AI Article Synopsis
- Treatment switching in clinical trials complicates causal inference, making intention-to-treat (ITT) analyses less reliable for determining the true treatment effect.
- The ALTA-1L trial on brigatinib versus crizotinib highlighted this issue, showing more promising results for brigatinib when removed from treatment switching scenarios, via methods like Inverse Probability of Censoring Weights (IPCW).
- Re-analysis using IPCW and g-methods suggested that the treatment effect of brigatinib on overall survival may be significantly better than previously estimated, indicating that standard ITT analysis might underestimate treatment benefits.
Article Abstract
Background: Treatment switching in randomized clinical trials introduces challenges in performing causal inference. Intention To Treat (ITT) analyses often fail to fully capture the causal effect of treatment in the presence of treatment switching. Consequently, decision makers may instead be interested in causal effects of hypothetical treatment strategies that do not allow for treatment switching. For example, the phase 3 ALTA-1L trial showed that brigatinib may have improved Overall Survival (OS) compared to crizotinib if treatment switching had not occurred. Their sensitivity analysis using Inverse Probability of Censoring Weights (IPCW), reported a Hazard Ratio (HR) of 0.50 (95% CI, 0.28-0.87), while their initial ITT analysis estimated an HR of 0.81 (0.53-1.22).
Methods: We used a directed acyclic graph to depict the clinical setting of the ALTA-1L trial in the presence of treatment switching, illustrating the concept of treatment-confounder feedback and highlighting the need for g-methods. In a re-analysis of the ALTA-1L trial data, we used IPCW and the parametric g-formula to adjust for baseline and time-varying covariates to estimate the effect of two hypothetical treatment strategies on OS: "always treat with brigatinib" versus "always treat with crizotinib". We conducted various sensitivity analyses using different model specifications and weight truncation approaches.
Results: Applying the IPCW approach in a series of sensitivity analyses yielded Cumulative HRs (cHRs) ranging between 0.38 (0.12, 0.98) and 0.73 (0.45,1.22) and Risk Ratios (RRs) ranging between 0.52 (0.32, 0.98) and 0.79 (0.54,1.17). Applying the parametric g-formula resulted in cHRs ranging between 0.61 (0.38,0.91) and 0.72 (0.43,1.07) and RRs ranging between 0.71 (0.48,0.94) and 0.79 (0.54,1.05).
Conclusion: Our results consistently indicated that our estimated ITT effect estimate (cHR: 0.82 (0.51,1.22) may have underestimated brigatinib's benefit by around 10-45 percentage points (using IPCW) and 10-20 percentage points (using the parametric g-formula) across a wide range of model choices. Our analyses underscore the importance of performing sensitivity analyses, as the result from a single analysis could potentially stand as an outlier in a whole range of sensitivity analyses.
Trial Registration: Clinicaltrials.gov Identifier: NCT02737501 on April 14, 2016.
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| http://dx.doi.org/10.1186/s12874-024-02437-6 | DOI Listing |
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660711 | PMC |
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Article Synopsis
- Treatment switching in clinical trials complicates causal inference, making intention-to-treat (ITT) analyses less reliable for determining the true treatment effect.
- The ALTA-1L trial on brigatinib versus crizotinib highlighted this issue, showing more promising results for brigatinib when removed from treatment switching scenarios, via methods like Inverse Probability of Censoring Weights (IPCW).
- Re-analysis using IPCW and g-methods suggested that the treatment effect of brigatinib on overall survival may be significantly better than previously estimated, indicating that standard ITT analysis might underestimate treatment benefits.
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