Speaker
Description
For the early benefit assessment of drugs in Germany, the pharmaceutical company must describe the extent of an added benefit of the drug to be assessed compared with an appropriate comparator therapy [1]. The confidence interval of a significant effect must lie completely outside a certain corridor around the null effect for the extent of the effect to be regarded as minor, considerable or major. The corridors are defined by different thresholds depending on outcome category. For endpoints in the category of adverse events regularly, no events in one of the arms are observed, and thus the standard Cox proportional hazard regression does not provide valid effect estimates with corresponding confidence intervals, while the log rank test provides appropriate p-values. Thus, in the case of a statistically significant effect, the extent cannot be determined, which can lead to an inadequate overall assessment of the early benefit.
Heinze and Schemper proposed an adaption of the Firth correction to reduce bias from maximum likelihood estimation for the Cox proportional hazard [2].
To assess the applicability of this approach, we performed a simulation study of time to event analyses with zero events. The simulations are based on example cases from previous dossier evaluations. We will present results from this study and discuss the situations, in which the application of the Firth correction provides reliable estimates. We further describe the impact that the use of the Firth correction can have on endpoint-level benefit assessment.
1. IQWiG. General Methods 7.0 [online]. (2020 )
2. Heinze and Schemper (2001). Biometrics 57(1):114–119.
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