Topic 1 | Section 4.8

Protocol Design Considerations: Study Endpoints

  • For trials where objective response (CR + PR) is the primary endpoint, and in particular where key drug development decisions are based on the observation of a minimum number of responders, it is recommended that all claimed responses be reviewed by an expert(s) independent of the study
  • Independent review of progression presents some more complex issues: for example, there are statistical problems with the use of central-review-based progression time in place of investigator-based progression time due to the potential introduction of informative censoring when the former precedes the latter
  • Ideally trials with PFS as the primary end-point should be randomized and double-blinded
  • When double-blinded trials are not feasible, independent review of imaging to determine progression may be used as an auditing tool to detect bias in local evaluations to increase confidence in the trial’s conclusions. Bias may have occurred if independent review identifies differential rates of unconfirmed progression according to treatment arm and/or higher rates of earlier progression in one treatment arm. However, independent review as the primary determinant of progression may introduce informative censoring and bias.
  • Phase III trials that use PFS should target treatment effects that are sufficiently large to be clinically important and robust