Fecal Transplants Bring Hope to Patients, Challenge the FDA
Fecal Transplants Bring Hope to Patients, Challenge the FDA
As FMT receives increasing attention from the development sector, concerns surrounding its safety have begun to escalate. In April 2013, the FDA stunned some in the clinical community by announcing that it had begun regulating human feces as an unapproved drug and that all FMT procedures and clinical trials would require Investigational New Drug (IND) approval. The agency's reasoning was that fecal microbiota were both a biologic product and a drug used in FMT to "prevent, treat, or cure a disease or condition" or "intended to affect the structure of any function of the body of man."
This regulatory move was met by a surge of concern from clinicians, researchers, and patient support groups. In response, on May 3, 2013, the FDA's Center for Biologics Evaluation and Research partnered with the National Institute for Allergy and Infectious Diseases to hold a public workshop on scientific and regulatory issues regarding fecal microbiota for transplantation. The workshop included presentations by some of the more experienced clinicians and researchers working with FMT. These experts said that the approximately 700 published cases of FMT showed notably few adverse effects and 90% efficacy in curing CDI diarrhea, with several of the presenters expressing their fears that the IND requirement would make FMT all but unavailable to many patients.
Ms Duff later told Medscape that "As someone who had C difficile eight times between 2005 and 2012, my only options by 2012 were a total colectomy or FMT. People with CDI who don't respond to repeated and prolonged antibiotic therapy experience isolation, depression, personal and financial ruin, as well as the continued damage to their gut microbiome that repeated antibiotic use can cause. Ensuring that FMT is readily available will save lives, and what could be more important than that?"
In the wake of the May 2013 workshop, the FDA kept the IND requirement in place but stopped enforcing it. An FDA spokesperson told Medscape that the agency still considers FMT an unapproved new drug and an unlicensed biological product requiring an IND approval, but as delineated in the agency's July 2013 guidance, has adopted an interim policy of exercising "enforcement discretion" regarding the use of FMT to treat C difficile infection not responsive to standard therapies.
The FDA intends to continue exercising discretion while they further consider the issue. Clinicians performing FMT for treatment of C difficile infection are not required to first obtain an IND approval, but should obtain "adequate informed consent from the patient or his or her legally authorized representative for the use of FMT products." Consent should include a statement that the use of FMT products to treat C difficile is investigational, along with offering a discussion of its potential risks. Physicians who have questions about the use of FMT or about submission of an IND are encouraged to contact the FDA at 1-800-835-4709 or 240-402-8010, or by email to OCOD@fda.hhs.gov.
According to an FDA spokesperson, the agency has the authority to regulate stool banks, does not distinguish between FMT obtained from stool banks and FMT obtained from individual donors, and expects to exercise "enforcement discretion" when several conditions are met. These include that the FMT product is obtained from a donor known to either the patient or the treating licensed healthcare provider. FDA is currently considering comments on the 2014 draft guidance, which was written to facilitate access to FMT for patients with treatment-resistant C difficile who have few or no other treatment options.
Another way around the regulatory dilemma might be for the FDA to regulate FMT as a tissue/transplant, similar to the rules governing transplants of hematopoietic stem cells derived from cord blood.
Dr Kelly noted that stool is a heterogeneous substance, composed primarily of bacteria and water, but also containing viral and fungal organisms, metabolic products of these organisms, undigested foods, bile, bilirubin, cholesterol, inorganic salts, dead cells, and mucus from the lining of the intestinal wall. "The colonic microbiome functions in a symbiotic relationship in the human body at a level of complexity akin to an organ or tissue. FMT takes whole stool from one person and infuses it into the gastrointestinal tract of another person with the goal of transplanting the entire community of physiologic gastrointestinal flora. The replacement of this highly complex whole community of microorganisms cannot be regulated as a 'drug,' per se. It is not possible to provide exact dosing/colonization data for this substance, which is highly variable among individual donors," she said.
There is widespread agreement among researchers that FMT can provide effective and safe treatment of recurrent CDI that has not responded to conventional antibiotic regimens. The current FDA guidance provides what amounts to a temporary amnesty for individual physicians who use FMT with patients who have given adequate informed consent.
New FMT formulations, such as frozen stool capsules and biosynthetic preparations, are expected to join conventional stool preparations in the FMT armamentarium within the next few years. Meanwhile, the American Gastroenterological Association Center for Gut Microbiome Research and Education provides up-to-date information and physician resources, as well as a directory of practitioners who perform FMT.
The FDA Takes On FMT
As FMT receives increasing attention from the development sector, concerns surrounding its safety have begun to escalate. In April 2013, the FDA stunned some in the clinical community by announcing that it had begun regulating human feces as an unapproved drug and that all FMT procedures and clinical trials would require Investigational New Drug (IND) approval. The agency's reasoning was that fecal microbiota were both a biologic product and a drug used in FMT to "prevent, treat, or cure a disease or condition" or "intended to affect the structure of any function of the body of man."
This regulatory move was met by a surge of concern from clinicians, researchers, and patient support groups. In response, on May 3, 2013, the FDA's Center for Biologics Evaluation and Research partnered with the National Institute for Allergy and Infectious Diseases to hold a public workshop on scientific and regulatory issues regarding fecal microbiota for transplantation. The workshop included presentations by some of the more experienced clinicians and researchers working with FMT. These experts said that the approximately 700 published cases of FMT showed notably few adverse effects and 90% efficacy in curing CDI diarrhea, with several of the presenters expressing their fears that the IND requirement would make FMT all but unavailable to many patients.
Ms Duff later told Medscape that "As someone who had C difficile eight times between 2005 and 2012, my only options by 2012 were a total colectomy or FMT. People with CDI who don't respond to repeated and prolonged antibiotic therapy experience isolation, depression, personal and financial ruin, as well as the continued damage to their gut microbiome that repeated antibiotic use can cause. Ensuring that FMT is readily available will save lives, and what could be more important than that?"
A New Stance
In the wake of the May 2013 workshop, the FDA kept the IND requirement in place but stopped enforcing it. An FDA spokesperson told Medscape that the agency still considers FMT an unapproved new drug and an unlicensed biological product requiring an IND approval, but as delineated in the agency's July 2013 guidance, has adopted an interim policy of exercising "enforcement discretion" regarding the use of FMT to treat C difficile infection not responsive to standard therapies.
The FDA intends to continue exercising discretion while they further consider the issue. Clinicians performing FMT for treatment of C difficile infection are not required to first obtain an IND approval, but should obtain "adequate informed consent from the patient or his or her legally authorized representative for the use of FMT products." Consent should include a statement that the use of FMT products to treat C difficile is investigational, along with offering a discussion of its potential risks. Physicians who have questions about the use of FMT or about submission of an IND are encouraged to contact the FDA at 1-800-835-4709 or 240-402-8010, or by email to OCOD@fda.hhs.gov.
According to an FDA spokesperson, the agency has the authority to regulate stool banks, does not distinguish between FMT obtained from stool banks and FMT obtained from individual donors, and expects to exercise "enforcement discretion" when several conditions are met. These include that the FMT product is obtained from a donor known to either the patient or the treating licensed healthcare provider. FDA is currently considering comments on the 2014 draft guidance, which was written to facilitate access to FMT for patients with treatment-resistant C difficile who have few or no other treatment options.
Another way around the regulatory dilemma might be for the FDA to regulate FMT as a tissue/transplant, similar to the rules governing transplants of hematopoietic stem cells derived from cord blood.
Dr Kelly noted that stool is a heterogeneous substance, composed primarily of bacteria and water, but also containing viral and fungal organisms, metabolic products of these organisms, undigested foods, bile, bilirubin, cholesterol, inorganic salts, dead cells, and mucus from the lining of the intestinal wall. "The colonic microbiome functions in a symbiotic relationship in the human body at a level of complexity akin to an organ or tissue. FMT takes whole stool from one person and infuses it into the gastrointestinal tract of another person with the goal of transplanting the entire community of physiologic gastrointestinal flora. The replacement of this highly complex whole community of microorganisms cannot be regulated as a 'drug,' per se. It is not possible to provide exact dosing/colonization data for this substance, which is highly variable among individual donors," she said.
The Future of FMT
There is widespread agreement among researchers that FMT can provide effective and safe treatment of recurrent CDI that has not responded to conventional antibiotic regimens. The current FDA guidance provides what amounts to a temporary amnesty for individual physicians who use FMT with patients who have given adequate informed consent.
New FMT formulations, such as frozen stool capsules and biosynthetic preparations, are expected to join conventional stool preparations in the FMT armamentarium within the next few years. Meanwhile, the American Gastroenterological Association Center for Gut Microbiome Research and Education provides up-to-date information and physician resources, as well as a directory of practitioners who perform FMT.
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