Evaluation of potential approaches for counting person-time in instances where no active comparator is present

Emulating the target trial framework in pharmacoepidemiology is challenging when there is no active comparator. We evaluate six approaches to finding surrogate index dates for untreated patients with the goal of identifying one or more solutions that indicate they would give potentially unbiased results. This numerical experiment used 73,070 patients from the MarketScan administrative databases (2013-2019) with type II diabetes, first-line therapy with metformin, and second-line therapy with either sodium-glucose cotransporter 2 inhibitors (SGLT2i's) or sulfonylureas. Patients taking sulfonylureas were converted into an experimental "untreated" arm. Part 1 sought to find surrogate index dates for the untreated arm. Part 2 compared the experimental estimates of the effect of SGLT2i's on cardiovascular disease (CVD) compared to sulfonylureas, using the surrogate index dates, to the reference estimate. The reference hazard ratio (HR) was 0.69. The HRs after the respective approaches for selecting surrogate index dates are as follows: rejection sampling 0.61, 0.63; median 1.10, 1.15; prediction model 0.96; matching algorithm 1.07. Only the rejection sampling approaches for selecting a surrogate index date provided results which indicate low amounts of potential bias. Extreme care should be taken when making study design decisions for observational research questions that lack an active comparator group.