BACKGROUND: Torcetrapib was spectacularly withdrawn in December 2006, when a Phase III clinical trial showed increased cardiovascular adverse events. OBJECTIVE: To consider possible reasons why the development of torcetrapib proceeded so far before adverse events became apparent. METHOD: Published preclinical and clinical data for torcetrapib are reviewed. RESULTS/ CONCLUSIONS: It seems likely that independent preclinical testing would have shown that torcetrapib increased blood pressure. Such a finding might have halted the development of torcetrapib prior to clinical trial. Although the early clinical testing of torcetrapib showed favourable effects on the surrogate endpoints, an ability to increase blood pressure started to become apparent. When clinical outcome studies were undertaken with torcetrapib, it was shown not to have any benefit on atherosclerosis and to increase cardiovascular events. These finding might have come to light earlier if clinical outcomes studies had had a higher priority than repeated trials, in different populations, of torcetrapib on surrogate outcomes.
BACKGROUND:Torcetrapib was spectacularly withdrawn in December 2006, when a Phase III clinical trial showed increased cardiovascular adverse events. OBJECTIVE: To consider possible reasons why the development of torcetrapib proceeded so far before adverse events became apparent. METHOD: Published preclinical and clinical data for torcetrapib are reviewed. RESULTS/ CONCLUSIONS: It seems likely that independent preclinical testing would have shown that torcetrapib increased blood pressure. Such a finding might have halted the development of torcetrapib prior to clinical trial. Although the early clinical testing of torcetrapib showed favourable effects on the surrogate endpoints, an ability to increase blood pressure started to become apparent. When clinical outcome studies were undertaken with torcetrapib, it was shown not to have any benefit on atherosclerosis and to increase cardiovascular events. These finding might have come to light earlier if clinical outcomes studies had had a higher priority than repeated trials, in different populations, of torcetrapib on surrogate outcomes.