FDA: New Approaches for Fatty Liver Clinical Trials

December 10, 2018

The FDA is encouraging fatty liver disease researchers to come up with new biomarkers for clinical trials to avoid invasive — and potentially dangerous — biopsies that drive away many would-be participants.

“The use of liver biopsies in clinical trials poses significant logistical challenges,” the agency says in new draft guidance. “Therefore, noninvasive biomarkers are needed (including imaging biomarkers) to supplant liver biopsy and provide a comparable or superior ability to accurately diagnose and assess” chronic inflammation or nonalcoholic steatophepatitis (NASH).

Nonalcoholic fatty liver disease can progress over years from fat in the liver to chronic fibrosis to cirrhosis. Only a fraction of NASH patients with liver fibrosis ever develop full-blown cirrhosis, but the FDA says there are no clear criteria to identify that slice of the population and last week’s draft guidance is an early move to help bring clarity to the regime.

It’s also an encouraging step, says Lindsay McNair, chief medical officer at WCG.

“Potential research participants may be understandably reluctant to enroll in studies which include multiple uncomfortable biopsy procedures, each involving procedural risks,” she tells CenterWatch. “We’re pleased to see the FDA again state the need for non-invasive methods to assess liver disease and to encourage sponsors to look for biomarker endpoints.”

Fibrosis is considered the strongest predictor of poor outcomes — including death — in fatty liver disease, so sponsors should probably start there, the FDA says.

Drugs intended to treat NASH should follow double-blind, placebo-controlled protocol designs. Because inflammation moves slowly, sponsors should focus on shorter-term endpoints, including either a combination of reducing inflammation and keeping fibrosis in check or slowing fibrosis and keeping a lid on inflammation.

The FDA tailored its recommendations to different trial phases.

For early Phase II trials, the agency says it recognizes that proof-of-concept trials are attractive to sponsors but stresses they have to provide “adequate rationale and justification” for their design, including enrollment criteria, duration of trials and choice of endpoints.

Researchers may not need baseline studies of damaged tissues, depending on the trial’s endpoints, but sponsors should make sure that “these early trials capture the same or similar patient populations as those planned for the Phase III development programs.”

Sponsors should also test multiple dose levels in the early stages of a Phase II trial, the draft doc says.

They should shift gears and zero in on damaged tissue if they prove — late in Phase II trials — that a drug works on its target population. A drug can move on to Phase III trials if:

  • It hits histological endpoints, such as reducing inflammation or improving liver fibrosis;
  • Researchers document its effects and variability among patients — and dose response; and
  • The Phase II trial has been given enough time, typically at least a year to 18 months (unless sponsors can “provide clear scientific justification” for a shortened study), to produce results.

Sponsors should also be prepared to design a biomarker strategy late in Phase II trials.

The draft guidance says sponsors should think carefully about inclusion and exclusion criteria for Phase III trials, noting that, in most cases, patients should have been diagnosed with NASH plus fibrosis no more than six months before they enroll in a trial.

Patients with high inflammation activity scores, high Model for End-Stage Liver Disease scores or a documented history of Gilbert’s syndrome can also be included, the FDA says.

The protocol should be clear about exclusion criteria and evidence of portal hypertension — and patients with liver enzyme levels more than five times the upper limit of normal should be excluded from Phase III trials. Ditto patients with other chronic liver diseases.

Read the draft guidance here: 

-By Bill Myers