this is exactly the kind of backlash that can and should be avoided. Regulatory authorities may be right on scientific or regulatory reasoning, but socio-politically, the optics on this decision are myopic. Frankly, the common use of FDA guidelines for organ/tissue transplantation to screen donors is probably inadequate or even inappropriate for something that is not a transplanted tissue.  In spite of our concerns about theoretical risks, the risks of well-screened fecal donation is currently less backed by published, peer-reviewed literature than is its benefit for people who have serious C. difficile infection whose only conventional recourse is complicated, costly, and often unsuccessful treatments. Labeling human stool a “new drug” conjures up recent federal decisions labeling corporations “people”, patenting genes, etc, in a time of increasing paranoia about government overreach. I worry that this decision could be the tipping point that gives the winning popular hand to stool-sharing for DIY use, or even hot-button issues like raw milk consumption or medical marijuana use, which carry broader public health risks in well-meaning but uninformed use.

The FDA could approach this in a manner less likely to seem punitive. Human milk banking, online milk selling, and private “milk sharing” groups raised very similar issues (a good volume of science backs up those safety concerns). However, FDA wisely solicited the input and collaboration with CDC, the Human Milk Bank Association of N. America, lactation professionals, and the American Academy of Pediatrics on the matter, and continues to issue public advisories and contribute to HMBNA’s annually updated donor and banking guidelines. They did not try to call human breast milk a “drug” requiring an NDI application. As a result, babies in need get well-screened, pasteurized milk with a minimum of medicolegal barriers, and the FDA continues to educate and steer the public to seek reputable and safe suppliers.

“Better to have them inside the tent pissing out than outside the tent pissing in.”

-President Lyndon B. Johnson

2 thoughts on “FDA IND Requirement for Fecal “Transplant”: Hitting the Fan

  1. I find it intriguing the FDA does not regulate oral bacterial nutraceuticals, most of which include bacteria commonly found in our colonic microflora. The disclaimer commonly used with these products states “This product is not intended to diagnose, treat, cure, or prevent any disease”, if this is true, what is its purpose?

    Dr. Sharon Hillier presented some intriguing data in the past – when looking to see if any of the Lactobacillus products sold OTC contained peroxide-producing strains (as most of the Lactobacillus species do in the female vaginal ecosystem), she found the product from a very large nutraceutical company did not contain peroxide-producing lactobacillus, but did include Enterococcus, which on antibiotic susceptibility testing revealed it to be vancomycin resistant. An FDA unregulated product with VRE, and FDA concerns regarding stool contents possibly associated with disease. Somewhat oxymoronic in my opinion.

    • Indeed, right? FDA regulates and licenses any such product, but ONLY if it expressly claims to diagnose, treat, cure or prevent a disease. That’s why most nutraceuticals carry that disclaimer. But FDA lacks the capacity to regulate the very many products that push the claims limit on every other part of their packaging and advertizing every day. Shoot, regulators can’t even keep up with the compounding pharmacies making their own versions of actual drugs as it is. To wit: the nationwide fungal meningitis outbreak caused by the shoddily-run New England Compounding Center last year, from which many are still suffering…Thanks for your comments!

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