Chronic Hepatitis D: FDA Drafts Drug Development Guidance

Regulatory NewsRegulatory News | 31 October 2019 |  By 

With no drugs currently approved to treat chronic hepatitis D (HDV), the US Food and Drug Administration (FDA) on Thursday issued draft guidance laying out recommendations for developing new treatments.
In an overview of current chronic hepatitis D management, authors Patrizia Farci, chief of the Hepatic Pathogenesis Section of the Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases and Grazia Niro, staff clinician at IRCCS Casa Sollievo Sofferenza Hospital write that “although significant advances have been made in the treatment of chronic viral hepatitis over the past decade, targeting HDV remains a major challenge because of the unconventional nature of the virus and the severity of its disease.”
According to FDA, HDV infection only occurs with concurrent hepatitis B virus (HBV) infection and is associated with more severe liver disease relative to HBV monoinfection. Global estimates of HBV/HDV coinfection range from 15-20 million to 62-72 million, with FDA noting that US prevalence is thought to be low.
The 17-page draft guidance provides advice to sponsors on stages of development ranging from nonclinical development through Phase III studies.
FDA explains that because there are no approved treatments for chronic HDV and the disease is serious and life-threatening, investigational drugs may be eligible for fast track, breakthrough therapy and priority review designations.
For Phase III efficacy studies, FDA says it would prefer to see sponsors conduct a double blind, placebo-controlled trial, but suggests several potential alternative trial designs, including a three-arm randomized controlled trial that includes pegylated interferon-α, which is commonly used to treat HDV, as a comparator in addition to a placebo.
Once a drug is approved to treat the disease, FDA says a randomized controlled superiority or noninferiority trial using an active comparator would be appropriate.
While FDA notes that “no surrogate endpoints have been definitively shown to predict clinical benefit,” the agency anticipates that sponsors will seek accelerated approval for initial candidates based on a surrogate endpoint reasonably likely to predict clinical benefit.
FDA offers one potential surrogate endpoint that could be used to support accelerated approval to treat chronic HDV: “The proportion of trial patients with undetectable serum HDV RNA (defined as less than the lower limit of quantification (LLOQ), target not detected (TND)) and [alanine aminotransferase] ALT normalization.”
The agency also offers a second surrogate endpoint that could potentially be used to support accelerated approval of a chronic suppressive therapy for HDV: “a greater than or equal to 2-log10 decline in HDV RNA and ALT normalization on-treatment.”
FDA suggests sponsors request a Type C formal meeting to discuss the use of a novel surrogate endpoint and says its preferred endpoints for confirming efficacy via long-term follow-up include decrease in progression to cirrhosis, progression to decompensated liver disease, liver transplantation, hepatocellular carcinoma and liver-related death.


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