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dc.contributor.authorLawrence, Nicola Jane
dc.date.accessioned2019-05-24T04:48:30Z
dc.date.available2019-05-24T04:48:30Z
dc.date.issued2019-02-18
dc.identifier.urihttp://hdl.handle.net/2123/20447
dc.description.abstractThe 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.en_AU
dc.publisherUniversity of Sydneyen_AU
dc.publisherFaculty of Medicine and Healthen_AU
dc.publisherSchool of Public Healthen_AU
dc.rightsThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en_AU
dc.subjectCancer clinical trialsen_AU
dc.subjectoncology,en_AU
dc.subjecttrial designen_AU
dc.subjecteffect sizeen_AU
dc.subjecttargeted therapiesen_AU
dc.subjectimmunological therapiesen_AU
dc.subject.otherincludes published articlesen_AU
dc.titleCANCER CLINICAL TRIAL DESIGN IN THE ERA OF TARGETED AND IMMUNOLOGICAL THERAPIESen_AU
dc.typePhD Doctorateen_AU
dc.type.pubtypeDoctor of Philosophy Ph.D.en_AU
dc.description.disclaimerAccess is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.en_AU


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