The aim of this thesis was to understand and improve the design of clinical trials testing targeted and immunological anticancer therapies.
My systematic review of contemporary phase 3 trials of targeted and immunological therapies identified that almost a quarter of trials (23%) with a statistically significant result for the primary endpoint of overall survival reported an observed effect size that was probably not clinically meaningful. The findings of preceding trials (n=542) that were cited as the justification for a subsequent phase 3 trial (n=205) were reported ‘positively’ by their authors in 87%, but a priori criteria for judging their findings ‘positive’ were specified in only 74%, and met in only 53%. Characteristics of the preceding trials that were associated with a positive primary outcome in the subsequent phase 3 trial were industry-sponsorship (odds ratio 2.0, p=0.01) and conduct in the same tumour type (odds ratio 2.4, p=0.05).
I analysed the views of investigators and patients participating in a randomised, phase 3 trial of adjuvant targeted therapy for renal cell carcinoma. Investigators judged larger survival benefits than their patients necessary to make adjuvant sorafenib worthwhile (2% of investigators vs 21% of patients judged sufficient an extra 1% beyond a five year survival rate of 65%, p<0.0001).
Phase 3 trials should be designed and powered such that observed effect sizes which are statistically significant are also clinically meaningful. Researchers should pre-specify and report the target level of activity in a phase 2 trial that would warrant further research. Researchers testing targeted or immunological therapies should obtain preliminary evidence of activity in the same tumour type prior to embarking on a large scale, phase 3 trial. Researchers and clinicians should appreciate that their judgements may differ from those of their patients and colleagues, and be wary of overestimating, or overstating, their potential benefits.