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

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.

Get full access to this article

View all access options for this article.

References

Foxman ,

Goldberg , and

Murdock

et al., “Conceptualizing Human Microbiota: From Multicelled Organ to Ecological Community,” Interdisciplinary Perspectives on Infectious Diseases 2008 (2008): art. no. 613979.

Sharon ,

T.R.

Sampson , and

D.H.

Geschwind

et al., “The Central Nervous System and the Gut Microbiome,” Cell 167, no. 4 (2016): 915–932.

K.Z.

Coyte ,

Schluter , and

K.R.

Foster , “The Ecology of the Microbiome: Networks, Competition, and Stability,” Science 350, no. 6261 (2015): 663–666.

Oren and

Rupnik , “Clostridium Difficile and Clostridioides Difficile: Two Validly Published and Correct Names,” Anaerobe 52 (2018): 125–126.

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): 1–2, at 1, available at <https://www.fda.gov/media/86440/download> (last visited September 13, 2019).

Lietzan

, “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).

Eiseman ,

Silen , and

G.S.

Bascom

et al., “Fecal Enema as an Adjunct in the Treatment of Pseudomembranous Enterocolitis,” Surgery 44, no. 5 (1958): 854–859.

M.S.

Segal

, “Luminary: Owen H. Wangensteen, M.D,” Metro-Doctors: The Journal of the Twin Cities Medical Society 13, no. 3 (2011): 32.

S.E.

Persky and

L.J.

Brandt , “Treatment of Recurrent Clostridium difficile-associated Diarrhea by Administration of Donated Stool Directly Through a Colonoscope,” American Journal of Gastroenterology 95 (2000): 3283–3285.

10.

Tvede and

Rask-Madsen , “Bacteriotherapy for Chronic Relapsing Clostridium Difficile Diarrhoea in Six Patients,” Lancet 333 (1989): 1156–1160.

11.

van der Waaij ,

J.M.

Vossen , and

C.K.

Altes

et al., “Reconventionalization Following Antibiotic Decontamination in Man and Animals,” American Journal of Clinical Nutrition 30, no. 11 (1977): 1887–1895.

12.

T.J.

Borody ,

E.F.

Warren , and

Leis

et al., “Treatment of Ulcerative Colitis Using Fecal Bacteriotherapy,” Journal of Clinical Gastroenterology 37, no. 1 (2003): 42–47

13.

C.P.

Kelly and

J.T.

LaMont , “Clostridium difficile–More Difficult than Ever,” New England Journal of Medicine 359 (2008): 1932–1940.

14.

Ochman ,

Worobey , and

C.H.

Kuo

et al., “Evolutionary Relationships of Wild Hominids Recapitulated by Gut Microbial Communities,” PLoS Biology 8, no. 11 (2010): e1000546.

15.

D.A.

Relman

, “The Human Microbiome: Ecosystem Resilience and Health,” Nutrition Reviews 70, supp. 1 (2012): S2–S9.

16.

M.J.

Hamilton ,

A.R.

Weingarden , and

Unno

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): 125–135.

17.

J.S.

Bakken ,

Borody , and

L.J.

Brandt

et al., “Treating Clostridium Difficile Infection with Fecal Microbiota Transplantation,” Clinical Gastroenterology and Hepatology 9, no. 12 (2011): 1044–1049

18.

Khoruts and

L.J.

Brandt , “Fecal Microbiota Transplant: A Rose by Any Other Name,” Correspondence, American Journal of Gastroenterology 114, no. 7 (2019): 1176.

19.

Bakken et al., supra note 17;

M.J.

Hamilton ,

A.R.

Weingarden , and

M.J.

Sadowsky et al., “Standardized Frozen Preparation for Transplantation of Fecal Microbiota for Recurrent Clostridium Difficile Infection,” American Journal of Gastroenterology 107, no. 5 (2012): 761–767.

20.

van Nood ,

Vrieze , and

Nieuwdorp

et al., “Duodenal Infusion of Donor Feces for Recurrent Clostridium Difficile,” New England Journal of Medicine 368, no. 5 (2013): 407–415.

21.

C.L.

Hvas ,

S.M.

Dahl Jørgensen , and

S.P.

Jørgensen

et al., “Fecal Microbiota Transplantation is Superior to Fidaxomicin for Treatment of Recurrent Clostridium difficile Infection,” Gastroenterology 156, no. 5 (2019): 1324–1332.

22.

Zuo ,

S.H.

Wong , and

Lam

et al., “Bacteriophage Transfer During Faecal Microbiota Transplantation in Clostridium difficile Infection is Associated with Treatment Outcome,” Gut 67 (2018): 634–643.

23.

S.J.

Ott ,

G.H.

Waetzig , and

Rehman

et al., “Efficacy of Sterile Fecal Filtrate Transfer for Treating Patients with Clostridium difficile Infection,” Gastroenterology 152, no. 4 (2017):799–811 e7.

24.

L.C.

McDonald ,

D.N.

Gerding , and

Johnson

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): 987–994.

25.

Hocquart ,

J.C.

Lagier , and

Cassir

et al., “Early Fecal Microbiota Transplantation Improves Survival in Severe Clostridium difficile Infections,” Clinical Infectious Diseases 66, no. 5 (2018): 645–650; Ossorio and Zhou, supra note 6, asserting there is little, if any, “high quality” evidence supporting use of FMT for any indication.

26.

S.P.

Costello ,

P.A.

Hughes , and

Waters

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): 156–164.

27.

Hamilton et al., supra note 19.

28.

M.B.

Smith ,

Kelly C, and

E.J.

Alm , “Policy: How to Regulate Faecal Transplants,” Nature 506, no. 7488 (2014): 290–291.

29.

U.S. Food & Drug Administration, Enforcement Policy Draft Guidance, supra note 5.

30.

Khanna ,

D.S.

Pardi , and

C.R.

Kelly

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): 173–181.

31.

Smith et al., supra note 28;

E.O.

Petrof and

Khoruts , “From Stool Transplants to Next-Generation Microbiota Therapeutics,” Gastroenterology 146, no. 6 (2014): 1573–1582.

32.

Scheeler

, “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): 524-540, (Table 1).

33.

P.N. Ossorio and Y. Zhou, supra note 6.

34.

P.N. Ossorio and Y. Zhou, supra note 6, asserting the potential superiority of defined consortia products.

35.

Staley ,

M.J.

Hamilton , and

B.P.

Vaughn

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): 940–947.

36.

May

, “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).

37.

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).

38.

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).

39.

Seres Therapeutics, Clostridium difficile Infection (CDI), available at <https://www.serestherapeutics.com/pipeline/ser-109> (last visited Aug. 21, 2019).

40.

Id.

41.

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).

42.

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).

43.

Id.

44.

Finch Therapeutics, “Recurrent C. Difficile,” available at <https://finchtherapeutics.com/cp101> (last visited September 13, 2019).

45.

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).

46.

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).

47.

Seres Therapeutics, supra note 39.

48.

Ferring Pharmaceuticals, supra note 37.

49.

21 C.F.R. § 316.21(b) (2013).

50.

21 C.F.R. § 316.21(c) (2013).

51.

G.K.

Ma ,

Brensinger , and

et al., “Increasing Incidence of Multiply Recurrent Clostridium difficile Infection in the United States: Cohort Study,” Annals of Internal Medicine 167, no. 3 (2017): 152–158.

52.

Thomas and

Caplan , “The Orphan Drug Act Revisited,” JAMA 321, no. 9 (2019): 833–834.

53.

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).

54.

McDonald et al., supra note 24.

55.

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).

56.

Id.

57.

U.S. Food & Drug Administration, Enforcement Policy Draft Guidance, supra note 5.

58.

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).

59.

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).

60.

Public Health Service Act, 42 U.S.C. §§ 201 et seq. (2018).

61.

U.S. Food & Drug Administration, Frequently Asked Questions, supra note 59.

62.

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).

63.

U.S. Food & Drug Administration, Frequently Asked Questions, supra note 59.

64.

Id.

65.

U.S. Food & Drug Administration, Guidance Document, supra note 62.

66.

K.B.

Armstrong and

J.A.

Staman , Congressional Research Service, R43609, “Enforcement of the Food, Drug, and Cosmetic Act: Select Legal Issues” (Feb. 9, 2018).

67.

See Cook v. FDA, 733 F.3d 1 (D.C. Cir. 2013).

68.

U.S. Food & Drug Administration, Enforcement Policy Draft Guidance, supra note 5.

69.

Id.

70.

S.M.D.

Jørgensen ,

C.L.

Hvas , and

J.F.

Dahlerup

et al., “Banking Feces: a New Frontier for Public Blood Banks?” Transfusion (Online Version of Record June 26, 2019): 1–7.

71.

Clinical Laboratories Improvement Amendments of 1988, 42 U.S.C. 263a (2012 & Supp. V 2013–2018).

72.

P.J.

Turnbaugh amd

J.I.

Gordon , “The Core Gut Microbiome, Energy Balance and Obesity,” Journal of Physiology 587, no. 17 (2009): 4153–4158.

73.

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).

74.

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).

75.

J.C.

Clemente ,

E.C.

Pehrsson , and

M.J.

Blaser

et al., “The Micro-biome of Uncontacted Amerindians,” Science Advances 1, no. 3 (2015): e1500183.

76.

See U.S. Food & Drug Administration, Chemistry, Manufacturing, and Controls Changes, supra note 73.

77.

Id.

78.

M.J.

Blaser

, “The Theory of Disappearing Microbiota and the Epidemics of Chronic Diseases,” Nature Reviews Immunology 17, no. 8 (2017): 461–463.

79.

Vangay ,

A.J.

Johnson , and

T.L.

Ward

et al., “US Immigration Westernizes the Human Gut Microbiome,” Cell 175, no. 4 (2018): 962–72.e10.

80.

Ossorio and Zhou, supra note 6.

81.

E.O.

Petrof ,

G.B.

Gloor , and

S.J.

Vanner

et al., “Stool Substitute Transplat Therapy for the Eradication of Clostridium difficile Infection: ‘RePOOPulating’ the Gut,” Microbiome 1, no. 3 (2013): art. no. 3.

82.

Millan ,

Park , and

Hotte

et al., “Fecal Microbial Transplants Reduce Antibiotic-resistant Genes in Patients With Recurrent Clostridium difficile Infection,” Clinical Infectious Diseases 62, no. 12 (2016): 1479–1486.

83.

Suez ,

Zmora ,

Zilberman-Schapira

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.

84.

Tariq ,

D.S.

Pardi , and

M.G.

Bartlett

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): 1351–1358.

85.

Allegretti

, “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).

86.

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).

87.

Hamilton et al., supra note 19;

C.H.

Lee ,

Steiner , and

E.O.

Petrof 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): 142–149.

88.

J.R.

Allegretti ,

Fischer , and

S.V.

Sagi

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): 1672–1678.

89.

Staley ,

M.J.

Hamilton , and

B.P.

Vaughn

90.

C.R.

Kelly ,

Ihunnah , and

Fischer

et al., “Fecal Microbiota Transplant for Treatment of Clostridium difficile Infection in Immunocompromised Patients,” American Journal Gastroenterology 109, no. 7 (2014): 1065–1071.

91.

C.R.

Kelly ,

Fischer , and

Grinspan

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).

92.

C.R.

Kelly ,

A.M.

Kim , and

Laine

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): 681–684.

93.

Ossorio and Zhou, supra note 6.

94.

Khoruts and

M.J.

Sadowsky , “Letter to the Editor,” Clinical Infectious Diseases (2019): ciz366, available at <https://doi.org/10.1093/cid/ciz366> (last visited September 13, 2019).

95.

Ossorio and Zhou, supra note 6.

96.

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).

97.

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).

98.

OpenBiome, OpenBiome is Seeking Input, supra note 96.

99.

Microbiome Therapeutics Innovation Group, available at <https://microbiometig.org/> (last visited August 21, 2019).

100.

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).

101.

Goodman

, “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).

102.

“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).

103.

Alang and

C.R.

Kelly , “Weight Gain After Fecal Microbiota Transplantation,” Open Forum Infectious Diseases 2, no. 1 (2015) ofv004, doi: 10.1093/ofid/ofv004.

104.

21 C.F.R. § 316.34(c) (2013).

105.

21 C.F.R. § 316.3(b)(14) (2013).

106.

21 C.F.R. §§ 316.3(b)(3), 316.31 (2013).

107.

Tariq et al., supra note 94.

108.

K. R.

Karst

, “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).

109.

E.R.

Dubberke ,

Lee , and

Orenstein

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.

110.

J.R.

Thomas , Congressional Research Service, R44951, “Regulatory Exclusivity Reform in the 115th Congress” (Sept. 15, 2017).

111.

42 U.S.C. § 262 (2012 & Supp. V 2013-2018).

112.

Anderson

, “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).

113.

OpenBiome, Frequently Asked Questions, available at <https://www.OpenBiome.org/patient-faqs> (last visited August 22, 2019).

114.

Find-A-Code, HCPCS Procedure & Supply Code – G0455 – 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).

115.

Id.

116.

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).

117.

J.A.

Doshi ,

A.R.

Pettit , and

Li , “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).

118.

Cubanski ,

Koma , and

Neuman , “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).

119.

Id.

120.

U.S. Food & Drug Administration, Enforcement Policy Draft Guidance, supra note 97.

121.

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”).

122.

L.J.

Craven ,

S.N.

Parvathy , and

Tat-Ko

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.

123.

Id.

124.

Hoffmann ,

Palumbo , and

Ravel

et al., “Improving Regulation of Microbiota Transplants,” Science 358, no. 6369 (2017): 1390–1391.

125.

Id.

126.

U.S. Food & Drug Administration, Enforcement Policy Draft Guidance, supra note 5

127.

OpenBiome, Our Mission, available at <https://www.openbiome.org/our-mission> (last visited August 22, 2019).

128.

Kelly et al., supra note 91.

129.

Newman et al., supra note 90;

L.M.

De Leon ,

J.B.

Watson , and

C.R.

Kelly , “Transient Flare of Ulcerative Colitis after Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection,” Clinical Gastroenterology and Hepatology 11, no. 8 (2013): 1036–1038.

130.

See also Ossorio and Zhao, supra note 6.