Comparison of treatment effect from randomised controlled phase II trials and subsequent phase III trials using identical regimens in the same treatment setting

Fei Liang; Zhenyu Wu; Miao Mo; Changming Zhou; Jie Shen; Zezhou Wang; Ying Zheng

doi:10.1016/j.ejca.2019.08.006

Comparison of treatment effect from randomised controlled phase II trials and subsequent phase III trials using identical regimens in the same treatment setting

Eur J Cancer. 2019 Nov:121:19-28. doi: 10.1016/j.ejca.2019.08.006. Epub 2019 Sep 14.

Authors

Fei Liang¹, Zhenyu Wu², Miao Mo³, Changming Zhou³, Jie Shen³, Zezhou Wang³, Ying Zheng³

Affiliations

¹ Clinical Statistic Center, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
² Department of Biostatistics, School of Public Health, Key Laboratory of Public Health Safety and Collaborative Innovation Center of Social Risks Governance in Health, Fudan University, Shanghai, 200032, China.
³ Clinical Statistic Center, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.

PMID: 31526874
DOI: 10.1016/j.ejca.2019.08.006

Abstract

Purpose: We aimed to determine whether treatment effect size differed between randomised controlled phase II trials and subsequent phase III trials and examine potential predictor of positive phase III trials.

Methods: We searched MEDLINE for randomised controlled phase II studies published from January 2006 to December 2015. Matched phase III trials that investigated same intervention in the same setting of the same cancer were identified through Web of Science, ClinicalTrials.gov and conference proceedings. For each pair of phase II and phase III trials, we extracted hazard ratios (HRs) with 95% confidence intervals (CIs) for both overall survival (OS) and progression-free survival (PFS) and evaluated the differences by ratio of HRs (rHRs): the HR for phase II trial to that for phase III trial. A summary rHR was obtained through a random-effect meta-analysis. Univariable analyses were conducted to identify predictors of positive phase III trials.

Results: We identified 57 pairs of phase II and phase III trials. Compared with phase III trials, treatment effect sizes of PFS were, on average, 26% larger in phase II trials (rHR = 0.74, P < 0.001, 95% CI: 0.68-0.80). Treatment effect sizes of OS were 27% greater in phase II trials than in phase III trials (rHR = 0.73, P < 0.001, 95% CI: 0.66-0.79). Fifteen (26.3%) phase III trials were positive, and the only predictor of positive phase III trials was positive phase II trials CONCLUSION: Treatment effects in randomised controlled phase II trials were greater than those in matched phase III trials. Caution must be taken when interpreting promising results from randomised controlled phase II trials.

Keywords: Phase II trials; Phase III trials; Randomised controlled trials; Treatment effect.

Publication types

Comparative Study
Meta-Analysis
Review

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Clinical Trials, Phase II as Topic / methods
Clinical Trials, Phase II as Topic / standards
Clinical Trials, Phase II as Topic / statistics & numerical data*
Clinical Trials, Phase III as Topic / methods
Clinical Trials, Phase III as Topic / statistics & numerical data*
Data Interpretation, Statistical
Humans
Neoplasms / drug therapy*
Neoplasms / pathology
Randomized Controlled Trials as Topic / methods
Randomized Controlled Trials as Topic / standards
Randomized Controlled Trials as Topic / statistics & numerical data*
Research Design
Treatment Outcome