Quality of transurethral resection of bladder tumor procedure influenced a phase III trial comparing the effect of KLH and mitomycin C

BACKGROUND Retrospective analysis of Center effect of the multi-center trial conducted to compare Immucothel (KLH Immunotherapy drug product) with Mytomycin-C (MM) concluded that efficacy evaluation of the drug product may be impacted by physician's subjective performance of Transurethral resection of bladder tumor (TURBT). METHODS A randomized trial was performed in 18 hospitals (clinical centers) and a total of 553 recruited, 283 patients under KLH arm and 270 patients under MM. An initial statistical analysis of efficacy comparisons between KLH and MM based on log-rank test performed for each center (hospital) showed 6 hospitals out of 18 hospitals a p-value of <0.05 and remaining 12 hospitals showed a p-values of >0.05. No association was observed between number of patients analysed and the associated p-values across hospitals. Final statistical analyses were carried out under each drug product using Kaplan-Meier survival analysis along with log-rank test after combining all eligible patients data for 6 hospital group and 12 hospital group. RESULTS Median recurrence free survival (RFS) times (in weeks) showed statistical significance (p-value = 0.03) between two groups of hospitals under KLH arm, while similar median values showed no statistical significance (p-value = 0.05). CONCLUSION Center effect with respect to median RFS values under KLH was more pronounced than under MM. Under the presence of such center effect, for reasons other than product related effects, concluding superiority of one drug product over another may create confounding bias conclusions in multi-center clinical trials. In the above cited clinical trial study, physician's prior experience on TURBT might have contributed to center effect in examining efficacies of KLH and MM. Similar observation was also noted in the literature on studies dealing with TURBT and in other clinical studies. TRIAL REGISTRATION Data set used in this study is based on previously documented clinical trial in the literature: See (Lammers et al., J Clin Oncol 30:2273-9, 2012) and Acknowledgments.