European Regulators Update Hepatitis C Clinical Trial Guideline

Recent advances in the field of hepatitis C therapy has prompted the European Medicines Agency to update its guideline for designing clinical trials on investigational direct-acting antiviral drugs that target chronic infection of the virus.

The updated draft replaces the 2008 Guideline on the clinical evaluation of direct acting antiviral agents intended for treatment of chronic hepatitis C, prepared by the EMA’s Committee for Medicinal Products for Human Use, according to the EMA website. Many of the new hepatitis C drugs do not always require use of interferon, which was standard treatment eight years ago when the guideline was last updated.

“Since 2013 direct-acting antivirals (DAAs) have been approved for the treatment of chronic HCV infections within interferon-free combination regimens,” states the EMA guideline executive summary. “Therefore this revision of the prior guidance concerns the development of DAA-only regimens.”

Newer DAA drugs approved to treat hepatitis C work faster and have higher cure rates than previous regimens. Approved in late 2013, Sovaldi developed by Gilead Sciences and other DAA drugs also tend to have fewer serious side effects, which in the past may have prompted some patients with the virus to avoid treatment.

Millions of people worldwide are infected with hepatitis C, a bloodborne virus that if left untreated can seriously damage the liver and lead to cirrhosis or cancer of the liver or the need for a liver transplant. In Europe the vast majority of cases are among patients who underwent blood transfusion before 1991 and people with ongoing or previous intravenous drug abuse, according to the 19-page updated guideline.

Key elements in the update address hepatitis C genotypic resistance testing, drug interactions with HIV medications, and defining sustained virological response. Informative study design for pivotal trials is also discussed.

“The primary endpoint in clinical trials aiming at viral clearance should be sustained virological response defined as plasma HCV RNA below the lower limit of quantification of the assay (LLOQ) 12 weeks after the planned end of therapy (SVR12),” states the guideline. “There should be further follow-up to confirm the durability of response for novel drug regimens.”

The guideline calls for use of a randomized controlled study design that incorporates an active comparator arm. This type of trial design is generally needed to document efficacy in particular if a DAA is under development as an add-on to an established drug combination or to substitute a drug component, according to the executive summary.

The drug-drug interaction profile of a new DAA or fixed dose combination should be characterized with a focus on co-medications that target HIV infection. Clinical studies should be designed to assess possible interactions with HIV drugs in situations where a relevant interaction with an important co-treating agent can’t be excluded with in vitro studies, according to the guideline.

Background information included in the guideline states that about 30% of HIV-infected patients also are infected with the hepatitis C virus in both Europe and the United states. In some regions the percentage is as high as 50%.

The deadline for public comment on the draft guideline is Dec, 31, 2016.