IRB Approval for FMT What does an IRB look for

in FMT Protocols?

William Tremaine, M.D. Mayo ClinicRochester, MN

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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?

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, …

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

Clinical Registry versus

Research Database

Clinical Registry Research Database

Plausible Clinical Need Laboratory monitoring Scheduling follow-up visits Contacting patients about updates

No Clinical Use Hypothesis driven Consent required For publication

Clinical Registry versus

Research Database

Clinical Registry Research 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 ApprovalMinimal RiskRetrospectiveWaiver of Consent and HIPAA

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?

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

Listed Fecal Transplant TrialsJuly 27, 2014

68 Listed Fecal Transplant Clinical Trials

Diagnosis Number of studies

C difficile 19

IBD 17

Pouchitis 1

Fecal Incontinence 2

IBS 2

Diabetes 1

Metabolic Syndrome 1

Chronic diarrhea 2

Ileus 1

Graft vs Host 1

Incorrect Listing 21

Clinicaltrials.gov July 27, 2014

4747

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: 597-601

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

FMT and Clinical Trials

Diagnosis Number of studies

C difficile 19

IBD 17

Pouchitis 1

Fecal Incontinence 2

IBS 2

Diabetes 1

Metabolic Syndrome 1

Chronic diarrhea 2

Ileus 1

Graft vs Host 1

Clinicaltrials.gov July 27, 2014

IND

17 IBD Studies Clinicaltrials.gov

Active, Recruiting

ActiveNot Recruiting

Completed Terminated

UC 5 1 1

Crohn’s 1 1

IBD 3 2 1

Pouchitis

1

17 IBD Studies Clinicaltrials.gov

Active, Recruiting

ActiveNot Recruiting

Completed Terminated

UC 5 1 1

Crohn’s 1 1

IBD 3 3 1

Pouchitis

1

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

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

Clinical Research Trials

Diagnosis Number of studies

C difficile 19

IBD 17

Pouchitis 1

Fecal Incontinence 2

IBS 2

Diabetes 1

Metabolic Syndrome 1

Chronic diarrhea 2

Ileus 1

Graft vs Host 1

IND

IND?

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

Investigator Initiated INDRegulatory Burden

Investigator Initiated INDRegulatory Burden

Safety Reports Annual Reports

Any Adverse experience associated with the use of the drug that is both serious and unexpected

Annual Report

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?

Is the FMT Proposal Scientifically Valid?

• Plausible Hypothesis

• Meaningful endpoints

• Sufficient statistical power

• Adequate resources

Scientifically valid?Comparison Group Issues

Comparator Pro Con

Placebo Power Ethics

Active Ethics Feasibility

Historical Easy Questionable validity

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?

Risks of FMT

Observed Potential

Abdominal discomfortBloatingFlare of ulcerative colitis Fever Worse diarrhea Increased CrP Orthostasis Pancreatitis

HepatitisHIVAutoimmune diseasesObesity

Rubin DT Amer J Gastro 2013. 108: 1631-2

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

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?

Elements of Informed ConsentOHRP

This is research Benefits

Purpose Alternatives

Duration Confidentiality

Procedure details Compensation for injury

Experimental procedures Whom to contact

Risks Voluntary

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?

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

Recommendations for FMT Donors

Inclusion Criteria Exclusion Criteria

Intimate longtime partnerAdult first degree relativeClose family friendWell-screened universal donor

Antibiotic use in < 3 monthsKnown GI diseaseAutoimmune or atopic illnessChronic pain syndromeMetabolic Syndrome or malnutritionHistory 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

FMT Research StudiesSafeguarding Privacy

Recipient Donor

Written informed consent Written informed consent

HIPAA HIPAA

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?

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