An adaptive design for early clinical development including interim decision for single-arm trial with external controls or randomized trial.
confounder adjustment
loss function
preference score
proof-of-concept
real-world data
Journal
Pharmaceutical statistics
ISSN: 1539-1612
Titre abrégé: Pharm Stat
Pays: England
ID NLM: 101201192
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
revised:
17
12
2021
received:
09
09
2020
accepted:
20
12
2021
pubmed:
22
1
2022
medline:
30
4
2022
entrez:
21
1
2022
Statut:
ppublish
Résumé
In early clinical development, randomized controlled trials (RCT) or single-arm trials with external controls (SATwEC) are design options, which allow adjustment for confounding: RCT via design, SATwEC via analysis using propensity score methods. SATwEC requires less investment than RCT. However, if the confounder space substantially differs between the experimental and external control group, the SATwEC might lead to inappropriate decisions for further development. We develop an adaptive two-stage design (ATD) for early clinical development that reduces the risk of unreliable decision-making at the end of a SATwEC. In Stage I, subjects are solely assigned to the experimental group. If at the interim the propensity score distributions of internal and external data are comparable based on the preference score, the subjects in stage II will again be solely assigned to the experimental arm; if not, a randomized stage II will be conducted. In a simulation study guided by a motivating example, data is generated using a time-to-event model with observable and unobservable confounders. The confounder space is varied to investigate the impact on false go/stop probabilities as well as a loss function, which reflects the quality of treatment effect estimates and decision-making. The proposed ATD provides a compromise between optimizing quality (as expressed by false go/stop probabilities and the loss function) and investment (defined by sample size and trial duration).
Types de publication
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
625-640Informations de copyright
© 2022 John Wiley & Sons Ltd.
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