Regulatory Perspectives From FDA Staff

Presented at The Liver Forum #5, November 2016, Boston, MA

Participation by Brian E. Harvey, MD, PhD

This is a summary of the important concepts and current regulatory thinking presented by FDA Medical Officer Dr. Lara Dimick-Santos at the most recent Liver Forum held just prior to the American Association for the Study of Liver Diseases (AASLD) Meeting.  The Liver Forum is an opportunity to bring together individuals from academics, government, industry, as well as medical practitioners and patient advocates, to learn about the current state of research in various liver diseases, as well as discuss potential paths forward for increasing knowledge of liver disease pathophysiology that help generate data supporting the development of safe and effective treatments.

This FDA presentation focused upon Non-Alcoholic Steatohepatitis (NASH), with an emphasis on appropriate clinical trial design that may increase the odds for generating data that will meet the FDA threshold for drug or biologic product approval.  The critical aspect of this is the choice of endpoints for the proposed pivotal clinical trial.  There are several potential pathways which involve the use of traditional clinical endpoints, intermediate clinical endpoints, as well as surrogate endpoints reasonably likely to predict clinical benefit in patients (  Dr. Dimick-Santos provided examples of traditional clinical endpoints such as “Reduction in All-Cause Mortality”, “Prevention of Liver Transplantation” (e.g., MELD Score Increase to 15 from less / equal to 12 = listing for liver transplant) and “Reduction of Decompensation Events” (


The FDA examples for potential surrogate endpoints for NASH were Complete Resolution of Steatohepatitis and No Worsening of Liver Fibrosis and “at least 1 point improvement in fibrosis using the Brunt/Kleiner Scale ( and no worsening of steatohepatitis, defined as no increase in ballooning or inflammation on NAS Score” (  A surrogate reasonably likely to predict clinical benefit could be used as the basis of an Accelerated Approval by FDA.  However, the Accelerated Approval must be followed by a Verification Trial with a traditional clinical endpoint.  A potential alternative for verification is a “seamless” Phase 3 / 4 design where patients are rolled over at the end of Phase 3 into a Phase 4 verification trial. 


When a sponsor is deciding between conducting one or two pivotal trials to support product approval, the following perspective is important to consider.  In order for one Phase 3 trial to be persuasive, the following FDA Guidance “Providing Clinical Evidence and Effectiveness for Human Drug and Biologic Products for Human Drug and Biologic Products” was referenced:  “Generally limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity, or prevention of a disease with potentially serious outcome and conformation of the results in a second trial would be practically or ethically impossible” (  Specifically, there should be a large, multicenter trial, with internal consistency across study sites, with evidence of an effect on multiple endpoints and statistically very persuasive efficacy results (“robust p value”).   


If a sponsor is planning for the Accelerated Approval pathway using two (2) seamless Phase 3 / 4 trials, then the following statistical considerations will be applied by FDA reviewers.  The alpha (α) must be controlled at or below 0.05 for each of the Phase 3 / 4 trials.  For example, for α = 0.01 for Phase 3 (Liver Histology based Endpoints), then α must be less than 0.04 for Phase 4 (Traditional Clinical Endpoints).  However, if the Sponsor is planning only one (1) seamless Phase 3 / 4 Trial to submit for FDA Approval, then the overall α less than 0.05 and split between Phase 3 (α << 0.05) and Phase 4 (α << 0.05)  (

A current example of a sponsor following this FDA advice is Intercept Pharmaceuticals in its development programs for NASH “Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment (REGENERATE)” (


In conclusion, the understanding and treatment of Liver Disease is a work in progress, despite recent success with Hepatitis C cures.  The next Liver Forum 6 will be held on Tuesday, April 18th, 2017 in Amsterdam.  Details will be provided when available at the website below (