Primary non‐adherence and the new‐user design

The new‐user design has been widely used in pharmacoepidemiology. By following patients from the initiation of a treatment, the new‐user design has several advantages over designs that begin follow‐up on prevalent users. The new‐user design allows study of the full time course of outcome risk after treatment initiation, with representation of early and late events. It also ensures appropriate temporal ordering of baseline confounders, exposures, and outcomes, avoiding adjustment for intermediate variables that may have been affected by treatment. Coupled with an active‐comparator design, new‐user approaches can mitigate the potential for immortal time‐bias and confounding by indication. The active comparator new‐user design helps to articulate clearly a causal question about the benefits and harms of starting a particular intervention in a more real‐world setting. These theoretical and conceptual advantages have led to the recommendation that such designs should be a default approach for comparative effectiveness research studies. The new‐user design is a special case of the treatment decision design, which begins follow‐up at the times when treatment decisions are made (Figure 1). Framing the research question and analysis in this way connects estimates to treatment decisions, providing information that is directly relevant to clinicians and patients. In the analysis, researchers often present an observational analog to the “intention‐to‐treat analysis,” in which patients are analyzed by their initial treatment (or assigned treatment) group, regardless of treatment changes and non‐adherence that occur during follow‐up. The use of the language from randomized controlled trials suggests that, under the assumption of no uncontrolled confounding, these adjusted estimates are similar to what one would obtain in parallel group randomized controlled trial conducted in the same population. However, when treatment groups are inferred from the treatment actually started by patients, we are implicitly conducting our analysis