Target Trial Emulation

Target trial emulation (TTE) is an observational, quasi-experimental research design that emulates a randomized clinical trial (RCT) structure within a large set of observational data; the "target trial" is a hypothetical RCT that would have ideally answered the research question. TTEs can address study objectives that, for ethical or logistic reasons, cannot easily be examined in RCTs. Advantages of TTEs over conventional approaches to observational data are that TTEs can reduce bias, improve the understanding of findings, and facilitate causal inference. This article explains what TTEs are, how TTEs are performed, and how TTEs differ from observational studies, quasi controlled studies, and RCTs. Prevalent user bias and immortal time bias are explained, as is how TTEs are designed to avoid these biases. Strengths and limitations of TTEs are discussed. This article also presents 2 recent studies: one, comprising 3 TTEs that examined scholastic outcomes in children gestationally exposed to benzodiazepines and z-drugs in different periods during pregnancy; and the other, a TTE that examined manic switch as an outcome in bipolar depression patients who received antidepressant treatment. The TTEs found that early, mid, or late pregnancy exposure to benzodiazepines or z-drugs was not associated with impairment in fifth-grade numeracy and literacy performance; and that, in patients with bipolar depression, antidepressant drugs (with or without concurrent mood stabilizers) did not increase the 1-year risk of hypomania, mania, or mixed episodes, nor did they reduce the risk of recurrence of bipolar depression. The TTEs that yielded these results had limitations, and so these findings are suggestive, not definitive. As a general conclusion, TTEs may be viewed as pragmatic, naturalistic, real-world emulations of RCTs, with some advantages over conventional observational studies, but they cannot drive causal inference.