Unblinded Monitoring In HCV Trials, A Case For A New Standard

By Cal Astry, PhD; Marion Morrison, MD

One of the goals of a well-designed clinical study is to minimize conscious or unconscious bias by keeping principle participants (i.e., investigator, subject, and sponsor) blinded to the investigative treatment assignments. Such double-blind trials allow more robust analyses of study data and greater confidence in final interpretations—but what if the blinded study design stands in the way of standard treatment modification decisions, or compromises the safety of the subject by not permitting monitoring of key disease markers on a real-time basis?

HCV TRIALS AND THEIR CHALLENGES
Hepatitis C Virus (HCV) infects nearly 200 million people worldwide with an estimated 35,000 new cases being diagnosed in the United States alone each year. About 80 percent of all HCV infections become chronic and many progress to chronic liver disease. In a recent study, HCV infection was associated with a 77-fold increase in the risk of primary liver cancers when compared to the general population. Current standard of care (SOC) treatment for chronic HCV infection includes a 24- to 48-week course of  pegylated interferon and ribavirin, depending upon the genotype of the virus. Even so, a sustained virologic response (SVR) is achieved in only 45 percent of those with  genotype 1 HCV. Given the significant side effects associated with SOC treatment, there is a clear unfilled need for novel anti-HCV therapeutic agents—a fact reflected in the more than 350 HCV active clinical trials in the United States.

The goal of current HCV clinical research is to identify new antiviral agents specifically targeting hepatitis C (STAT-C therapies) and to determine how best to individualize treatment regimens in order to optimize outcomes (i.e., increase the SVR rate) and minimize both drug toxicity and the development of resistance. Further consideration must be given to the very heterogeneous nature of the HCV population. Variables such as viral genotype, IL28B polymorphism, baseline viral load, degree of liver damage, and prior history of HCV treatment can result in differing viral response rates.

The challenge to individualizing treatment strategies is to keep all of these variables in mind while carefully monitoring individual treatment response so that, ultimately, shorter durations and lower dose regimens are utilized for rapid responders while reserving longer durations and higher dose regimens for those patients responding more slowly.