This article argues that current data for the safety and efficacy of fecal microbiota transplants as a treatment for any indication, including recurrent Clostridioides difficile infection, is low-quality. It develops a governance proposal that encourages production of high-quality evidence by incentivizing well-designed RCTs of stool and stoolderived microbial products. The proposal would require that FDA change its current enforcement approach, but it would not require any change in statutes or regulations.
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116.
Rebiotix, Comment on the Food and Drug Administration (FDA) Notice: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies: Draft Guidance for Industry (June20, 2016), Regulations.gov Website, available at <https://www.regulations.gov/document?D=FDA-2013-D-0811-0116> (last visited September 18, 2019).
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M.F.Riley and B.Olle, “FDA's Pathway for Regulation of FMT: Not So Fraught,”Journal of Law and the Biosciences2, no. 3 (2015): 742–746; Ossorio and Zhou, supra note 67. The controversy is described in Lietzan, supra note 10, at 1254–1257.
118.
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U.S. Food and Drug Administration, Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies (February2014), available at <https://www.govinfo.gov/content/pkg/FR-2014-02-26/pdf/FR-2014-02-26.pdf> (last visited September 18, 2019); U.S. Food and Drug Administration, supra note 83.
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U.S. Food and Drug Administration, supra note 83.
121.
In January of 2018, the supervisory pharmacist who oversaw the distribution of contaminated drugs from the compounding pharmacy was convicted of racketeering, conspiracy, mail fraud, and introduction of misbranded drugs into interstate commerce, and sentenced to eight years in prison, two years of supervised release, and forfeiture and restitution to be determined. U.S. Food and Drug Administration, January 31, 2018: New England Compounding Center Pharmacist Sentenced for Role in Nationwide Fungal Meningitis Outbreak (January31, 2018), available at <https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/criminal-investigations/january-31-2018-new-england-compounding-center-pharmacist-sentenced-role-nationwide-fungal> (last visited September 18, 2019).
21 C.F.R. § 314.420(a). A drug master file consists of important regulatory information submitted to the FDA. The holder of the master file can authorize other persons to rely on the master file in support of the other person's IND submission. The holder of the drug master file can keep information in confidence, even withholding the information from persons the holder has authorized to reference the file.
SeeA.Khoruts, Comment on the Food and Drug Administration (FDA) Notice: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies: Draft Guidance for Industry (April25, 2016), Regulations.gov Website, available at <https://www.regulations.gov/document?D=FDA-2013-D-0811-0065> (last visited September 17, 2019). Note that OpenBiome's website claimed the organization had shipped over 43,000 doses of stool as of January, 2019. However, because some people might have received more than one dose and some might not have received the intervention after their provider ordered the stool, one cannot determine how many people have received FMT using stool from OpenBiome. OpenBiome, Our Impact (January, 2019), available at <https://www.openbiome.org/impact> (last visited September 17, 2019).
128.
C.R.Kelly, M.Fischer, A.Grinspan, J.R.Allegretti, “Patients Eligible for Trials of Microbe-Based Therapeutics Do Not Represent the Population with Recurrent Clostridioides difficile Infection,”Clinical Gastroenterology and Hepatology (2019) [epub ahead of print], available at <https://doi.org/10.1016/j.cgh.2019.06.034> (last visited September 17, 2019) (Finding that 17% of rCDI patients who were eligible for a clinical trial testing an oral stool-derived product refused to participate; one reason patients gave was because they might be randomized to a placebo group.).
129.
Hoffmann, et al., supra note 117. One firm with a stool-derived product currently in clinical trials recently stated: “Prospective enrollees have repeatedly told principal investigators that they will forgo involvement in the clinical trial and instead obtain an unapproved product [for FMT] sold by a stool bank over the internet.” Rebiotix, supra note 116, at 2.
130.
McDonald, et al., supra note 53 and accompanying text.
131.
21 C.F.R. § 312.315.
132.
Id.
133.
An investigator is “an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team.” 21 C.F.R. § 312.3.
134.
21 C.F.R. § 312.305(a)(3).
135.
A sponsor-investigator is “an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed.” 21 C.F.R. § 312.3.
136.
Khoruts, supra note 127; C.R.Kelly, S.S.Kunde, and A.Kho-ruts, “Guidance on Preparing an Investigational New Drug Application for Fecal Microbiota Transplantation Studies,”Clinical Gastroenterology and Hepatology12, no. 2 (2014): 283–288. Note that a research-IND is used when there is no commercial sponsor for an FDA-regulated study.
137.
Id.; M.E.B.Holbien, “Understanding FDA Regulatory Requirements for Investigational New Drug Applications for Sponsor-Investigators,”Journal of Investigative Medicine57, no. 6 (2009): 688–694.
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143.
21 C.F.R. § 312.3.
144.
21 C.F.R. § 312.315(c)(3).
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21 C.F.R. § 312.305(c)(5).
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Cross ref. to Khoruts, et al., supra note 8.
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