MRC Biostatistics Unit

Transcription

1 MRC Biostatistics Unit Adrian Mander MRC Biostatistics Unit Hub for Trials Methodology Research Cambridge June 2014 Adrian Mander June /12

2 MRC Biostatistics Unit The 4 themes DART Design and Analysis of Randomised Trials Adrian Mander and Ian White SGX Statistical Genomics Sylvia Richardson, Lorenz Wernisch and Sach Mukherjee COLD methods for the analysis of Complex Observational and Longitudinal Data Vern Farewell, Fiona Matthews and Brian Tom ESH Evidence Synthesis to inform Health Daniela DeAngelis and Sheila Bird Adrian Mander June /12

3 DART: Design and Analysis of Randomised Trials The standard trial design Good for confirmatory phase 3 trials Intervention Control Adrian Mander June /12

4 Adaptive Trials An adaptive design allows modifications to be made based on the accruing information of an ongoing trial The modifications we consider are by design (prospective) rather than ad hoc unplanned changes Adrian Mander June /12

5 Adaptive Trials An adaptive design allows modifications to be made based on the accruing information of an ongoing trial The modifications we consider are by design (prospective) rather than ad hoc unplanned changes Adrian Mander June /12

6 DART: Design and Analysis of Randomised Trials Adaptive Trial Designs Dual-agent Phase 1 dose-escalation trials Dose-ranging studies phase II Sample size re-estimation Stopping for futility or efficacy Multi-arm multi-stage designs (MAMS) MAMS for crossover studies (stepped-wedge designs) Biomarker-driven designs Adaptive enrichment (Simon two-stage design) Linking multiple drugs to multiple biomarkers (Bayesian Adaptive Randomisation) Adrian Mander June /12

7 Phase 2 Dose ranging The aim of an early phase 2 trial is to understand the dose-response relationship. This translates into three possible sub-aims to estimate the whole curve in a therapeutic dose range Minimise the variance of the estimated model parameters (D-optimality) to target specific dose/response Pick the targeted dose (patient gain) Minimise the variance of the dose that gives a targeted response Need to select a model to help pick doses Adrian Mander June /12

8 Dose response model shapes Adrian Mander June /12

9 Trial of ProleukinR(IL-2) in Type 1 diabetes A trial designed in collaboration between CIMR, Cambridge CTU and BSU Identify doses that induce a 10% or 20% increase in Treg Minimise the variance of both doses Fitted multiple models and had a discussion about dose choice via the Dose Determining Committee Doses were chosen from models after 1 3 patient(s) Drug was injected so doses are continuous There were only a maximum of 40 patients to be recruited F Waldron-Lynch et al. (2014) BMJ open 4(6) Adrian Mander June /12

10 Phase 2 Dose finding simulation study dose y True id 0 Fitted dose Res var= 1 Adrian Mander June /12

11 Sample size re-estimation Later phase trials might focus more on hypothesis testing of treatment effects and therefore need to specify the sample size How do you calculate a sample size if the treatment effect or variance is unknown? Can do a blinded or unblinded sample size re-calculation If the recalculated sample size is too big stop early (or stop if evidence to reject null hypothesis) For results in the middle consider increasing sample size up to an upper limit Bowden and Mander (2014) Pharm. Stat. 13(3), Adrian Mander June /12

12 Sample size re-estimation Later phase trials might focus more on hypothesis testing of treatment effects and therefore need to specify the sample size How do you calculate a sample size if the treatment effect or variance is unknown? Can do a blinded or unblinded sample size re-calculation If the recalculated sample size is too big stop early (or stop if evidence to reject null hypothesis) For results in the middle consider increasing sample size up to an upper limit Bowden and Mander (2014) Pharm. Stat. 13(3), Adrian Mander June /12

13 The sample size re-estimation rule Adrian Mander June /12

14 Conclusions These designs can improve efficiency of your trials We have a group of experts in the MRC Biostatistics Unit Give us plenty of time to help you (these designs aren t easy) Adrian Mander June /12