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IRB Approval for FMT What does an IRB look for in FMT Protocols? William Tremaine, M.D. Mayo Clinic Rochester, MN.

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Presentation on theme: "IRB Approval for FMT What does an IRB look for in FMT Protocols? William Tremaine, M.D. Mayo Clinic Rochester, MN."— Presentation transcript:

1 IRB Approval for FMT What does an IRB look for in FMT Protocols? William Tremaine, M.D. Mayo Clinic Rochester, MN

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3 IRB Review of an FMT Protocol Is FMT human research? Is FMT human research? Is an IND required Is an IND required Is the proposal scientifically valid? Is the proposal scientifically valid? Are the risks minimized? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be protected? Will the privacy of the participants and donors be protected?

4 What Constitutes Research? OHRP Systematic investigation Systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledgeFDA Any experiment that involves a test article and one or more human subjects, and that either must meet the requirements for prior submission to the FDA...or the results of which are intended to be later submitted to, or held for inspection by, the FDA as part of an application for a research or marketing permit. food and color additives, drugs for human use, medical devices for human use, biological products for human use, …

5 Is FMT Human Research? Yes if any of these applyNo if all of these apply An IND is requiredNo IND is required Systematic collection of data for analysis Just for treatment For publicationNot for main purpose of publication

6 Clinical Registry versus Research Database Clinical RegistryResearch Database Plausible Clinical Need Laboratory monitoring Scheduling follow-up visits Contacting patients about updates No Clinical Use Hypothesis driven Consent required For publication

7 Clinical Registry versus Research Database Clinical RegistryResearch Database Plausible Clinical Need Laboratory monitoring Scheduling follow-up visits Contacting patients about updates No Clinical Use Hypothesis driven Consent required For publication Research IRB Approval Minimal Risk Retrospective Waiver of Consent and HIPAA

8 IRB Review of an FMT Protocol Is FMT human research? Is FMT human research? Is an IND required Is an IND required Is the proposal scientifically valid? Is the proposal scientifically valid? Are the risks minimized? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be protected? Will the privacy of the participants and donors be protected?

9 Smith MB et al. Nature 2014: 506: 290-1

10 Listed Fecal Transplant Trials July 27, 2014

11 68 Listed Fecal Transplant Clinical Trials DiagnosisNumber of studies C difficile19 IBD17 Pouchitis1 Fecal Incontinence2 IBS2 Diabetes1 Metabolic Syndrome1 Chronic diarrhea2 Ileus1 Graft vs Host1 Incorrect Listing21 Clinicaltrials.gov July 27,

12 Safety, Tolerability, and Clinical Response After Fecal Transplantation in Children and Young Adults with Ulcerative Colitis Prospective, uncontrolled, single center Prospective, uncontrolled, single center Grand Rapids, MI Grand Rapids, MI Investigator-initiated IND for fecal transplant in UC Investigator-initiated IND for fecal transplant in UC Local IRB approved Local IRB approved Fecal retention enemas Fecal retention enemas Cohort Cohort 10 children ages 7-21 Mild to moderate activity Stable on maintenance Rx for 2 months Donors Donors Family or friends Exclusion criteria in the IND Kunde S et al. JPGN 2013: 56:

13 FMT for C. difficile FDA Guidance July 2013 Enforcement discretion No IND required provided that Treating physician obtains informed consent Treating physician obtains informed consent Informed consent includes Informed consent includes A statement that FMT for C difficile is investigational A statement that FMT for C difficile is investigational Potential risks are discussed Potential risks are discussed This enforcement discretion is temporary until an FDA policy regarding FMT is implemented

14 FMT and Clinical Trials DiagnosisNumber of studies C difficile19 IBD17 Pouchitis1 Fecal Incontinence2 IBS2 Diabetes1 Metabolic Syndrome1 Chronic diarrhea2 Ileus1 Graft vs Host1 Clinicaltrials.gov July 27, 2014 IND

15 17 IBD Studies Clinicaltrials.gov Active, Recruiting Active Not Recruiting CompletedTerminated UC511 Crohn’s11 IBD321 Pouchitis1

16 17 IBD Studies Clinicaltrials.gov Active, Recruiting Active Not Recruiting CompletedTerminated UC511 Crohn’s11 IBD331 Pouchitis1

17 Fecal Microbiota Transplant for IBD 9 Active Recruiting Trials INDNo INDNo Response U.S.3 Non U.S. *51 *Finland, China, Netherlands, Israel

18 FMT for C. difficile FDA Guidance July 2013 Enforcement discretion policy does not extend to other uses of FMT Enforcement discretion policy does not extend to other uses of FMT FDA will continue to work with any sponsors who wish to submit INDs for this use (C. difficile treatment) of FMT FDA will continue to work with any sponsors who wish to submit INDs for this use (C. difficile treatment) of FMT

19 Clinical Research Trials DiagnosisNumber of studies C difficile19 IBD17 Pouchitis1 Fecal Incontinence2 IBS2 Diabetes1 Metabolic Syndrome1 Chronic diarrhea2 Ileus1 Graft vs Host1 IND IND?

20 Is and IND Required for FMT? Yes ifMaybeNo if The treatment isn’t for C. difficile The treatment is a research study for C. difficile, not primarily for clinical care The treatment is for C. difficile for clinical care

21 Investigator Initiated IND Regulatory Burden

22 Safety ReportsAnnual Reports Any Adverse experience associated with the use of the drug that is both serious and unexpected

23 Annual Report

24 IRB Review of an FMT Protocol Is FMT human research? Is FMT human research? Is an IND required Is an IND required Is the proposal scientifically valid? Is the proposal scientifically valid? Are the risks minimized? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be protected? Will the privacy of the participants and donors be protected?

25 Is the FMT Proposal Scientifically Valid? Plausible Hypothesis Plausible Hypothesis Meaningful endpoints Meaningful endpoints Sufficient statistical power Sufficient statistical power Adequate resources Adequate resources

26 Scientifically valid? Comparison Group Issues ComparatorProCon PlaceboPowerEthics ActiveEthicsFeasibility HistoricalEasyQuestionable validity

27 IRB Review of an FMT Protocol Is FMT human research? Is FMT human research? Is an IND required Is an IND required Is the proposal scientifically valid? Is the proposal scientifically valid? Are the risks minimized? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be protected? Will the privacy of the participants and donors be protected?

28 Risks of FMT ObservedPotential Abdominal discomfort Bloating Flare of ulcerative colitis Fever Worse diarrhea Increased CrP Orthostasis Pancreatitis Hepatitis HIV Autoimmune diseases Obesity Rubin DT Amer J Gastro : Smith MB et al. Nature 2014: 506: 290-1

29 IRB Review of an FMT Protocol Is FMT human research? Is FMT human research? Is an IND required Is an IND required Is the proposal scientifically valid? Is the proposal scientifically valid? Are the risks minimized? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be protected? Will the privacy of the participants and donors be protected?

30 Elements of Informed Consent OHRP This is researchBenefits PurposeAlternatives DurationConfidentiality Procedure detailsCompensation for injury Experimental proceduresWhom to contact RisksVoluntary

31 IRB Review of an FMT Protocol Is FMT human research? Is FMT human research? Is an IND required Is an IND required Is the proposal scientifically valid? Is the proposal scientifically valid? Are the risks minimized? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be insured? Will the privacy of the participants and donors be insured?

32 FMT Donor Registry Sarah Location: New York City, NY, USA Gender: Female Age: 49 Have Donated Previously: No Liability Agreement Required: Yes Cost: All fees associated with required testing & negotiable ‘per donation’ fee Why Donating: I believe in the theory of FMT and have been a pristine eater all my life so I figure I can help others. thepowerofpoop.com

33 Recommendations for FMT Donors Inclusion CriteriaExclusion Criteria Intimate longtime partner Adult first degree relative Close family friend Well-screened universal donor Antibiotic use in < 3 months Known GI disease Autoimmune or atopic illness Chronic pain syndrome Metabolic Syndrome or malnutrition History of malignant disease HAV-IgMC difficile toxin B HBsAg+ stool culture Anti-HCV-ab+ O & P HIV-EIA RPR AGA, ACG, ASGE, NASPGHAN, IDSA July 15, 2013

34 FMT Research Studies Safeguarding Privacy RecipientDonor Written informed consent HIPAA

35 IRB Review of an FMT Protocol Is FMT human research? Is FMT human research? Is an IND required Is an IND required Is the proposal scientifically valid? Is the proposal scientifically valid? Are the risks minimized? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be insured? Will the privacy of the participants and donors be insured?

36 IRB Approval for FMT Summary The divide between FMT for clinical practice and research is complicated The divide between FMT for clinical practice and research is complicated The FDA rules on INDs for FMT are not finalized The FDA rules on INDs for FMT are not finalized The usual IRB concerns for human research studies apply for the: The usual IRB concerns for human research studies apply for the: Recipient Recipient Donor Donor


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