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Saturday, April 16, 2016

ICON-6: the danger of changing study design midstream - Comment

The Lancet


.... Most importantly, we must do everything we can as clinical trialists to reassure the patients and the public that their participation is always considered with the utmost care and constant vigilance around the emerging risk–benefit ratio, and never taken for granted. To get patients to participate in research is already challenging, and we are too permissive of stakeholders changing their minds midstream.....
 Jonathan Ledermann and colleagues1, 2 report the ICON-6 randomised trial findings for the tyrosine kinase inhibitor cediranib in relapsed platinum-sensitive ovarian cancer. Cediranib offered the prospect of improved efficacy with tolerable side-effects, and ICON-6 was a pragmatic trial to provide real-world evidence of the effectiveness, safety, and acceptability of cediranib plus chemotherapy (either concurrent or concurrent plus maintenance as long as patients were deriving benefit), compared with chemotherapy plus placebo. ICON-6 found ”meaningful improvement in progression free survival”2 (hazard ratio 0·56, 95% CI 0·44–0·72) for concomitant plus maintenance cediranib compared with placebo, as well as significantly more diarrhoea, hypothyroidism, and voice changes. However, after unexpected and major design changes were enforced, we still await data for overall survival; the safety data are less informative than might be necessary, and there are no convincing data yet for patient acceptability and quality of life, which can be particularly relevant to inform trade-offs between improved efficacy and increased side-effects. These design changes should not have been necessary, and clinical trials should be better structured to make sure this does not recur.....


  1. Ledermann J, Perren TJ, Raja FA, et al. Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: results of the ICON6 trial. European Cancer Congress; Amsterdam, Netherlands; Sept 27–Oct 1, 2013. Abstr 10.
  2. Ledermann, JA, Embleton, AC, Raja, F..., and on behalf of the ICON6 collaborators. Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016; 387: 1066–1074


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