Randomized controlled trials in the era of molecular oncology: methodology, biomarkers, and end points

BACKGROUND: We previously reported metrics of systemic therapy randomized controlled trials (RCTs) in breast cancer, colorectal cancer (CRC), and non-small-cell lung cancer (NSCLC) published 1975-2004. To evaluate trends in the era of targeted therapies (TT), we have repeated a similar analysis of RCTs published 2005-2009. METHODS: A search for phase III RCTs of systemic agents published in five major journals 2005-2009 was carried out. Trials were classified as TT if they involved any non-hormonal targeted agent. We extracted data regarding biomarker use. Integral biomarkers were defined as tests used to determine eligibility, stratification, or allocation. Descriptive statistics were used to analyze trends over time. RESULTS: One hundred and thirty-seven eligible RCTs were evaluated. Compared with 1995-2004, the number (17-27 RCTs/year) and size (median sample size 446-722, P < 0.001) of RCTs increased. The proportion of RCTs evaluating TT increased from 4% (7/167) to 29% (40/137) (P < 0.001). There was an increase in the proportion of trials with financial support from industry [57% (95/167) to 78% (107/137), P = 0.001]. Biomarkers were included in 58% (80/137) of RCTs; integral biomarkers were included in 36% (49/137) of trials. Among the 49 RCTs using integral biomarkers, 40 (82%) used HER2 and/or ER/PR status in studies of breast cancer. CONCLUSIONS: RCTs published in 2005-2009 are larger, more likely to evaluate TT, and be supported by industry. Biomarkers may be increasingly used, but the most common use relates to traditional use of ER/PR and evolving use of HER2 in breast cancer RCTs.