Impact of Biomarker-based Design Strategies on the Risk of False-Positive Findings in Targeted Therapy Evaluation

Abstract

When there is more than one potentially predictive biomarker for a new drug, the drug is often evaluated in different subpopulations defined by different biomarkers. We aim to (i) estimate the risk of false-positive findings with this approach and (ii) evaluate the cross-validated adaptive signature design (CVASD) as a potential alternative. By using numerically simulated data, we compare the current approach and the CVASD across different settings and scenarios. We consider three strategies for CVASD. The first two CVASD strategies are different in terms of the partitioning of the overall significance level (between the population test and the subgroup test). In the third CVASD strategy, the order of the two tests is reversed, that is, the population test is realized when the prioritized subgroup test is not statistically significant. The current approach results in a high risk of false-positive findings, whereas this risk is close to the nominal level of 5% once applying the CVASD, regardless of the strategy. When the treatment is equally effective to all patients, only the CVASD strategies could specify correctly the absence of a sensitive subgroup. When the treatment is only effective for some sensitive responders, the third CVASD strategy stands out by its ability to correctly identify the predictive biomarker(s). The drug-biomarker coevaluation based on a series of independent enrichment trials can result in a high risk of false-positive findings. CVASD with some appropriate adjustments can be a good alternative to overcome this multiplicity issue.

Adaptive Signature Design- review of the biomarker guided adaptive phase –III controlled design

“…Inflation of type-I error is a major issue in “testing-in-all-direction" approach (TIADA) and CV-ASD. Accordingly, tweaking the pre-specified significance level with recalibration can be an appropriate substitute to handle the multiplicity issue which arises due to the inclusion of several biomarkers [ 57 ].…”