Liver Forum Cirrhosis Working Group Arun J. Sanyal

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Delilah Norton
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1 Liver Forum Cirrhosis Working Group Arun J. Sanyal Z Reno Vlahcevic Professor of Medicine VCU School of Medicine Richmond, VA

2 2 Liver Forum 8 DRUG DEVELOPMENT PATHWAYS Regular approval pathway: based on demonstration of clinically meaningful benefit: Clinical outcomes that affect patient survival, functional status or quality of life Use of surrogates generally accepted to reflect a meaningful change in health status

3 3 Liver Forum 8 CLINICALLY MEANINGFUL BENEFIT Based on how a patient feels: symptoms quality of life Based on how a patient functions: functional status (impairment or improvement in ability to lead a normal active life) Based on how a patient survives: survival liver-related outcomes rates of hospitalization (resource utilization)

4 4 Liver Forum 8 DRUG DEVELOPMENT PATHWAYS Accelerated pathway (subpart H) Based on use of surrogate endpoints that are reasonably likely to reflect changes in clinically meaningful outcomes Requires post-approval completion of long-term study to objectively document improvement in clinically meaningful outcomes or changes in surrogates generally accepted to reflect changes in clinically meaningful outcomes.

5 5 Liver Forum 8 SURROGATE ENDPOINTS Generally accepted Substantial body of literature available Quality of data is strong Surrogate should reflect: Survival Other clinical outcomes Surrogate should have: Content and face validity Sensitivity to change Reasonably likely Less amount of data available Quality of data not as strong Surrogate should have: Reasonable likelihood of reflecting change in health status based on its relationship to biology of disease Sensitivity to change Biomarkers that are still under development are unlikely to be accepted as endpoints

6 6 Liver Forum 8 THE FDA-AASLD NASH WORKSHOP 2013: A TURNING POINT Two major barriers to therapeutic development for NASH are: lack of noninvasive tools to evaluate the disease lack of a clear regulatory pathway for drug or diagnostics approval for NASH

7 7 Liver Forum 8 CONCEPT OF THE LIVER FORUM A platform for ongoing multi-stakeholder dialogue to identify barriers, prioritize research and identify solutions to accelerate therapeutic development for NASH and progressive fibrosis

8 8 Liver Forum 8 LEVERAGING THE DRUG RESISTANCE ACTION GROUP TO FORM THE LIVER FORUM Regulatory Agencies FORUM FOR COLLABORATIVE RESEARCH Veronica Miller Professional Organizations (AASLD-EASL) Patients FORUM Arun Sanyal KOLs Industry Academia VIRGINIA COMMONWEALTH UNIVERSITY

9 9 Liver Forum 8 THE LIVER FORUM TIMELINE FDA-AASLD Workshop Conception of Liver Forum FDA and EMA Approval Steering committee formed Liver Forum Launched First 2 Working Groups Pediatric Working Group SOC Working Group Biomarker Workshop Baseline Parameters Published Case Definitions Published New Regulatory Agencies Cirrhosis Working Group

10 10 Liver Forum 8 HOW REGULATORY SCIENCE DIFFERS FROM TRADITIONAL SCIENCE Defining the population: is this the right population for a given drug and MOA are there subpopulations with different risk profiles are there standardized, implementable case definitions that are translatable to practice Additional forum perspective- what is the burden to patient for diagnostics and burden to payer and what is the value proposition for the diagnostic Endpoints: Clinically meaningful or surrogate Biological plausibility Objective or subjective Quantifiable Robustness of measure Sensitive to change Best practices in interpreting changes in the endpoint

11 11 Liver Forum 8 POTENTIAL UNMET NEEDS Defining the populations and aligning with natural history - case definitions (from regulatory perspective) - alignment with biology - alignment with clinical course - rigorous analysis of the validity of methods Defining clinically meaningful benefit Developing endpoints: is mortality a good endpoint?

12 Liver Forum 8 AGENDA FOR TODAY Review key unmet needs and identify top two priorities for the working group (compensated and decompensated cirrhosis working

12 12 Liver Forum 8 AGENDA FOR TODAY Review key unmet needs and identify top two priorities for the working group (compensated and decompensated cirrhosis working groups) Rules of engagement: composition of working groups integration of activities how multi-stakeholder consensus is developed policies establish timelines and milestones

NASH Regulatory Landscape. Veronica Miller, PhD Forum for Collaborative Research UC Berkeley SPH

NASH Regulatory Landscape. Veronica Miller, PhD Forum for Collaborative Research UC Berkeley SPH NASH Regulatory Landscape Veronica Miller, PhD Forum for Collaborative Research UC Berkeley SPH Disclosures Liver Forum sponsors (last slides) Advisory (Sanofi) Miller_July 7_2017 www.forumresearch.org