Approaches to Selecting “Time Zero” in External Control Arms with Multiple Potential Entry Points: A Simulation Study of 8 Approaches

Abstract

Background When including data from an external control arm to estimate comparative effectiveness, there is a methodological choice of when to set “time zero,” the point at which a patient would be eligible/enrolled in a contemporary study. Where patients receive multiple lines of eligible therapy and thus alternative points could be selected, this issue is complex. Methods A simulation study was conducted in which patients received multiple prior lines of therapy before entering either cohort. The results from the control and intervention data sets are compared using 8 methods for selecting time zero. The base-case comparison was set up to be biased against the intervention (which is generally received later), with methods compared in their ability to estimate the true intervention effectiveness. We further investigate the impact of key study attributes (such as sample size) and degree of overlap in time-varying covariates (such as prior lines of therapy) on study results. Results Of the 8 methods, 5 (all lines, random line, systematically selecting groups based on mean absolute error, root mean square error, or propensity scores) showed good performance in accounting for differences between the line at which patients were included. The first eligible line can be statistically inefficient in some situations. All lines (with censoring) cannot be used for survival outcomes. The last eligible line cannot be recommended. Conclusions Multiple methods are available for selecting the most appropriate time zero from an external control arm. Based on the simulation, we demonstrate that some methods frequently perform poorly, with several viable methods remaining. In selecting between the viable methods, analysts should consider the context of their analysis and justify the approach selected. Highlights There are multiple methods available from which an analyst may select “time zero” in an external control cohort. This simulation study demonstrates that some methods perform poorly but most are viable options, depending on context and the degree of overlap in time zero across cohorts. Careful thought and clear justification should be used when selecting the strategy for a study.

Impact of "time zero" of Follow-Up Settings in a Comparative Effectiveness Study Using Real-World Data with a Non-user Comparator: Comparison of Six Different Settings

“…In a comparative effectiveness study, multiple choices are available for when and how to set the time zero of follow-up [ 11 , 19 , 20 ], and the time-zero setting is particularly challenging in a study with a non-user comparator arm [ 12 ]. In this study, we implemented six methods to set time zero in a comparative RWD study with a non-user comparator and compared the effect estimates obtained from these settings.…”

“…As such, various options are available for selecting time zero, but the proper selection is crucial to avoid time-related bias [ 11 , 12 ]. There are studies using simulated data [ 19 ] or RWD [ 20 ], which examined various approaches for selecting time zero, although they focused on time-zero setting of external control cohort with multiple line initiation as potential time zeros in oncology.…”

External comparators and estimands

“…There are also cases where patients are eligible multiple times, for example, at the start date of the third and higher lines of treatment (Backenroth, 2021;Hatswell et al, 2022). In such cases, using all of the available data by allowing patients to enter the study at multiple timepoints (multiple baselines) may be an efficient solution, though more complex statistical methodology is needed to handle correlated data correctly.…”

Application of the target trial emulation framework to external comparator studies

“…For an EC with an active comparator treatment, the assignment of time zero is generally straightforward: time zero begins at treatment initiation for all patients in the referent trial and the comparator arm. However, when patients in the comparator arm can meet eligibility criteria at multiple time points (e.g., because the comparator treatment strategy is 'no treatment' or is an active treatment that can be delivered in multiple treatment lines), there are a variety of approaches to defining time zero (Hernán and Robins, 2016;Kutcher et al, 2021;Hatswell et al, 2022). For specific situations, randomly assigning an eligible timepoint to patients in the EC arm, matching pre-treatment person-time between the EC and referent trial arms, and defining multiple time zeros across the study period by creating a series of nested trials have shown to be valid approaches to assigning index dates to patients in the EC arm.…”

“…For specific situations, randomly assigning an eligible timepoint to patients in the EC arm, matching pre-treatment person-time between the EC and referent trial arms, and defining multiple time zeros across the study period by creating a series of nested trials have shown to be valid approaches to assigning index dates to patients in the EC arm. For a comprehensive evaluation of various approaches to selecting time zero in EC studies, refer to Hatswell et al (Hatswell et al, 2022).…”