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The Impact of Regulatory Policies on the Future of Fecal Microbiota Transplantation

Published online by Cambridge University Press:  01 January 2021

Abstract

In this article, the authors explore the impact of a potential future regulatory decision by FDA whether or not to continue its enforcement discretion policy allowing physicians to perform, and stool banks to sell, stool product for fecal microbiota transplantation as a treatment for recurrent Clostridium Difficile infection without an Investigative New Drug (IND) application. The paper looks at the Agency's regulatory options in light of the current gut microbiota based products that are in the FDA pipeline for drug approval and the potential impact and repercussions of their approval on FDA action. In laying out FDA's options we consider the implications of market exclusivity and off-label use of newly approved drugs. Ultimately, we explore the potential impact of FDA's decision on patients, research, and innovation.

Type
Symposium 1 Articles
Copyright
Copyright © American Society of Law, Medicine and Ethics 2019

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References

Foxman, B., Goldberg, D., and Murdock, C. et al., “Conceptualizing Human Microbiota: From Multicelled Organ to Ecological Community,” Interdisciplinary Perspectives on Infectious Diseases 2008 (2008): art. no. 613979.CrossRefGoogle Scholar
Bäckhed, F., Ley, R.E., and Sonnenburg, J.L. et al., “Host-Bacterial Mutualism in the Human Intestine,” Science 307, no. 5717 (2005): 19151920; Kim, S., Covington, A., and Pamer, E.G., “The Intestinal Microbiota: Antibiotics, Colonization Resistance, and Enteric Pathogens,” Immunological Review 279, no. 1 (2017): 90–105; Torres-Fuentes, C., Schellekens, H., and Dinan, T.G. et al., “The Microbiota-Gut-Brain Axis in Obesity,” Lancet Gastroenterology & Hepatology 2 (2017): 747756; Sharon, G., Sampson, T.R., and Geschwind, D.H. et al., “The Central Nervous System and the Gut Microbiome,” Cell 167, no. 4 (2016): 915932.CrossRefGoogle Scholar
Coyte, K.Z., Schluter, J., and Foster, K.R., “The Ecology of the Microbiome: Networks, Competition, and Stability,” Science 350, no. 6261 (2015): 663666.CrossRefGoogle Scholar
Oren, A. and Rupnik, M., “Clostridium Difficile and Clostridioides Difficile: Two Validly Published and Correct Names,” Anaerobe 52 (2018): 125126.CrossRefGoogle Scholar
U.S. Food & Drug Administration, Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies, Guidance for Industry (July 2013): 12, at 1, available at <https://www.fda.gov/media/86440/download> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
Ossorio, P. N. and Zhou, Y., “FMT and Microbial Medical Products: Generating High-Quality Evidence through Good Governance,” Journal of Law, Medicine & Ethics 47, no. 4 (2019): 505523. See also; Lietzan, E., “Access Before Evidence and the Price of the FDA's New Drug Authorities,” University of Richmond Law Review 53, no. 1243 (2019) (arguing that enforcement discretion is not appropriate for FMt for rCDI).CrossRefGoogle Scholar
Eiseman, B., Silen, W., and Bascom, G.S. et al., “Fecal Enema as an Adjunct in the Treatment of Pseudomembranous Enterocolitis,” Surgery 44, no. 5 (1958): 854859.Google Scholar
Segal, M.S., “Luminary: Owen H. Wangensteen, M.D,” Metro-Doctors: The Journal of the Twin Cities Medical Society 13, no. 3 (2011): 32.Google Scholar
Aas, J., Gessert, C.E., and Bakken, J.S., “Recurrent Clostridium difficile Colitis: Case Series Involving 18 Patients Treated with Donor Stool Administered via a Nasogastric Tube,” Clinical Infectious Diseases 36, no. 5 (2003): 580585; Persky, S.E. and Brandt, L.J., “Treatment of Recurrent Clostridium difficile-associated Diarrhea by Administration of Donated Stool Directly Through a Colonoscope,” American Journal of Gastroenterology 95 (2000): 32833285.CrossRefGoogle Scholar
Tvede, M. and Rask-Madsen, J., “Bacteriotherapy for Chronic Relapsing Clostridium Difficile Diarrhoea in Six Patients,” Lancet 333 (1989): 11561160.CrossRefGoogle Scholar
van der Waaij, D., Vossen, J.M., and Altes, C.K. et al., “Reconventionalization Following Antibiotic Decontamination in Man and Animals,” American Journal of Clinical Nutrition 30, no. 11 (1977): 18871895.CrossRefGoogle Scholar
The definition of “dysbiosis” is not agreed upon — some experts use the term only if the altered microbiota composition causes disease, while others are satisfied with an association only. See Bennet, J.D. and Brinkman, M., “Treatment of Ulcerative Colitis by Implantation of Normal Colonic Flora,” Lancet 333 (1989): 164; Borody, T.J., Warren, E.F., and Leis, S. et al., “Treatment of Ulcerative Colitis Using Fecal Bacteriotherapy,” Journal of Clinical Gastroenterology 37, no. 1 (2003): 4247CrossRefGoogle Scholar
Kelly, C.P. and LaMont, J.T., Clostridium difficile–More Difficult than Ever,” New England Journal of Medicine 359 (2008): 19321940.CrossRefGoogle Scholar
Ochman, H., Worobey, M., and Kuo, C.H. et al., “Evolutionary Relationships of Wild Hominids Recapitulated by Gut Microbial Communities,” PLoS Biology 8, no. 11 (2010): e1000546.CrossRefGoogle Scholar
Relman, D.A., “The Human Microbiome: Ecosystem Resilience and Health,” Nutrition Reviews 70, supp. 1 (2012): S2S9.CrossRefGoogle Scholar
Khoruts, A., Dicksved, J., and Jansson, J.K. et al., “Changes in the Composition of the Human Fecal Microbiome after Bacteriotherapy for Recurrent Clostridium difficile-associated Diarrhea,” Journal of Clinical Gastroenterology 44, no. 5 (2010): 354360; Hamilton, M.J., Weingarden, A.R., and Unno, T. et al., “High-throughput DNA Sequence Analysis Reveals Stable Engraftment of Gut Microbiota Following Transplantation of Previously Frozen Fecal Bacteria,” Gut Microbes 4, no. 2 (2013): 125135.CrossRefGoogle Scholar
Bakken, J.S., Borody, T., and Brandt, L.J. et al., “Treating Clostridium Difficile Infection with Fecal Microbiota Transplantation,” Clinical Gastroenterology and Hepatology 9, no. 12 (2011): 10441049CrossRefGoogle Scholar
Khoruts, A. and Brandt, L.J., “Fecal Microbiota Transplant: A Rose by Any Other Name,” Correspondence, American Journal of Gastroenterology 114, no. 7 (2019): 1176.CrossRefGoogle Scholar
Bakken et al., supra note 17; Hamilton, M.J., Weingarden, A.R., and Sadowsky, M.J. et al., “Standardized Frozen Preparation for Transplantation of Fecal Microbiota for Recurrent Clostridium Difficile Infection,” American Journal of Gastroenterology 107, no. 5 (2012): 761767.CrossRefGoogle Scholar
van Nood, E., Vrieze, A., and Nieuwdorp, M. et al., “Duodenal Infusion of Donor Feces for Recurrent Clostridium Difficile,” New England Journal of Medicine 368, no. 5 (2013): 407415.CrossRefGoogle Scholar
Cammarota, G., Masucci, L., and Ianiro, G. et al., “Randomised Clinical Trial: Faecal Microbiota Transplantation by Colonos-copy vs. Vancomycin for the Treatment of Recurrent Clostridium Difficile Infection,” Alimentary Pharmacology and Therapeutics 41, no. 9 (2015): 835843; Kelly, C.R., Khoruts, A., and Staley, C. et al., “Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial,” Annals of Internal Medicine 165, no. 9 (2016): 609616; Hvas, C.L., Dahl Jørgensen, S.M., and Jørgensen, S.P. et al., “Fecal Microbiota Transplantation is Superior to Fidaxomicin for Treatment of Recurrent Clostridium difficile Infection,” Gastroenterology 156, no. 5 (2019): 13241332.CrossRefGoogle Scholar
Broecker, F., Russo, G., and Klumpp, J. et al., “Stable Core Virome Despite Variable Microbiome after Fecal Transfer,” Gut Microbes 8, no. 3 (2017): 214220; Zuo, T., Wong, S.H., and Lam, K. et al., “Bacteriophage Transfer During Faecal Microbiota Transplantation in Clostridium difficile Infection is Associated with Treatment Outcome,” Gut 67 (2018): 634643.CrossRefGoogle Scholar
Khoruts, A. and Sadowsky, M. J., “Understanding the Mechanisms of Faecal Microbiota Transplantation,” Nature Reviews Gastroenterology & Hepatology 13, no. 9 (2016): 508516; Ott, S.J., Waetzig, G.H., and Rehman, A. et al., “Efficacy of Sterile Fecal Filtrate Transfer for Treating Patients with Clostridium difficile Infection,” Gastroenterology 152, no. 4 (2017):799811 e7.CrossRefGoogle Scholar
Surawicz, C.M., Brandt, L.J., and Binion, D.G. et al., “Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections,” American Journal of Gastroenterology 108, no. 4 (2013): 478498; McDonald, L.C., Gerding, D.N., and Johnson, S. et al., “Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA),” Clinical Infectious Diseases 66, no. 7 (2018): 987994.CrossRefGoogle Scholar
Fischer, M., Sipe, B., and Cheng, Y.W. et al., “Fecal Microbiota Transplant in Severe and Severe-Complicated Clostridium difficile: A Promising Treatment Approach,” Gut Microbes 8, no. 3 (2017): 289302; Hocquart, M., Lagier, J.C., and Cassir, N. et al., “Early Fecal Microbiota Transplantation Improves Survival in Severe Clostridium difficile Infections,” Clinical Infectious Diseases 66, no. 5 (2018): 645650; Ossorio and Zhou, supra note 6, asserting there is little, if any, “high quality” evidence supporting use of FMT for any indication.CrossRefGoogle Scholar
Moayyedi, P., Surette, M.G., and Kim, P.T. et al., “Fecal Micro-biota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial,” Gastroenterology 149, no. 1 (2015): 102109; Paramsothy, S., Kamm, M.A., and Kaakoush, N.O. et al., “Multidonor Intensive Faecal Microbiota Transplantation for Active Ulcerative Colitis: a Randomised Placebo-Controlled Trial,” Lancet 389, no. 10075 (2017): P12181228; Costello, S.P., Hughes, P.A., and Waters, O. et al., “Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial,” JAMA 321, no. 2 (2019): 156164.CrossRefGoogle Scholar
Hamilton et al., supra note 19.Google Scholar
Smith, M.B., Kelly, C. C, and Alm, E.J., “Policy: How to Regulate Faecal Transplants,” Nature 506, no. 7488 (2014): 290291.CrossRefGoogle Scholar
U.S. Food & Drug Administration, Enforcement Policy Draft Guidance, supra note 5.Google Scholar
Khanna, S., Pardi, D.S., and Kelly, C.R. et al., “A Novel Micro-biome Therapeutic Increases Gut Microbial Diversity and Prevents Recurrent Clostridium difficile Infection,” Journal of Infectious Diseases 214, no. 2 (2016): 173181.CrossRefGoogle Scholar
Smith et al., supra note 28; Petrof, E.O. and Khoruts, A., “From Stool Transplants to Next-Generation Microbiota Therapeutics,” Gastroenterology 146, no. 6 (2014): 15731582.CrossRefGoogle Scholar
Scheeler, A., “Where Stool is a Drug: International Approaches to Regulating the Use of Fecal Microbiota for Transplantation,” Journal of Law, Medicine & Ethics 47, no. 4 (2019): 524540, (Table 1).CrossRefGoogle Scholar
P.N. Ossorio and Y. Zhou, supra note 6.Google Scholar
P.N. Ossorio and Y. Zhou, supra note 6, asserting the potential superiority of defined consortia products.Google Scholar
Staley, C., Hamilton, M.J., and Vaughn, B.P. et al., “Successful Resolution of Recurrent Clostridium difficile Infection Using Freeze-Dried, Encapsulated Fecal Microbiota; Pragmatic Cohort Study,” American Journal of Gastroenterology 112, no. 6 (2017): 940947.CrossRefGoogle Scholar
May, B., “Microbiota-Based Enema Prevents Recurrent C. difficile Infections,” MD Magazine, July 20, 2018, available at <https://www.mdmag.com/medical-news/microbiotabased-enema-prevents-recurrent-c-difficile-infections> (last visited September 13, 2019).Google Scholar
Ferring Pharmaceuticals, Press Release, “Ferring Acquires Innovative Biotechnology Company and Microbiome Pioneer Rebiotix Inc.,” April 5, 2018, available at <https://www.rebiotix.com/wp-content/uploads/ferring-acquires-innovative-biotechnology-company-and-microbiome-pioneer-rebiotixinc.pdf> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
Rebiotix, Press Release, “Rebiotix Announces First patient Enrolled in Phase 3 Clinical Trial of RBX2660 for the Prevention of Recurrent Clostridium difficile Infection,” Aug. 7, 2017, available at <https://www.rebiotix.com/wp-content/uploads/rebiotix-announces-first-patient-enrolled-phase-3-clinical-trial-rbx2660-recurrent-clostridium-difficile-infection.pdf> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
Seres Therapeutics, Clostridium difficile Infection (CDI), available at <https://www.serestherapeutics.com/pipeline/ser-109> (last visited Aug. 21, 2019).+(last+visited+Aug.+21,+2019).>Google Scholar
Vedanta Biosciences, Press Release, “Vedanta Biosciences Announces Initiation of Phase 1a/1b Trial for New Drug Class of Rationally-Defined Bacterial Consortia Derived from the Human Microbiome,” Dec. 7, 2017, available at <https://www.vedantabio.com/news-media/press-releases/detail/2298/vedanta-biosciences-announces-initiation-of-phase-1a1b> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
Vedanta Biosciences, Press Release, “Vedanta Biosciences Initiates Phase 2 Study to Lead Rationally-Defined Bacterial Consortium Product Candidate, VE303,” Dec. 17, 2018, available at <https://www.vedantabio.com/news-media/press-releases/detail/2493/vedanta-biosciences-initiates-phase-2-study-for-lead> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
Finch Therapeutics, “Recurrent C. Difficile,” available at <https://finchtherapeutics.com/cp101> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
PureTech Health, Press Release, “PureTech's Vedanta Biosciences Announces Initiation of Phase 2 Study for Lead Product Candidate, VE303,” Dec. 17, 2018, available at <https://puretechhealth.com/news/23-press-releases/1080-puretechs-vedanta-biosciences-announces-initiation-of-a-phase-2-study-for-lead-product-candidate-ve303> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
Finch Therapeutics, Press Release, “Finch Therapeutics' Investigational Drug CP101 Granted Breakthrough Therapy Designation from FDA for Recurrent C. Difficile Infection” (Feb. 8, 2019), available at <https://finchtherapeutics.com/news/2019/2/8/finch-therapeutics-investigational-drug-cp101-granted-breakthrough-therapy-designation-from-fda-for-recurrent-c-difficile-infection> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
Seres Therapeutics, supra note 39.Google Scholar
Ferring Pharmaceuticals, supra note 37.Google Scholar
21 C.F.R. § 316.21(b) (2013).Google Scholar
21 C.F.R. § 316.21(c) (2013).Google Scholar
Lessa, F.C., Mu, Y., and Bamberg, W. et al., “Burden of Clostridium difficile Infection in the United States,” New England Journal of Medicine 372 (2015): 825834; Ma, G.K., Brensinger, C., and Wu, Q. et al., “Increasing Incidence of Multiply Recurrent Clostridium difficile Infection in the United States: Cohort Study,” Annals of Internal Medicine 167, no. 3 (2017): 152158.CrossRefGoogle Scholar
Thomas, S. and Caplan, A., “The Orphan Drug Act Revisited,” JAMA 321, no. 9 (2019): 833834.CrossRefGoogle Scholar
U.S. Food & Drug Administration, Frequently Asked Questions: Breakthrough Therapies (June 28, 2019), available at <https://www.fda.gov/regulatory-information/food-and-drug-administration-safety-and-innovation-act-fdasia/frequently-asked-questions-breakthrough-therapies> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
McDonald et al., supra note 24.Google Scholar
U.S. Food & Drug Administration, Fast Track (Jan. 4, 2018), available at <https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
U.S. Food & Drug Administration, Enforcement Policy Draft Guidance, supra note 5.Google Scholar
U.S. Food & Drug Administration, FDA 101: Regulating Biological Products (July 25, 2008), available at <https://www.fda.gov/consumers/consumer-updates/fda-101-regulating-biological-products> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
U.S. Food & Drug Administration, Frequently Asked Questions About Therapeutic Biological Products (July 7, 2015), available at <https://www.fda.gov/drugs/therapeutic-biologics-applications-bla/frequently-asked-questions-about-therapeutic-biological-products> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
Public Health Service Act, 42 U.S.C. §§ 201 et seq. (2018).Google Scholar
U.S. Food & Drug Administration, Frequently Asked Questions, supra note 59.Google Scholar
U.S. Food & Drug Administration, Guidance Document: Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products (April 1996), available at <https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstration-comparability-human-biological-products-including-therapeutic-biotechnology-derived> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
U.S. Food & Drug Administration, Frequently Asked Questions, supra note 59.Google Scholar
U.S. Food & Drug Administration, Guidance Document, supra note 62.Google Scholar
Armstrong, K.B. and Staman, J.A., Congressional Research Service, R43609, “Enforcement of the Food, Drug, and Cosmetic Act: Select Legal Issues” (Feb. 9, 2018).Google Scholar
See Cook v. FDA, 733 F.3d 1 (D.C. Cir. 2013).Google Scholar
U.S. Food & Drug Administration, Enforcement Policy Draft Guidance, supra note 5.Google Scholar
Jørgensen, S.M.D., Hvas, C.L., and Dahlerup, J.F. et al., “Banking Feces: a New Frontier for Public Blood Banks?” Transfusion (Online Version of Record June 26, 2019): 17.Google Scholar
Clinical Laboratories Improvement Amendments of 1988, 42 U.S.C. 263a (2012 & Supp. V 2013–2018).Google Scholar
Turnbaugh, P.J. amd Gordon, J.I., “The Core Gut Microbiome, Energy Balance and Obesity,” Journal of Physiology 587, no. 17 (2009): 41534158.CrossRefGoogle Scholar
U.S. Food & Drug Administration, Chemistry, Manufacturing, and Controls Changes to an Approval Application: Certain Biological Products, Draft Guidance for Industry (Dec. 2017), available at <https://www.fda.gov/media/109615/download> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
U.S. Food & Drug Administration, Important Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms (June 13, 2019), available at <https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/important-safety-alert-regarding-usefecal-microbiota-transplantation-and-risk-serious-adverse> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
Rampelli, S., Schnorr, S.L., and Consolandi, C. et al., “Metagenome Sequencing of the Hadza Hunter-Gatherer Gut Micro-biota,” Current Biology 25, no. 13 (2015): 16821693; Clemente, J.C., Pehrsson, E.C., and Blaser, M.J. et al., “The Micro-biome of Uncontacted Amerindians,” Science Advances 1, no. 3 (2015): e1500183.CrossRefGoogle Scholar
See U.S. Food & Drug Administration, Chemistry, Manufacturing, and Controls Changes, supra note 73.Google Scholar
Blaser, M.J., “The Theory of Disappearing Microbiota and the Epidemics of Chronic Diseases,” Nature Reviews Immunology 17, no. 8 (2017): 461463.CrossRefGoogle Scholar
Vangay, P., Johnson, A.J., and Ward, T.L. et al., “US Immigration Westernizes the Human Gut Microbiome,” Cell 175, no. 4 (2018): 962–72.e10.CrossRefGoogle Scholar
Ossorio and Zhou, supra note 6.Google Scholar
Petrof, E.O., Gloor, G.B., and Vanner, S.J. et al., “Stool Substitute Transplat Therapy for the Eradication of Clostridium difficile Infection: ‘RePOOPulating’ the Gut,” Microbiome 1, no. 3 (2013): art. no. 3.CrossRefGoogle Scholar
Millan, B., Park, H., and Hotte, N. et al., “Fecal Microbial Transplants Reduce Antibiotic-resistant Genes in Patients With Recurrent Clostridium difficile Infection,” Clinical Infectious Diseases 62, no. 12 (2016): 14791486.CrossRefGoogle Scholar
Zmora, N., Zilberman-Schapira, G., and Suez, J. et al., “Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features,” Cell 174, no. 6 (2018): 1388–1405.e21; Suez, J., Zmora, N., Zilberman-Schapira, G. et al., “Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT,” Cell 174, no. 6 (2018): 1406–23.e16.CrossRefGoogle Scholar
Tariq, R., Pardi, D.S., and Bartlett, M.G. et al., “Low Cure Rates in Controlled Trials of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection: A Systematic Review and Meta-analysis,” Clinical Infectious Diseases 68, no. 8 (2019): 13511358.CrossRefGoogle Scholar
Allegretti, J., “Stool Transplants are now Standard of Care for Recurrent C. difficile Infections,” Harvard Health Blog: Harvard Medical School (June 3, 2019), available at <https://www.health.harvard.edu/blog/stool-transplants-are-now-standard-of-care-for-recurrent-c-difficile-infections-2019050916576> (last visited September 13, 2019).Google Scholar
For FDA recommendations for choice of control group, see U.S. Food & Drug Administration, E 10 Choice of Control Group and Related Issues in Clinical Trials, Guidance for Industry (May 2001), available at <https://www.fda.gov/media/71349/download> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
Hamilton et al., supra note 19; Lee, C.H., Steiner, T., and Petrof, E.O. et al., “Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial,” JAMA 315, no. 2 (2016): 142149.CrossRefGoogle Scholar
Kao, D., Roach, B., Silva, M. et al., “Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection: A Randomized Clinical Trial,” JAMA 318, no. 20 (2017): 19851993; Allegretti, J.R., Fischer, M., and Sagi, S.V. et al., “Fecal Microbiota Transplantation Capsules with Targeted Colonic Versus Gastric Delivery in Recurrent Clostridium difficile Infection: A Comparative Cohort Analysis of High and Lose Dose,” Digestive Diseases and Sciences 64, no. 6 (2019): 16721678.Google Scholar
Staley, C., Hamilton, M.J., and Vaughn, B.P. et al., “Successful Resolution of Recurrent Clostridium difficile Infection Using Freeze-Dried, Encapsulated Fecal Microbiota; Pragmatic Cohort Study,” American Journal of Gastroenterology 112, no. 6 (2017): 940947.CrossRefGoogle Scholar
Newman, K.M., Rank, K., and Vaughn, B.P. et al., “Treatment of Recurrent Clostridium difficile Infection using Fecal Micro-biota Transplantation in Patients with Inflammatory Bowel Disease,” Gut Microbes 8, no. 3 (2017): 303309; Fischer, M., Kao, D., and Kelly, C. et al., “Fecal Microbiota Transplantation is Safe and Efficacious for Recurrent or Refractory Clostridium difficile Infection in Patients with Inflammatory Bowel Disease,” Inflammatory Bowel Disease 22, no. 10 (2016): 24022409; Kelly, C.R., Ihunnah, C., and Fischer, M. et al., “Fecal Microbiota Transplant for Treatment of Clostridium difficile Infection in Immunocompromised Patients,” American Journal Gastroenterology 109, no. 7 (2014): 10651071.Google Scholar
Kelly, C.R., Fischer, M., and Grinspan, A. et al., “Patients Eligible for Trials of Microbe-Based Therapeutics do not Represent the Population With Recurrent Clostridioides difficile Infection,” Clinical Gastroenterology and Hepatology (June 27, 2019), available at <https://www.ncbi.nlm.nih.gov/pubmed/31254675> (last visited September 13, 2019).Google Scholar
Kelly, C.R., Kim, A.M., and Laine, L. et al., “The AGA's Fecal Microbiota Transplantation National Registry: An Important Step Toward Understanding Risks and Benefits of Microbiota Therapeutics,” Gastroenterology 152, no. 4 (2017): 681684.CrossRefGoogle Scholar
Ossorio and Zhou, supra note 6.Google Scholar
Tariq, R., Pardi, D.S., and Bartlett, M.G. et al., “Low Cure Rates in Controlled Trials of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection: A Systematic Review and Meta-analysis,” Clinical Infectious Diseases 68, no. 8 (2019): 13511358; Khoruts, A. and Sadowsky, M.J., “Letter to the Editor,” Clinical Infectious Diseases (2019): ciz366, available at <https://doi.org/10.1093/cid/ciz366> (last visited September 13, 2019).Google Scholar
Ossorio and Zhou, supra note 6.Google Scholar
OpenBiome, OpenBiome is Seeking Input on a Draft Proposal to FDA about Regulation of FMT (Nov. 7, 2018), available at <https://www.openbiome.org/comment-to-fda> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
U.S. Food & Drug Administration, Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies, Guidance for Industry (March 2016), available at <https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enforcement-policy-regarding-investigationalnew-drug-requirements-use-fecal-microbiota-0> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
OpenBiome, OpenBiome is Seeking Input, supra note 96.Google Scholar
Microbiome Therapeutics Innovation Group, available at <https://microbiometig.org/> (last visited August 21, 2019).+(last+visited+August+21,+2019).>Google Scholar
Letter to Scott Gottlieb from J.R. Allegretti and Thirty-Nine Additional Physicians who Offer FMT to Their Patients with rCDI (Jan. 14, 2019) (on file with author).Google Scholar
Goodman, B., “The Rise of the Do-It-Yourself Fecal Transplant,” WebMD, Dec. 9, 2015, available at <https://www.webmd.com/digestive-disorders/news/20151209/diy-fecal-transplant#1> (last visited September 13, 2019).Google Scholar
See also Goodman, B., id.; Hurst, M., “DIY Fecal Transplants to Cure yourself of Ulcerative Colitis,” YouTube (June 4, 2013), available at <https://www.youtube.com/watch?v=WEMnRC22oOs> (last visited September 13, 2019); Pattibiomed, D., “Fecal Microbiota Transplant: Science & Do It Yourself Instructions,” YouTube (Aug. 17, 2017), available at <https://www.youtube.com/watch?v=2pHU-ynn2Vw> (last visited September 13, 2019); “How to Perform a Fecal Transplant at Home,” The Healthy Home Economist, available at <https://www.thehealthyhomeeconomist.com/how-to-perform-a-fecal-transplant-at-home/> (last visited September 13, 2019).+(last+visited+September+13,+2019);+Pattibiomed,+D.,+“Fecal+Microbiota+Transplant:+Science+&+Do+It+Yourself+Instructions,”+YouTube+(Aug.+17,+2017),+available+at++(last+visited+September+13,+2019);+“How+to+Perform+a+Fecal+Transplant+at+Home,”+The+Healthy+Home+Economist,+available+at++(last+visited+September+13,+2019).>Google Scholar
Alang, N. and Kelly, C.R., “Weight Gain After Fecal Microbiota Transplantation,” Open Forum Infectious Diseases 2, no. 1 (2015) ofv004, doi: 10.1093/ofid/ofv004.CrossRefGoogle Scholar
21 C.F.R. § 316.34(c) (2013).CrossRefGoogle Scholar
21 C.F.R. § 316.3(b)(14) (2013).CrossRefGoogle Scholar
21 C.F.R. §§ 316.3(b)(3), 316.31 (2013).Google Scholar
Tariq et al., supra note 94.Google Scholar
Karst, K. R., “Orphan Drug Clinical Superiority: An Overview of Precedents Shows that MC-to-PC Clinical Superiority is Not so Unusual,” FDA Law Blog, March 27, 2016, available at <http://www.fdalawblog.net/2016/03/orphan-drug-clinical-superiority-an-overview-of-precedents-shows-that-mc-to-pc-clinical-superiority/> (last visited September 13, 2019).Google Scholar
There has not been a head-to-head comparison between enema versus colonoscopy, but all three enema studies listed here have a lower success rate relative to the multitude of colonoscopy FMT studies: See Lee et al., supra note 87; Hota, S.S., Sales, V., and Tomlinson, G. et al., “Oral Vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: an Open-Label, Randomized Controlled Trial,” Clinical Infectious Diseases 64, no. 3 (2017): 265271; Dubberke, E.R., Lee, C., and Orenstein, R. et al., “Efficacy and Safety of RBX2660 for the Prevention of Recurrent Clostridium difficile Infection: Results of the PUNCH CD 2 Trial,” Open Forum Infectious Diseases 3, no. supp.1 (2016): 1341.CrossRefGoogle Scholar
Thomas, J.R., Congressional Research Service, R44951, “Regulatory Exclusivity Reform in the 115th Congress” (Sept. 15, 2017).Google Scholar
42 U.S.C. § 262 (2012 & Supp. V 2013-2018).Google Scholar
Anderson, C., “How Much Does a Colonoscopy Cost?” Bankrate, Dec. 30, 2016, available at <https://www.bankrate.com/finance/smart-spending/how-much-does-colonoscopy-cost.aspx> (last visited September 13, 2019).+(last+visited+September+13,+2019).>Google Scholar
OpenBiome, Frequently Asked Questions, available at <https://www.OpenBiome.org/patient-faqs> (last visited August 22, 2019).+(last+visited+August+22,+2019).>Google Scholar
Find-A-Code, HCPCS Procedure & Supply CodeG0455 – Preparation with Instillation of Fecal Microbiota by any Method, Including Assessment of Donor Specimens, available at <https://www.findacode.com/hcpcs/g0455-preparation-with-instillation-of-fecal.html> (last visited August 22, 2019).+(last+visited+August+22,+2019).>Google Scholar
Medicare.gov, What Drug Plans Cover, available at <https://www.medicare.gov/drug-coverage-part-d/what-drug-plans-cover> (last visited August 22, 2019).+(last+visited+August+22,+2019).>Google Scholar
Doshi, J.A., Pettit, A.R., and Li, P., “Addressing Out-Of-Pocket Specialty Drug Costs In Medicare Part D: The Good, The Bad, The Ugly, And The Ignored,” Health Affairs Blog (July 25, 2018), available at <https://www.healthaffairs.org/do/10.1377/hblog20180724.734269/full/> (last visited September 13, 2019).Google Scholar
Cubanski, J., Koma, W., and Neuman, T., “The Out-of-Pocket Cost Burden for Specialty Drugs in Medicare Part D in 2019,” Henry J. Kaiser Family Foundation: KFF, Feb. 1, 2019, available at <https://www.kff.org/medicare/issue-brief/the-outof-pocket-cost-burden-for-specialty-drugs-in-medicare-part-d-in-2019/> (last visited September 13, 2019).Google Scholar
U.S. Food & Drug Administration, Enforcement Policy Draft Guidance, supra note 97.Google Scholar
OpenBiome, Find a Doctor Near You, available at <https://www.OpenBiome.org/find-a-doctor> (last visited Aug. 22, 2019) (stating OpenBiome “partner[s] with clinicians at over 1,000 hospitals, outpatient centers, and private practices across all 50 U.S. states”).+(last+visited+Aug.+22,+2019)+(stating+OpenBiome+“partner[s]+with+clinicians+at+over+1,000+hospitals,+outpatient+centers,+and+private+practices+across+all+50+U.S.+states”).>Google Scholar
Craven, L.J., Parvathy, S.N., and Tat-Ko, J. et al., “Extended Screening Costs Associated with Selecting Donors for Fecal Microbiota Transplantation for Treatment of Metabolic Syndrome-Associated Diseases,” Open forum Infectious Diseases 4, no. 4 (2017): ofx243.CrossRefGoogle Scholar
Hoffmann, D., Palumbo, F., and Ravel, J. et al., “Improving Regulation of Microbiota Transplants,” Science 358, no. 6369 (2017): 13901391.CrossRefGoogle Scholar
U.S. Food & Drug Administration, Enforcement Policy Draft Guidance, supra note 5Google Scholar
OpenBiome, Our Mission, available at <https://www.openbiome.org/our-mission> (last visited August 22, 2019).+(last+visited+August+22,+2019).>Google Scholar
Kelly et al., supra note 91.Google Scholar
Newman et al., supra note 90; De Leon, L.M., Watson, J.B., and Kelly, C.R., “Transient Flare of Ulcerative Colitis after Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection,” Clinical Gastroenterology and Hepatology 11, no. 8 (2013): 10361038.CrossRefGoogle Scholar
See also Ossorio and Zhao, supra note 6.Google Scholar