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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 test 1
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IRB Review of an FMT Protocol
Is FMT human research? Is an IND required Is the proposal scientifically valid? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be protected?
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What Constitutes Research?
OHRP Systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge FDA 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, …
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Yes if any of these apply
Is FMT Human Research? Yes if any of these apply No if all of these apply An IND is required No IND is required Systematic collection of data for analysis Just for treatment For publication Not for main purpose of publication
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Clinical Registry versus Research Database
Plausible Clinical Need Laboratory monitoring Scheduling follow-up visits Contacting patients about updates No Clinical Use Hypothesis driven Consent required For publication
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Clinical Registry versus Research Database
Plausible Clinical Need Laboratory monitoring Scheduling follow-up visits Contacting patients about updates No Clinical Use Hypothesis driven Consent required For publication IRB Approval Minimal Risk Retrospective Waiver of Consent and HIPAA Research
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IRB Review of an FMT Protocol
Is FMT human research? Is an IND required Is the proposal scientifically valid? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be protected?
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Smith MB et al. Nature 2014: 506: 290-1
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Listed Fecal Transplant Trials July 27, 2014
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68 Listed Fecal Transplant Clinical Trials
Diagnosis Number of studies C difficile 19 IBD 17 Pouchitis 1 Fecal Incontinence 2 IBS Diabetes Metabolic Syndrome Chronic diarrhea Ileus Graft vs Host Incorrect Listing 21 47 47 Clinicaltrials.gov July 27, 2014
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Safety, Tolerability, and Clinical Response After Fecal Transplantation in Children and Young Adults with Ulcerative Colitis Prospective, uncontrolled, single center Grand Rapids, MI Investigator-initiated IND for fecal transplant in UC Local IRB approved Fecal retention enemas Cohort 10 children ages 7-21 Mild to moderate activity Stable on maintenance Rx for 2 months Donors Family or friends Exclusion criteria in the IND Kunde S et al. JPGN 2013: 56:
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FMT for C. difficile FDA Guidance July 2013
Enforcement discretion No IND required provided that Treating physician obtains informed consent Informed consent includes A statement that FMT for C difficile is investigational Potential risks are discussed This enforcement discretion is temporary until an FDA policy regarding FMT is implemented
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FMT and Clinical Trials
Diagnosis Number of studies C difficile 19 IBD 17 Pouchitis 1 Fecal Incontinence 2 IBS Diabetes Metabolic Syndrome Chronic diarrhea Ileus Graft vs Host IND Clinicaltrials.gov July 27, 2014
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17 IBD Studies Clinicaltrials.gov
Active, Recruiting Active Not Recruiting Completed Terminated UC 5 1 Crohn’s IBD 3 2 Pouchitis
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17 IBD Studies Clinicaltrials.gov
Active, Recruiting Active Not Recruiting Completed Terminated UC 5 1 Crohn’s IBD 3 Pouchitis
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Fecal Microbiota Transplant for IBD 9 Active Recruiting Trials
IND No IND No Response U.S. 3 Non U.S. * 5 1 *Finland, China, Netherlands, Israel
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FMT for C. difficile FDA Guidance July 2013
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
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Clinical Research Trials
Diagnosis Number of studies C difficile 19 IBD 17 Pouchitis 1 Fecal Incontinence 2 IBS Diabetes Metabolic Syndrome Chronic diarrhea Ileus Graft vs Host IND? IND
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Is and IND Required for FMT?
Yes if Maybe No 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
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Investigator Initiated IND Regulatory Burden
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Investigator Initiated IND Regulatory Burden
Safety Reports Annual Reports Any Adverse experience associated with the use of the drug that is both serious and unexpected
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Annual Report
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IRB Review of an FMT Protocol
Is FMT human research? Is an IND required Is the proposal scientifically valid? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be protected?
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Is the FMT Proposal Scientifically Valid?
Plausible Hypothesis Meaningful endpoints Sufficient statistical power Adequate resources
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Scientifically valid? Comparison Group Issues
Comparator Pro Con Placebo Power Ethics Active Feasibility Historical Easy Questionable validity
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IRB Review of an FMT Protocol
Is FMT human research? Is an IND required Is the proposal scientifically valid? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be protected?
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Risks of FMT Rubin DT Amer J Gastro 2013. 108: 1631-2
Observed Potential 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
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IRB Review of an FMT Protocol
Is FMT human research? Is an IND required Is the proposal scientifically valid? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be protected?
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Elements of Informed Consent OHRP
This is research Benefits Purpose Alternatives Duration Confidentiality Procedure details Compensation for injury Experimental procedures Whom to contact Risks Voluntary
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IRB Review of an FMT Protocol
Is FMT human research? Is an IND required Is the proposal scientifically valid? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be insured?
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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
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Recommendations for FMT Donors
Inclusion Criteria Exclusion 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-IgM C difficile toxin B HBsAg + stool culture Anti-HCV-ab + O & P HIV-EIA RPR AGA, ACG, ASGE, NASPGHAN, IDSA July 15, 2013
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FMT Research Studies Safeguarding Privacy
Recipient Donor Written informed consent HIPAA
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IRB Review of an FMT Protocol
Is FMT human research? Is an IND required Is the proposal scientifically valid? Are the risks minimized? Will potential participants receive sufficient information to make an informed decision? Will the privacy of the participants and donors be insured?
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IRB Approval for FMT Summary
The divide between FMT for clinical practice and research is complicated The FDA rules on INDs for FMT are not finalized The usual IRB concerns for human research studies apply for the: Recipient Donor
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