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Title: Issues around the use of surrogate outcomes in health technology assessment
Author: Ciani , Oriana
ISNI:       0000 0004 5351 6713
Awarding Body: Exeter and Plymouth Peninsula Medical School
Current Institution: Exeter and Plymouth Peninsula Medical School
Date of Award: 2014
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Licensing and reimbursement decisions on health technologies should be ideally based on randomised controlled trials (RCTs) that report final patient relevant outcomes, such as overall survival or health-related quality of life. However, biomarkers and intermediate endpoints are often used in clinical trials as surrogate outcomes, i.e., as substitutes for final patient-relevant outcomes. Surrogate outcomes may occur faster or may be easier to assess than final outcomes. Nevertheless, relying on surrogate outcomes evidence alone has been shown to lead to inadequate conclusions about the value of new treatments. This PhD thesis by publication explores key issues related to the use of surrogate outcomes in health technology assessment, particularly in the field of oncology. The specific aims of the four component papers are: I. To quantify and compare the treatment effect of RCTs reporting surrogate outcomes versus RCTs using final patient-relevant primary outcomes across a range of diseases; 11. To review the statistical methods used in meta-analyses for validating surrogate endpoints in a specific disease area (i.e., advanced solid tumours) and assess the available level of evidence against current standardised frameworks for surrogate evaluation; Ill. To assess the within-trial surrogate-to-finaI outcome relationship in advanced colorectal cancer, according to different methods and depending on several trial characteristics; IV. To illustrate the use of surrogate end points in a real HTA process (i.e., the technology appraisa l of imatinib, nilotinib and dasatinib as first-line treatment in chronic myeloid leukemia at the National Institute for Health and Care Excellence). In publication I, clinical trials reporting surrogate primary outcomes were found to be more likely to report larger treatment effects (by up to 47%) than clinical trials reporting final patient-relevant outcomes. The review of statistical methods in publication 11 shows that the level of evidence for the use of surrogate outcomes in advanced solid tumours to date is generally poor according to common evaluation tools. In publication IV, I confirm the findings from publication I: the treatment effect observed on the surrogate endpoint appears always to be larger than that observed on the final endpoint, by 3% to 45%. In 4 publication IV, using the case study of chronic myeloid leukemia, the validation of two surrogate outcomes was performed and their link with long-term effectiveness and cost-effectiveness was built for three treatments under comparison. A final overall discussion section brings together the findings of these four publications and identifies practical recommendations and future research implications.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available