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dc.contributor.authorBennett, Maxine Sarah
dc.date.accessioned2018-01-25T17:29:00Z
dc.date.available2018-01-25T17:29:00Z
dc.date.issued2018-04-28
dc.date.submitted2018-01-29
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/271133
dc.description.abstractThe most common type of confirmatory trial is a randomised trial comparing the experimental treatment of interest to a control treatment. Confirmatory trials are expensive and take a lot of time in the planning, set up and recruitment of patients. Efficient methodology in clinical trial design is critical to save both time and money and allow treatments to become available to patients quickly. Often there are data available on the control treatment from a previous trial. These historical data are often used to design new trials, forming the basis of sample size calculations, but are not used in the analysis of the new trial. Incorporating historical control data into the design and analysis could potentially lead to more efficient trials. When the historical and current control data agree, incorporating historical control data could reduce the number of control patients required in the current trial and therefore the duration of the trial, or increase the precision of parameter estimates. However, when the historical and current data are inconsistent, there is a potential for biased treatment effect estimates, inflated type I error and reduced power. We propose two novel weights to assess agreement between the current and historical control data: a probability weight based on tail area probabilities; and a weight based on the equivalence of the historical and current control data parameters. For binary outcome data, agreement is assessed using the posterior distributions of the response probability in the historical and current control data. For normally distributed outcome data, agreement is assessed using the marginal posterior distributions of the difference in means and the ratio of the variances of the current and historical control data. We consider an adaptive design with an interim analysis. At the interim, the agreement between the historical and current control data is assessed using the probability or equivalence probability weight approach. The allocation ratio is adapted to randomise fewer patients to control when there is agreement and revert back to a standard trial design when there is disagreement. The final analysis is Bayesian utilising the analysis approach of the power prior with a fixed weight. The operating characteristics of the proposed design are explored and we show how the equivalence bounds can be chosen at the design stage of the current study to control the maximum inflation in type I error. We then consider a design where a treatment arm is added to an ongoing clinical trial. For many disease areas, there are often treatments in different stages of the development process. We consider the design of a two-arm parallel group trial where it is planned to add a new treatment arm during the trial. This could potentially save money, patients, time and resources. The addition of a treatment arm creates a multiple comparison problem. Dunnett (1955) proposed a design that controls the family-wise error rate when comparing multiple experimental treatments to control and determined the optimal allocation ratio. We have calculated the correlation between test statistics for the method proposed by Dunnett when a treatment arm is added during the trial and only concurrent controls are used for each treatment comparison. We propose an adaptive design where the sample size of all treatment arms are increased to control the family-wise error rate. We explore adapting the allocation ratio once the new treatment arm is added to maximise the overall power of the trial.
dc.language.isoen
dc.rightsNo Creative Commons licence (All rights reserved)
dc.subjectadaptive designs
dc.subjecthistorical data
dc.subjectBayesian
dc.subjectmultiple testing
dc.subjectpower prior
dc.subjectclinical trial design
dc.subjectadding a treatment arm
dc.titleImproving the efficiency of clinical trial designs by using historical control data or adding a treatment arm to an ongoing trial
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.publisher.departmentMathematics
dc.date.updated2018-01-25T13:47:24Z
dc.identifier.doi10.17863/CAM.18107
dc.identifier.doi10.17863/CAM.18107
dc.identifier.doi10.17863/CAM.18107
dc.publisher.collegeSt Catharine's
dc.type.qualificationtitlePhD in Statistics
cam.supervisorMander, Adrian Paul
rioxxterms.freetoread.startdate2019-01-25


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