Austrian Federal Office for Safety in Health Care, European Medicines Agency, France's ANSM (Agence Nationale de Securite du Medicament), Hepatitis, HIV, Mark B. Smith, Open Biome, Salmonella, Syphilis, UK's NICE (National Institute of Care and Excellence)
Answer by Tirumalai Kamala:
I will cover the definition of FMT (Fecal Microbiota Transplant), why FMT is a challenge for regulatory agencies, the type and purpose of screening required for donors and recipients.
What is FMT (Fecal Microbiota Transplant)?
Commensal bacteria in the stool samples from healthy individuals are transplanted through colonoscopy, nasoduodenal tubes or enemas into the GI tract of patients with GI tract infections (1). Currently, FMT is most commonly done for drug-resistant Clostridium difficile infection (C.diff, CDI) patients, and not for other types of GI tract infections or issues. FMT introduces into their GI tract commensal microbes that outcompete the pathogenic C.diff for limited nutrients.
The first randomized control trial for FMT (2), published in 2013, was so successful that they ended it ahead of time. What were the dramatically beneficial results that induced such an unusual step? 13 of 16 patients (81.3%) resolved C.diff with just one infusion of FMT compared to 4 of 13 (30.7%) treated with vancomycin, and 3 of 13 (23%) treated with vancomycin plus bowel lavage. Such an enhanced benefit has spurred great interest in making this treatment more widely available. Drawbacks of this 2013 study included small test size, which is inherently not representative, data collection was not blinded, and cross-over among subjects during study.
A 2nd pilot controlled trial study (3) also reported very encouraging results, including resolution of diarrhea in 14 of 20 patients (70%) after one infusion.
These results need to be reproduced using additional randomized control trials, with larger test sizes, in additional countries and for conditions other than recurrent GI C.diff infections. Further, though the treatment itself is simple, the material, human stool, offers unique challenges for regulatory agencies.
Regulatory hurdles in making FMT use widespread
Proper classification of human stool is a major regulatory dilemma, very complicated to say the least. Is it a tissue, akin to human tissue or is it a drug, akin to conventional drugs?
Current regulatory agency definitions of human stool for the purpose of FMT
The latest (March 2014) FDA enforcement Policy states that it intends “to exercise enforcement discretion regarding the IND (Investigational New Drug) requirements for the use of FMT to treat C.diff infection not responding to standard therapies” (4). In other words, FMT can currently be done in USA without requiring any mandatory screening only for recurrent C. diff infections. All other uses of FMT require submission of INDs. Approval of INDs is very complicated and lengthy, making it a huge regulatory burden that discourages physicians from exploring it, and deters expanding its use. The term IND also implies the FDA considers human stool a drug. This is similar to the position of the French regulatory agency, ANSM (5).
Austria, on the other hand, has gone the other way and considers FMT a therapeutic intervention and not a pharmaceutical drug. “The Austrian Federal Office for Safety in Health Care, which executes federal policy in areas of infectious disease control and pharmaceuticals, sees FMT as a therapeutic intervention which should not be considered a pharmaceutical drug and therefore not be regulated by the Austrian Medicines Act. FMT is also not subject to the Medical Devices Act or to the Austrian Transplantation Act” (6).
The European Medicines Agency has not yet openly stated its position with respect to FMT (7).
UK’s National Institute of Care and Excellence (NICE) complicates the regulatory stance further by stating that it does not consider FMT to be a transplant in the regular sense of the word, “The Committee recognised that the enteric infusion of donor faeces is not a transplant in the usual sense of transplanting body tissues, but it accepted that faecal microbiota transplant has become an accepted term to describe this procedure” (8).
Problems with classifying human stool as a drug
Human stool contains gut microbiota (bacteria, viruses, fungi), mucus, metabolites and human cells. Even from the same person, it is different in composition each time, i.e. it is inherently variable and irreproducible. This makes it manifestly different from what we typically consider a drug where we use stringent quality control measures to minimize batch-to-batch or lot-to-lot variations.
Further, in contrast to a conventional drug, donor stool provides therapeutic benefit not just by alleviating the C. diff infection but also by not transmitting any infection itself.
Classifying human stool as a drug also places it under the purview of hospital pharmacies, requiring that they store it (9). I don’t see how this could ever happen in practice. All the stakeholders from pharmacists and doctors to patients would be up in arms.
Is human stool is a tissue instead?
Mark B.Smith, a co-founder of OpenBiome argues human stool is a tissue (10). However, as Megerlin et al convincingly rebut (7) human stool is not a human tissue either. After all, we can call human stool a tissue only metaphorically. This definition does not withstand close scrutiny when we ask if is a human tissue. Rather, Megerlin et al consider the stool donor as a bioreactor producing “the faecal substrate of therapeutic interest”, and from this standpoint, they call human stool a sui generis (singlular/stand-alone product) drug.
From a regulatory standpoint, human stool shares many properties with human blood and milk, with the additional caveat that unlike the ways in which we use the latter, with FMT, the explicit goal is to transfer live micro-organisms. This makes it a unique product requiring novel regulatory guidelines. Thus, devising proper regulatory classification of human stool is not just a stomachache but rather the mother of all stomachaches!
Current human donor and stool screening process
In USA, current FDA stipulations (4) dictate the following: “(1) the licensed health care provider treating the patient obtains adequate informed consent from the patient or his or her legally authorized representative for the use of FMT products; (2) the FMT product is obtained from a donor known to either the patient or to the licensed health care provider treating the patient; and (3) 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”.
is a public stool bank that offers frozen, pre-screened and filtered human stool preparations. In a Jan 2015 interview ( ) their founders say, “We have a multiple stage screening program. The first stage is sitting down with a nurse to go through your medical history. Any conditions linked to the biome—gastrointestinal, neuropsychiatric, anyone who’s taken antibiotics recently, recent travel to any countries with high risk to waterborne infections—and you’re out. It’s a 107-point questionnaire. If you pass, the next step is a blood sample and stool sample. We run it through 27 tests, looking for pathogens like HIV, hepatitis, , white and red blood cell counts, E. coli, salmonella, and any parasites”, and that “Less than 20% of people end up becoming donors”.
At a minimum, screening should rule out HIV, hepatitis (A, B, C), syphilis, enteric pathogens (e.g. Salmonella). Both serum and stool of the potential donor thus need to be screened. For example, in Austria, they screen serum for Hepatitis B and C, HIV, Treponema pallidum, CMV, and they screen stool for C. diff, Salmonella, Campylobacter, EHEC, Shigella, Yersinia, Giardia lamblia, Cryptosporidium, norovirus and rotavirus (6).
Detailed medical histories should include information about high risk sexual behaviors, known exposure to infectious diseases and inflammatory bowel disease, history of autoimmunity, and travel to regions endemic for diarrheal diseases. Human stool thus requires intensive screening. This adds considerable laboratory costs (11).
The Atlantic magazine reviewed current practices and the FDA guidelines here:
Other useful web-sites:
- Vyas, Dinesh, Apoorva Aekka, and Arpita Vyas. “Fecal transplant policy and legislation.” World journal of gastroenterology: WJG 21.1 (2015): 6. .
- van Nood, Els, et al. “Duodenal infusion of donor feces for recurrent Clostridium difficile.” New England Journal of Medicine 368.5 (2013): 407-415. .
- Youngster, Ilan, et al. “Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study.” Clinical Infectious Diseases 58.11 (2014): 1515-1522.
- Kump, Patrizia K., et al. “Faecal microbiota transplantation—the Austrian approach.” Clinical Microbiology and Infection 20.11 (2014): 1106-1111.
- Megerlin, F., et al. “Faecal microbiota transplantation: a sui generis biological drug, not a tissue.” Annales pharmaceutiques françaises. Vol. 72. No. 4. Elsevier Masson, 2014.
- Moore, Thomas, Andres Rodriguez, and Johan S. Bakken. “Fecal microbiota transplantation: a practical update for the infectious disease specialist.” Clinical infectious diseases 58.4 (2014): 541-545.
- Smith, Mark B., Colleen Kelly, and Eric J. Alm. “Policy: How to regulate faecal transplants.” Nature 506.7488 (2014): 290-291.
- Allen-Vercoe, Emma, et al. “A Canadian Working Group report on fecal microbial therapy: microbial ecosystems therapeutics.” Canadian Journal of Gastroenterology 26.7 (2012): 457.