It’s been a little more than a year since the first-ever clinical trial of fecal transplants — the practice of infusing diluted donor stool into the colon of someone suffering from Clostridium difficile infection — demonstrated that the low-tech process not only works to overcome the disease’s painful, life-disrupting diarrhea, but works better than the standard treatment of antibiotics.
That finding confirmed what gastroenterologists had known for a while — not to mention what patients who had sought out the procedure, in the United States or in other countries, could confirm from their own experience of being rapidly and, for the most part, permanently cured.
Despite that result, and despite significant pent-up demand from patients and physicians both, fecal transplants’ status in US medicine has barely budged in the ensuing year. The procedure is caught in a bind at the Food and Drug Administration, which has struggled to define under which of its regulatory authorities the transplants fall. Last May, the agency proposed forcing physicians who wanted to perform the procedure — many of whom were already doing so — to obtain a cumbersome Investigational New Drug application beforehand. After an outcry, the agency backed off, but many practitioners had been spooked, and many patients (judging by my email at least) returned to seeking out the procedure in a semi-underground manner.
In Nature last week, a team of researchers (including gastroenterologist Colleen Kelly, MD, who heads a US clinical trial that is still underway) argued for a way out of the paralysis. They propose that the FDA evaluate stool infusions not under the rules for drugs, with all the clinical trial requirements that implies, but rather under the rules for tissues such as blood, cartilage, skin and bone.
…the long-term status of (fecal microbiota transplantation) for C. difficile infection is unresolved, and regulatory policy is complicating research into the exploration of FMT for other conditions, such as inflammatory bowel diseases or obesity.
Whether and when the therapeutic potential of FMT is realized will depend on how the FDA and other agencies regulate the use of stool. Although treating it as a drug creates strict requirements to protect patients, it limits access to care. Reclassifying stool as a tissue product or giving it its own classification, as the FDA does for blood, would keep patients safe, ensure broad access and facilitate research.
While carefully enumerating the potential risks of fecal transplants (which, as their acronym implies, transfer samples of a healthy bacterial community from one person’s GI system into another’s), they argue that the greater risk comes from the procedure being performed without any oversight. Websites explaining how to do fecal transplants at home are becoming common, they point out, but patients who pursue this outside of medicine cannot be protected from diseases transferred with the gut contents, or from injuries if the transplant is done badly.
The FDA defines drugs, in part, as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease”. However, stool is unlike conventional drugs, which are produced under controlled conditions with consistent, known ingredients. Stool is a variable, complex mixture of microbes, metabolites and human cells. It cannot be characterized to the rigorous standards applied to conventional drugs. The material is also widely available — it comes from healthy volunteers, rather than chemical factories or controlled cell cultures.
The FDA regulates blood, cartilage, bone, skin and egg cells as human tissues or under similar customized statutes. Transplanting these products into people requires meticulous record-keeping and screening for communicable diseases. These are exactly the safety precautions that should be taken with FMT. Under current US law, products that are excreted from the body or that depend on living cells from non-relatives are excluded from this category, disqualifying faeces. Exceptions have been made for semen, which is a tissue product, and blood, which has its own bespoke rules. In our view, statutes should be changed so that faeces too can be regulated as a tissue, not a drug. Risks can be reduced by rigorous screening, and the potential for clinical benefit is substantial.
Their argument has gotten support in the form of an online editorial at Scientific American. (Disclosures: I write for SciAm; the author of the editorial is one of my editors; and SciAm and Nature are owned by the same publishing company, but independent.) The editorial says:
Imagine if in the 1960s surgeons like Christiaan Barnard or Norman Shumway had had to use the same rules that govern the development and testing of pharmaceutical medications when they were teaching the rest of the world how to transplant hearts from the recently deceased into their patients. The idea is absurd on the face of it. For starters, hearts do not come in standard sizes. Nor do all transplanted organs have the same “shelf life” the way different lots of properly manufactured drugs do…
…FDA rules would make it harder to test fecal transplants for no good reason. Regulating fecal transplants like other tissue products would still keep patients safe… [and] keep the cost of treatment lower than would otherwise be possible if some large company with deep pockets had to undertake the sorts of tests that would need to be done to approve fecal transplants as if they were drugs.
I have written about fecal transplants several times at this blog and also for SciAm. Judging by the huge amount of mail I received each time, the demand for this procedure is enormous — and patients who believe it can help them are not waiting for the regulatory process to grind conscientiously but slowly through the evidence. If we want to honor the intent behind the FDA’s authority, which is to protect the vulnerable, then the process of examining fecal transplants must somehow be accelerated. Perhaps the Nature authors’ proposal will show the way.
Cite: Smith MD, Kelly C and Alm EJ. Policy: How to regulate faecal transplants. Nature 506, 290–291 (20 February 2014) doi:10.1038/506290a
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