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Molecules to Medicine

Molecules to Medicine

Demystifying drug development, clinical research, medicine, and the role ethics plays

The s**t hits the fan - FDA, INDs, and fecal microbiota transplants

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Bristol Stool Chart

This weekend, the proverbial s**t hit the fan over the Food & Drug Administration's (FDA) decision to require an Investigational New Drug (IND) application for stool transplants—formally known as “fecal microbiota transplants (FMT)”—for the treatment of C. difficile colitis. “C. diff,” as it is known, is a severe inflammation of the bowel complicating treatment of other infections with antibiotics or treatment with chemotherapy.

There have been excellent discussions of this issue by Maryn McKenna, Mike Edmond and a twitter exchange this weekend with Eli Perencivich (@eliowa), Carl Zimmer (@carlzimmer), Amesh Adjala (@AmeshAA, myself and others, captured in Maryn's Storify. But once again, as an experienced infectious disease clinician, I’d like to weigh in on the impact of the FDA’s decision, as I can offer a different perspective.

Over the last 10 years of my practice, I saw a change in the patients I treated for C. diff. More patients were affected, they were generally more severely ill, and the infection became increasingly difficult to treat. It went from responding to a brief course of Flagyl (metronidazole), to more prolonged and very expensive courses of oral Vancomycin, to the infection now often being refractory to therapy.

Treatment with stool transplants, while not commonplace, was more often entertained for patients with chronic and recurrent infections. In the past several years, I began to see more patients who relapsed despite prolonged oral Vancomycin, and who became very debilitated and unable to recover from their other infections and illnesses, due to the severe and persistent diarrhea. I also began to see patients floridly septic from C. diff, occasionally needing emergency surgery to remove their colon (colectomy).

It is these severely ill patients who changed my thinking about this illness and caused me to wonder whether we shouldn’t be treating severe cases of acute C. diff with stool transplants. I reasoned that it was a better alternative to an emergency colectomy.

Others appear to have had the same idea, and there are now occasional case reports about using FMTs as first-line treatment. There are barriers to doing so, however:

First, there is the “ick” factor. Thus far, resistance to transplants I have recommended has not come from patients or their families, who are desperate for relief. It has come from other health care workers, especially physicians, who seem to find the idea particularly distasteful.

There is cost and time—while the “medicine” is inexpensive and readily available, current recommendations are that the stool donor be tested for a variety of infectious diseases at a cost of $1500-2000. There might be a week’s delay, while the donor is tested for hepatitis and other infections, particularly if the need arises at a community hospital that relies on sending out specimens for lab testing.

And now there is the new FDA requirement for an IND, which will be the coup de grace for this treatment.

The FDA has now decided that stool transplants, colloquially known now as “FMT” to not offend sensibilities, meet the definition of a biologic therapy and therefore fall under their regulatory purview. Because it is not an approved therapy, they will now require an IND be submitted for each proposed use.

Except perhaps for academic settings with an extensive infrastructure, INDs are incredibly burdensome, time-consuming, and expensive for an independent practitioner to obtain. They involve hours of paperwork (my office practice consisted of me and 1-1.5 secretaries; who has time?).

Unresolved questions

Yes, there are many questions involving FMT that do warrant further study. For example, what is the best diluent for the stool? Saline or water or milk or other? What is the most efficacious route of administration—colonoscopy vs enema vs nasoduodenal tube?

Ironies

There is better efficacy data for this FMT treatment than for many things that we do to our patients. In fact, according to a freshly released article in Clinical Infectious Diseases, “Ninety-two percent of patients experienced resolution, 89% after a single treatment, and 5% after retreatment due to failure or relapse.” Some studies have reported even better results, up to 94%.

As Boston Infectious Disease expert Dr. Paul Sax notes: “A person struggling with C diff can walk into any pharmacy, Whole Foods, Trader Joe’s, GNC, etc, and spend a small fortune on various probiotics, the efficacy of which is marginal at best.”

Similarly, stem cell “treatments,” which are far more dangerous and expensive, are unregulated, and deserve considerably more attention from the FDA. The same holds true over probiotics and many “nutritional supplements” with widespread advertising to patients.

I have done clinical research in a variety of settings and am all too familiar with both with the labor involved in completing an IND and the FDA’s admirable goal of improving patient safety. I admire their intent, but believe their efforts are seriously misplaced here. Frankly, having been immersed in reading about clinical research ethics scandals, particularly at the University of Minnesota’s Department of Psychiatry, my gut reaction to the news of the IND requirement was, “Doesn’t the FDA have anything better to do?” Wouldn't their efforts be more likely to result in improved patient outcomes if they looked first at areas where there is evidence to suggest that known problems exist?

I think it is reasonable for the FDA to provide guidance and to try to collect data in some standardized format so that we can learn more about best approaches. My understanding is that individual physicians will have to develop and submit their own plan for treatment—which is both burdensome and will not result in any generalizable conclusions. While the FDA says that in emergencies, physicians can seek urgent approval, rather than wait for a 30 day turnaround time on their IND submission, in practical terms, this isn’t going to happen.

At a minimum, I would suggest the FDA exclude non-academic/non-research centers from the IND requirement, or centers that want to perform less than X number of procedures per month. They should also exclude attempts at emergency use of FMT from burdensome IND submissions. Perhaps they could develop, with clinicians, a simple data checklist or CRF, which needn’t be more than 1 page, and would gather standardized data for analysis of otherwise anecdotal treatments.

Otherwise, physicians will increasingly give patients directions for home do-it-yourself (DIY) treatments, which families can administer to patients in the privacy of their homes. But then the sole data will come from some ambitious citizen science group, and acutely or seriously ill hospitalized patients, too ill to be treated at home, will be deprived of potentially life-saving treatment.

Then, the FDA’s stated goal of patient safety will sadly backfire, and result in unnecessary patient deaths.

Credits:

Bristol Stool Chart mug courtesy Butt Fudge Sundae

"Molecules to Medicine" banner © Michele Banks

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The views expressed are those of the author and are not necessarily those of Scientific American.

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