Tuesday, December 9, 2014

Life, Death, Feces, and the FDA’s Dilemma

Emily Eakin provided a fascinating description in The New Yorker of the developments occurring in one of the most interesting and rapidly developing areas of medical science. It was titled The Excrement Experiment: Treating Disease with Fecal Transplants

It has become clear that antibiotics can kill some or all of the bacteria that control functions occurring in our digestive system.  While usually beneficial, antibiotics can cause both long-term and short-term changes in our microbial makeup (our microbiome) leading to chronic illnesses and, occasionally, immediate threat of death.  Abnormal excursions in bacterial population can occur in cases that may not be associated with antibiotics and are suspected of causing other serious health problems.  Since so little is understood concerning our microbiome, the most direct way to introduce a “healthy” distribution of bacteria into the digestive tract is via insertion of what has come to be known as a fecal transplant from a healthy person.  This procedure has now received the more official descriptor fecal microbiota transplantation (FMT).

Although fast moving now, the idea of using human excrement to address intestinal issues was first addressed by a Chinese physician well over a thousand years ago.

“In the United States, the first description of FMT appeared sixteen centuries later, in 1958, when Ben Eiseman, a surgeon at the V.A. Hospital in Denver, published four case reports in the journal Surgery. Stool was then widely assumed to be mainly a source of disease; there was little empirical support for the notion that bowel bacteria were important for health. Several of Eiseman’s patients had become deathly ill after the requisite preoperative course of antibiotics, however, and he concluded that the drugs were destroying normal gut flora. He sent a resident to collect stool specimens from a nearby maternity ward, reasoning that pregnant women were likely to be young and healthy and to have avoided antibiotics. The stool, transferred to Eiseman’s patients, saved their lives.”

What was probably occurring with Eiseman’s patients was due to the nasty bug known as Clostridium difficile.  This is a naturally occurring microbe in our digestive systems that is held in control by the array of other bacteria.  However, when massive doses of antibiotics are applied, usually in hospital settings, C. difficile, can be the last microbe left standing since it is highly resistant to known antibiotics.  Left alone it causes severe diarrhea and can be fatal.

“Scattered case reports in the medical literature described C. difficile patients, some on their deathbeds, who received fecal transplants and recovered, often within hours. Then, in January, 2013, The New England Journal of Medicine published the results of the first randomized controlled trial involving FMT, comparing the therapy to treatment with vancomycin for patients with recurrent disease. The trial was ended early when doctors realized that it would be unethical to continue: fewer than a third of the patients given vancomycin recovered, compared with ninety-four per cent of those who underwent fecal transplants—the vast majority after a single treatment. A glowing editorial accompanying the article declared that the trial’s significance ‘goes far beyond the treatment of recurrent or severe C. difficile’ and predicted a spate of research into the benefits of fecal transplants for other diseases.”

For this application, a 94% success rate puts feces in the miracle drug category.  It is not surprising that other applications for FMT would become of interest.  Eakin points out that Eiseman’s results were not totally ignored.

“For years, virtually the only proponent of FMT was Thomas Borody, a gastroenterologist in Sydney, Australia, who, in 1988, after reading Eiseman’s paper, decided to try a fecal transplant on a patient who had contracted an intestinal ailment in Fiji. The patient recovered, and Borody estimates that he has since performed the procedure five thousand times, including, with stool supplied by his father, on his mother, who suffered from crippling constipation. In addition to C. difficile patients, Borody says that he has successfully treated people with autoimmune disorders, including Crohn’s and multiple sclerosis.”

It is not surprising that researchers have begun to postulate and investigate all sorts of disorders that might be associated with dysfunctions of the microbiome, from obesity to autism.

“The Cleveland Clinic named fecal transplantation one of the top ten medical innovations for 2014, and biotech companies are competing to put stool-based therapies through clinical trials and onto the market. In medicine, at any rate, human excrement has become a precious commodity.”

It is also not surprising that with such a readily available product there is a lot of self medicating going on.  Eakins goes into great detail providing the history of Tom Gravel who suffered from Crohn’s disease which causes inflammation of a bowel section accompanied by pain and severe diarrhea.  Gravel suffered through ineffective medical interventions for over three years before he decided to try self-administered fecal doses provided by a presumably healthy neighbor. Gravel was able to obtain relief in this way and intends to continue this procedure indefinitely.

On the one hand there are how-to books and YouTube videos demonstrating how individuals can try the procedure on their own; on the other hand you have the FDA which is legally bound to treat excrement as a drug.

“The agency defines a drug as any material that is intended for “use in the diagnosis, cure, mitigation, treatment, or prevention of disease.” An exception has been written into law for body parts, including skin, bone, and cartilage, which are classified as tissue. But the statute excludes most human secretions from this category.”

“Substances labeled drugs are subject to a rigorous approval process. Pharmaceutical companies typically spend many years and millions of dollars researching and testing a drug before submitting it to the agency for approval. Until the F.D.A. approved a fecal-transplant therapy, the procedure would be considered experimental. In order to offer it to patients, doctors would need to file an investigational new-drug application, or I.N.D., and obtain the agency’s permission.”

“I.N.D.s are intended to capture every aspect of a prospective therapy in exacting detail….one gastroenterologist said that it had taken her hundreds of hours to complete the paperwork. Many others lacked the resources and staff to devote to such a task.”

The FDA is torn between the need to follow a lengthy process designed to insure patient safety and verify effectiveness of drugs, and evidence that thousands of sufferers could be provided immediate relief by a simple and inexpensive procedure.

“’What do we do with the fifteen thousand patients who are really desperate for something that works?’ a doctor from the Mayo Clinic asked F.D.A. officials. ‘If your mother shows up with severe or recurrent C. difficile, are you going to not offer something that you know how to do safely, effectively, and say, ‘I can’t do it because the regulatory agencies in the United States have decided that this requires a special licensure’?”

The FDA appears to be trying to be accommodating.

“….the F.D.A. declared an exception for doctors treating recurrent C. difficile: they would be allowed to perform fecal transplants without an I.N.D. In revising its position, the agency said that it would be exercising ‘enforcement discretion’—a temporary measure. As an F.D.A. spokeswoman later explained in an e-mail, the directive did not reflect a change of policy; it was intended as an acknowledgment that ‘there are often few or no other treatment options for these patients’.”

There are good reasons for the FDA to follow the traditional path for drug approval.  However, as Eakin points out, that encourages sufferers to try the procedure on their own.  These people are, in fact, producing a wealth of clinical data that is going to be lost.  A less onerous process that allows doctors to participate in administering doses while monitoring the patients and reporting the results would rapidly accumulate more data than drug manufacturers could ever produce.

The seemingly irreconcilable problem is that excluding excrement from the requirement that it be treated as a drug would require congressional legislation.  Even if congress were so moved to act, it is unlikely that the pharmaceutical industry would ever give them permission to threaten a potentially large profit source.

Consequently, we are being forced to endure an expensive and lengthy process that only drug companies can afford to pursue.  Eventually they will claim to have turned shit into gold and sell it back to us at as high a price as the market will bear.

The community has already decided on what to call these wonder pills when they finally emerge: crapsules.

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