I did my first fecal microbiota transplantation (FMT) about five years ago. At the time, I was a clinical gastroenterologist caring for a young woman who had contracted C. difficile (C. diff), a bacteria that causes severe diarrhea, after taking antibiotics for a sinus infection. The antibiotics killed off her normal colonic bacteria, allowing the resistant C. diff to take over. She had suffered from pain and diarrhea for more than six months, failing all available treatments, mainly different types of antibiotics used to try to kill off the C. diff. Although I had heard of "stool transplants," I had never considered actually doing one. This brave patient, frustrated with our lack of progress, came with a stack of published papers and the names of a few doctors scattered around the U.S. and the rest of the world who had experience with stool transplants, begging me to do it and offering to be my "guinea pig." I read through the reports and contacted Lawrence J. Brandt, M.D., at Montefiore Medical Center in the Bronx, who reassured me about FMT's safety and who talked me through the procedure, which seemed logical and safe. FMT involves transferring fecal material, containing bacteria and other microorganisms, from a healthy donor to a recipient with relapsing C. diff to restore the missing components of their intestinal bacterial flora.
The patient chose her boyfriend as a donor and he passed all the screening criteria. The results were impressive. She felt better almost immediately, her diarrhea stopped and she was able to resume her normal life without the need for further treatments. I've now treated more than 100 patients, all of whom suffered from disabling and resistant C. diff. Patients come to me who have become hopeless, debilitated and depressed because of the severe diarrhea that recurs within days of finishing each course of the expensive antibiotics that are supposed to treat C. diff. They've described feeling isolated and hopeless. A few have lost their jobs after exceeding their allowed sick time. Many have lost weight and stopped going out of the house without a diaper. After the fecal transplant makes them well again, and it almost always does so, many send letters and cards stating "there is no way I can thank you enough."
C. diff infections are increasing in incidence and severity, causing thousands of deaths and resulting in an economic burden exceeding $3 billion annually in the U.S. On the front lines of the C. diff epidemic, I understand how powerful and effective FMT is. Brandt and I are currently conducting an NIH-funded, randomized, placebo-controlled clinical trial of FMT for recurrent C. diff infections that was inspired by an elderly woman who traveled to Rhode Island from South Carolina (with her donor) for the treatment, at great personal expense. After seeing how well FMT works, it seemed ridiculous that this therapy wasn't more widely available. Understanding that the lack of efficacy data from randomized controlled trials was preventing some doctors from offering FMT, and inhibiting some hospitals and institutions from allowing it to be done, moved me from simply treating these patients to conducting clinical research.
Very early in the process of planning our study, I was informed by the NIH and by my institutional review board (which oversees and reviews medical research) that an investigational new drug (IND) application from the U.S. Food and Drug Administration (FDA) was necessary in order to conduct a clinical trial of FMT. Very simply, fecal transplant was being used as a therapeutic agent in human subjects; therefore it was necessary to submit the treatment protocol and research plan to the FDA. After an initial, naïve phone call to the agency, I was informed that administered stool would constitute a "biological product" as defined in Section 351(i) of the Public Health Service Act [42 U.S.C. 262(i)], in that stool is a "regulated article" applicable to the prevention, treatment or cure of a disease or condition of human beings. FMT would also constitute a "drug" within the meaning of Section 201(g) of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 321(g)], in that it is "intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or is intended to affect the structure or function of the body." I was told that the Center for Biologics Evaluation and Research (CBER), in the Division of Vaccines, Blood and Biologics at the FDA, would now be handling the regulation of FMT by the government.
The task of obtaining an IND for our study was overwhelming. There is no "IND for Dummies" and the FDA-published guidance documents are directed at regulatory experts and pharmaceutical companies. Though the people at the agency were helpful, my inquiries were typically met with general instructions, directing me to a certain form or explaining the time frame for the applications and how an IND would either be put "on hold" or "become active" within 30 days of submission. After two years, at least 1,000 hours of effort and a 22-pound application package, I became the proud sponsor of an active IND for our clinical trial last June.
We had argued that FMT was similar to an organ or tissue transplant. Studies have demonstrated that patients suffering from recurrent C. diff are deficient in populations of bacteria normally dominant in the colon, and which are known to play a valuable ecologic role (yes, your colon is an ecosystem) in the establishment and maintenance of gut homeostasis. FMT takes whole stool from one person and infuses it into the gastrointestinal tract of another person, with the goal of transplanting and restoring an entire community of beneficial gastrointestinal flora. Categorizing fecal material as a transplant would require establishments to screen and test donors; to prepare and follow written procedures to prevent the the spread of communicable disease; and to maintain records of its use.
At a public workshop in early May, the agency announced that it viewed FMT not as a transplant or a tissue, but as a "drug." As such, it was an "unapproved drug," and an IND was therefore required of any doctor treating a patient using FMT. From the FDA's perspective, it does not matter if a doctor is treating one patient or 3,000 patients, or whether FMT is being done for routine clinical care or as part of a study. The FDA views ANY use of FMT as "research." This announcement sent shock waves through the medical community, where doctors had recently become more comfortable offering FMT after the first randomized trial published in January's The New England Journal of Medicine demonstrated superior efficacy of FMT over oral vancomycin (the standard of care in recurrent C. diff). That study was actually stopped early because it was deemed unethical to continue to treat patients with an inferior treatment (i.e. the vancomycin), as the response to FMT was so far superior. Following the FDA announcement, many doctors who had been performing FMT put their programs on hold, frustrating and disappointing patients, some of whom have even resorted to performing home enemas of donor stool when they were unable to find a physician who was willing or able to perform FMT.
To be fair, the FDA is rightfully concerned that there are potential long-term safety consequences of FMT that are yet unknown. Many diseases, such as obesity, inflammatory bowel disease (IBD) and colon cancer have been shown to be associated with alterations in the bacterial populations in the gut. Certainly, attempts to manipulate the gut microbiota via FMT may prove to have unintended adverse consequences. Besides the obvious risk of transmitting an infection, the replacement of this highly complex community of microorganisms may have incompletely understood effects, which would put patients at risk for these and other conditions in the future. The successful use of FMT for C. diff has also raised the question of whether other diseases (such as IBD and irritable bowel syndrome (IBS)) may also be successfully treated with FMT. I receive emails daily from patients requesting I perform FMT for these conditions and for unrelated medical conditions lacking good treatments (from alopecia to autism). Clinics offering FMT for any indication to desperate patients, for fees of up to $10,000, are out there. Certainly if FMT goes entirely unregulated, bad things can happen. Remember the recent Massachusetts compounding pharmacy fiasco? Publication of guidelines for donor screening would go a long way toward helping doctors develop safe treatment protocols. Requiring serious adverse events (deaths, infections) related to FMT be reported is another function of the IND requirement and is a good thing. Clinical trials overseen by the FDA are necessary to determine the efficacy of FMT in alternative indications. I am optimistic that the FDA will make the path to an IND less arduous.
Proof that this may not be just wishful thinking came on June 17, when the FDA published an announcement that it would exercise "enforcement discretion" regarding the IND requirement for FMT used to treat C. diff infection, provided that treating physicians obtain adequate informed consent, which should include a statement that FMT is investigational, as well as a discussion of FMT's potential risks. The agency is encouraging compliance with the IND requirement and plans on developing policies for the study and use of FMT products under INDs. So to put it simply, the FDA would prefer we all perform FMT under an IND, but there won't (maybe) be any negative consequences if we don't. I believe this statement was a smart move on the part of an agency that never intended to interfere with patient care.
I am hopeful that our study provides further evidence for the efficacy and safety of FMT in C. diff infection. I want patients to have access to this therapy and I want doctors performing FMT to do it safely and for the right indication. To be certain, a strong and vocal community has developed around FMT. The Fecal Transplant Foundation was recently formed by a former C. diff patient who has now become an advocate (full disclosure: I sit on the foundation's board of advisors). FMT Science is a collaborative effort of physicians and researchers to promote the science regarding FMT. My own organization, the American Gastroenterological Association, is working relentlessly to advance FMT research and to streamline the process of getting FMT to patients in need. It is important to determine how FMT can be administered effectively and safely.
I believe the FDA will ultimately help this process, not hinder it. However, it is unlikely that most individual physicians, trying to help their occasional patients with recurrent C. diff, could devote the enormous amount of time required to obtain an IND in its current form. This puts the onus on physicians to perform FMT without an IND -- taking on the vague risk that if FMT causes some unforeseen problem, they may be subject to future FDA regulatory action. This worry may scare off the interested physician or his or her institution -- or cause the physician to refer their patients, if they are able and have the resources to travel, to the handful of doctors with an IND for FMT. The problem is that C. diff infection is debilitating and often fatal to patients with the condition, and FMT seems to be an important treatment for patients who have failed all the usual options. Unless the IND process is modified in some way to make it less burdensome, this highly-effective therapy may continue to be out of reach for most patients.