Adjusting for treatment selection in phase II/III clinical trials with time to event data

Josephine N. Khan, Peter K. Kimani, Ekkehard Glimm, Nigel Stallard

Research output: Contribution to journalArticlepeer-review

Abstract

Phase II/III clinical trials are efficient two-stage designs that test multiple experimental treatments. In stage 1, patients are allocated to the control and all experimental treatments, with the data collected from them used to select experimental treatments to continue to stage 2. Patients recruited in stage 2 are allocated to the selected treatments and the control. Combined data of stage 1 and stage 2 are used for a confirmatory phase III analysis. Appropriate analysis needs to adjust for selection bias of the stage 1 data. Point estimators exist for normally distributed outcome data. Extending these estimators to time to event data is not straightforward because treatment selection is based on correlated treatment effects and stage 1 patients who do not get events in stage 1 are followed-up in stage 2. We have derived an approximately uniformly minimum variance conditional unbiased estimator (UMVCUE) and compared its biases and mean squared errors to existing bias adjusted estimators. In simulations, one existing bias adjusted estimator has similar properties as the practically unbiased UMVCUE while the others can have noticeable biases but they are less variable than the UMVCUE. For confirmatory phase II/III clinical trials where unbiased estimators are desired, we recommend the UMVCUE or the existing estimator with which it has similar properties.

Original languageEnglish
Pages (from-to)146-163
Number of pages18
JournalStatistics in Medicine
Volume42
Issue number2
DOIs
Publication statusPublished - 30 Jan 2023
Externally publishedYes

Keywords

  • adaptive seamless design
  • multi-arm multi-stage
  • point estimation
  • survival data

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