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Model-Based Assessment of Alternative Study Designs in Pediatric Trials. Part II: Bayesian Approaches.

ABSTRACT: This study presents a pharmacokinetic-pharmacodynamic based clinical trial simulation framework for evaluating the performance of a fixed-sample Bayesian design (BD) and two alternative Bayesian sequential designs (BSDs) (i.e., a non-hierarchical (NON-H) and a semi-hierarchical (SEMI-H) one). Prior information was elicited from adult trials and weighted based on the expected similarity of response to treatment between the pediatric and adult populations. Study designs were evaluated in terms of: type I and II errors, sample size per arm (SS), trial duration (TD), and estimate precision. No substantial differences were observed between NON-H and SEMI-H. BSDs require, on average, smaller SS and TD compared to the BD, which, on the other hand, guarantees higher estimate precision. When large differences between children and adults are expected, BSDs can return very large SS. Bayesian approaches appear to outperform their frequentist counterparts in the design of pediatric trials even when little weight is given to prior information from adults.

SUBMITTER: Smania G

PROVIDER: S-EPMC4999603 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Model-Based Assessment of Alternative Study Designs in Pediatric Trials. Part II: Bayesian Approaches.

Smania G G Baiardi P P Ceci A A Cella M M Magni P P

CPT: pharmacometrics & systems pharmacology 20160817 8

This study presents a pharmacokinetic-pharmacodynamic based clinical trial simulation framework for evaluating the performance of a fixed-sample Bayesian design (BD) and two alternative Bayesian sequential designs (BSDs) (i.e., a non-hierarchical (NON-H) and a semi-hierarchical (SEMI-H) one). Prior information was elicited from adult trials and weighted based on the expected similarity of response to treatment between the pediatric and adult populations. Study designs were evaluated in terms of: ...[more]

PMID: 27530374

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Project description:BackgroundBayesian adaptive designs can be more efficient than traditional methods for multi-arm randomised controlled trials. The aim of this work was to demonstrate how Bayesian adaptive designs can be constructed for multi-arm phase III clinical trials and assess potential benefits that these designs offer.MethodsWe constructed several alternative Bayesian adaptive designs for the Collaborative Ankle Support Trial (CAST), which was a randomised controlled trial that compared four treatments for severe ankle sprain. These designs incorporated response adaptive randomisation (RAR), arm dropping, and early stopping for efficacy or futility. We studied the operating characteristics of the Bayesian designs via simulation. We then virtually re-executed the trial by implementing the Bayesian adaptive designs using patient data sampled from the CAST study to demonstrate the practical applicability of the designs.ResultsWe constructed five Bayesian adaptive designs, each of which had high power and recruited fewer patients on average than the original designs target sample size. The virtual executions showed that most of the Bayesian designs would have led to trials that declared superiority of one of the interventions over the control. Bayesian adaptive designs with RAR or arm dropping were more likely to allocate patients to better performing arms at each interim analysis. Similar estimates and conclusions were obtained from the Bayesian adaptive designs as from the original trial.ConclusionsUsing CAST as an example, this case study shows how Bayesian adaptive designs can be constructed for phase III multi-arm trials using clinically relevant decision criteria. These designs demonstrated that they can potentially generate earlier results and allocate more patients to better performing arms. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials.Trial registrationCAST study registration ISRCTN, ISRCTN37807450. Retrospectively registered on 25 April 2003.

Dataset Information

Model-Based Assessment of Alternative Study Designs in Pediatric Trials. Part II: Bayesian Approaches.

Publications

Model-Based Assessment of Alternative Study Designs in Pediatric Trials. Part II: Bayesian Approaches.

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