Gary D. Wu, M.D Ferdinand G. Weisbrod Professor of Medicine Division of Gastroenterology Perelman School of Medicine University of Pennsylvania Professional.

Gary D. Wu, M.D

Ferdinand G. Weisbrod Professor of MedicineDivision of GastroenterologyPerelman School of Medicine

University of Pennsylvania

Professional Societies, Advocacy, and the Gov’t-How do we get along?

The AGA Center for Gut Microbiome Research & Education

The Center’s Mission Statement

To advance research and education on the gut microbiome in human health and disease.

The Center will serve as the focus of all AGA activities and programs in this field and will be built around the pillars of the AGA Strategic Plan: Research-Education-Advocacy-Practice.

AGA Microbiome Scientific Advisory Board

Provides guidance to AGA Board on scientific matters relevant to the microbiome: strategic direction, topic and programmatic priorities, program participants. Eight members representing:

Computational biology Metagenomics Animal models Microbiology Translational research Nutrition and obesity Motility Pediatrics Clinical Practice (FMT) Regulatory and policy

issues

Members: Gary D. Wu, MD, SAB Chair, University of

Pennsylvania, Philadelphia, PA Martin J. Blaser, MD, New York University,

New York, NY Gail A. Hecht, MD, Loyola University,

Maywood, IL Purna Kashyap, MD, Mayo Clinic,

Rhochester, MN Colleen Kelly, MD, Brown University,

Providence, RI Lee M. Kaplan, MD, PhD, Harvard

University/MGH, Boston, MA Rob Knight, PhD, University of Colorado,

Boulder, CO Loren Laine, MD, Yale University, New

Haven, CT Mary Ellen Sanders, PhD, Consultant,

Centennial, CO R. Balfour Sartor, MD, University of North

Carolina, Chapel Hill, NC Phillip Tarr, MD, Wash. Univ., St. Louis, MO Ex officio mbrs: Council chair; GB basic

science councillor

Fecal Microbiota Transplantation (FMT), a Success Story for the Treatment of Refractory CDI—But with a Note of Caution

Prescreening of donors to prevent transmission of currently known pathogens

Homogenization, filtration, and administration usually through a colonoscope.

• Success rate of around 90% when fecal microbiota transplantation (FMT) is used to treat CDI

• Currently over 500 cases reported in the literature• Placebo-controlled clinical trial: Duodenal Infusion of Donor Feces

for Recurrent Clostridium difficile. N Engl J Med 2013; 368:407-41

Response of the Microbiome Center SAB to Issues Related to FDA FMT IND for CDI

• May 2013: Notification of AGA membership that an IND was required for FMT used for any indication including the treatment of refractory CDI. Emergency use IND hotline provided to membership.

• Nine member committee established (5 AGA, 2 NASPGHAN, 2 IDSA) to provide feedback to FDA regarding IND for FMT.

• FDA issues “regulatory restraint” on use of FMT for CDI—AGA membership notified of decision.

• AGA committee develops “Current Consensus Guidance on Donor Screening and Stool Testing for FMT” document for FDA together with IDSA, NASPGHAN, ACG, and ASGE.

Although the short-term infectious risks of FMT seem to be definable and quantifiable, we should remember the entire generation of patients infected with HCV by blood transfusion before this pathogen was identified.

The field should move cautiously because the long-term consequences of FMT in humans are unknown.

• The gut microbiome contains a highly complex and dense community of microbes that include bacteria, fungi and viruses, many of which have not been fully characterized.

• It is a dynamic and living consortium that can change over time in ways that scientists cannot currently fully predict.

• Animal model data suggests that the gut microbiome may play a role in the pathogenesis of several human diseases.

“You Shouldn’t Do it Just Because You Can—Caution about FMT and the Need for Regulation

Normon et al. Gastro 2014

Bacteria

Viruses

FungiArchaea

CompetitionSyntro

phy

Enhanced Pathogenicity

Predator-PreyRelationship

“A How to Guide: Investigational New Drug Application for Fecal Microbiota Transplantation” Colleen R. Kelly, MD; Sachin S. Kunde, MD, MPH; Alexander Khoruts, MD

Clinical Gastroenterology and Hepatology

What's the Value of an FDA IND for Fecal Microbiota Transplantation in Clostridium difficile Infection?

Gail A. Hecht, MD, MS and Members of the SAB for the AGA Center for Gut Microbiome Research and Education

Clinical Gastroenterology and Hepatology

AGA-Sponsored Webinar: In planning stages

Publications on FMT for the Clinician

•FMT is a window into the biology of the gut microbiome in humans:• Translation of findings in animal models into human biology.• Understand the long term consequences of manipulating the gut microbiota in humans

FMT and the Treatment of Type 2 Diabetes

The Scientific Value of FMT

•The success of FMT in the treatment of CDI is “proof of principle” that the dysbiotic human microbiota can be modified to treat disease.

•Emphasizes the importance of using a resilient microbial community to modify dysbiosis.

The Future of FMT: Transplantation of Defined Microbial Communities

•Customization of consortium membership of bacteria with specific biological properties to produce predictable responses and reduce both short- and long-term adverse outcomes

•Laboratory defined conditions prevent pathogen transmission

•Development of standardized conditions for the transplantation (inoculation) and maintenance of the community

•Durable communities that are resilient to change

Human Intervention Studies

Animal Models(functional data)

Human Association Studies

Novel TherapeuticsNext generation pre-, pro-, synbiotics

FMT for CDI

Past/Current Status of the field: “Safe” traditional view.

Future status of the field: Higher risk but higher reward.

Evolution of the microbiom

e fieldEvolution of Microbiome Research

The Progression of Science, Reduction to Practice, and Development of New Gut Microbiota-Based Products

Yes Likely Yes Possibly YesLawley TD PLoS Pathog. 2012;8(10):e1002995

Petrof EO. Microbiome. 2013 Jan 9;1(1):3

CDI

+ ++ +++Safety

? ?Other diseasesFocus of

technology development

Goals of the FMT Registry• To gather information on practice in the U.S. and assess effectiveness of the intervention.• To assess short-term and long-term safety. • To aid practitioners and sponsors in satisfying regulatory requirements.• To promote scientific investigation.

FMT Processed Fecal Products

Defined Microbial Consortia

Evolution of Scientific and Product

Development

Initiation Sustainability

A National FMT Registry

FMT RegistryNIH NIAID Application for a

R24 (resource related research project)

AGA Registry expertise with a CRO (ACI

Clinical)

BiobankStool/microbial products

Penn-CHOP Microbiome

Initiative

•AGA Microbiome Center Scientific Advisory Board• Infectious Disease Society of America (IDSA)

• NASPGHAN• CCFA

Academia, CDC, NIH and Other (i.e. Industry)

Basic and clinical investigation, product development

FDA Oversight of FMT, Stool-based

products, and “next generation” probiotics

Professional SocietiesClinical practice standards (efficacy/safety), liability,

reimbursement

Thank You