The Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) issued draft recommendations for sponsors looking to develop drugs to treat nonalcoholic steatohepatitis (NASH) with compensated cirrhosis.
NASH is associated with a range of common diseases, including type 2 diabetes, hypertension and obesity, among others. “It is a growing public health concern and is anticipated to be the leading cause of liver transplantation within a decade,” the agency says
. But “no standard treatment exists for NASH.”
The guidance follows a separate draft guidance
issued in December that provides recommendations for early NASH drug development and developing drugs to treat noncirrhotic NASH.
To aid sponsors of drugs to treat compensated NASH cirrhosis during clinical development, the draft guidance details the agency’s current recommendations regarding components of phase 3 programs.
Specifically, the guidance details patient enrollment criteria, clinical trial design, efficacy endpoints and safety considerations for phase 3 trials.
FDA emphases that sponsors should only enroll patients in phase 3 clinical trials whose cirrhosis is secondary to NASH and should rule out other causes of chronic liver disease, such as alcoholic liver disease, viral hepatitis and Wilson’s disease.
The guidance also provides recommendations for diagnosing patients with compensated cirrhosis and for excluding patients with decompensated cirrhosis, among other enrollment criteria.
FDA says that sponsors should evaluate drugs to treat compensated NASH cirrhosis in randomized, placebo-controlled, double-blind clinical trials, and recommends that sponsors should discuss proposed stratification factors with the agency before beginning phase 3 trials.
For efficacy endpoints, FDA says sponsors should “evaluate the effect of the investigational drug relative to placebo on the composite endpoint of time from randomization to the first of any one of” six outcomes, including complication of ascites, variceal hemorrhage, hepatic encephalopathy, worsening in the Model for End-State Liver Disease (MELD) score, liver transplantation or death from any cause.
The agency says it “strongly recommends clinical outcome trials to support a marketing application.” Yet a drug for the treatment of NASH cirrhosis will likely undergo FDA evaluation through the traditional approval pathway due to a current lack of evidence to support an FDA accelerated approval.