The challenges of new drugs benefits and risks analysis: lessons from the ximelagatran FDA Cardiovascular Advisory Committee.

Ximelagatran is a new oral anticoagulant that acts by direct and reversible inhibition of thrombin and has the potential to replace warfarin. In 2004, the FDA Cardiovascular and Renal drug Advisory Committee (CRAC) reviewed the ximelagatran clinical program. Three indications were proposed: the prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement surgery (TKR), the prevention of stroke and other thromboembolic complications associated with atrial fibrillation (AF), and the long-term secondary prevention of VTE after standard treatment of an episode of acute VTE. The database consisted of a total of 30,698 subjects and included five phase III pivotal studies. During the advisory panel debate, widely divergent analyses of the benefits and risks of ximelagatran were presented. Ximelagatran hepatic toxicity was a key feature leading the CRAC to conclude that the benefit risk ratio of ximelagtran was unfavorable for the three proposed indications. Some design issues also undermined the strength of efficacy data. This paper reviews the benefits and risks of ximelagatran and analyzes the reasons leading to conflicting conclusions among various experts. The aim of this review is to facilitate the interpretation of benefits and risks associated with a new drug product and to improve future clinical drug developments.