December 18, 2013

Beyond phase 3 registration trials: defining safety for triple therapy with protease inhibitors in cirrhosis

Gut doi:10.1136/gutjnl-2013-306480


P Ferenci1, G Dusheiko2

+ Author Affiliations

Correspondence toDr Peter Ferenci, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Wien A 1090, Austria;

Received 22 November 2013
Accepted 26 November 2013
Published Online First 13 December 2013

Clinical trials are the standard method for evaluating a new drug for treatment of disease in humans. The phase 3 trial is designed to evaluate a new agent's clinical benefit and possible side effects; as such, it is considered to be the definitive test of the agent's usefulness. While there is no substitute for well-designed phase 3 trials, one should be aware of their limitations.1 Usually, the protocols use very strict selection criteria, creating ‘ideal’ patients, not necessarily reflecting the patient population seen by treating physicians. Good examples were the phase 3 studies for treatment of chronic hepatitis C by triple therapy with peginterferon/ribavirin (PEGIFN/RBV) and a first-generation protease inhibitor (telaprevir or boceprevir). All studies2–5 showed that this treatment augments cure rates substantially but failed to include sufficient patients with the highest need for an effective antiviral therapy, namely patients with advanced cirrhosis.6 In all studies, histologic grades F3 and F4 (according to the METAVIR classification) were grouped as ‘advanced fibrosis’. It should be stressed that F3 is not yet cirrhosis, and F4 is not the same as clinically symptomatic cirrhosis with portal hypertension. …

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