(155) Guidance for the Design of Observational Studies to Estimate the Effects of Long-term Drug Exposures

Background: The secondary use of real-world data in research provides an opportunity to fill a gap in evidence about the comparative effectiveness and safety of long-term drug exposures that clinical trials often cannot provide. Despite advances in observational research methods used to estimate the effects of long-term drug exposures, deficiencies in study design persist, potentially compromising the validity of reported evidence.

Objectives: To provide guidance on how to design an observational study to estimate the effects of long-term drug exposures.

Methods: Informed by results of a scoping review on methods used in observational studies examining antidiabetic medications and fracture risk, this guidance reviews key study design aspects to consider when assessing the effects of long-term drug exposures. We focus on establishing purposeful connections between etiologic and clinical pharmacology foundations and principles of pharmacoepidemiology. We present a case example to demonstrate how to appropriately consider key study design aspects when designing an observational study to estimate the effects of antidiabetic medications on hip fracture risk.

Results: We emphasize the need for careful consideration and transparent reporting of three key study design aspects as fundamental when designing a study to estimate the effects of long-term drug exposure: (1) pathophysiology of the health condition that indicated the drug exposure and how it may be implicated in the pathogenesis of the drug exposure-outcome relationship under study; (2) clinical pharmacology of the drug exposure; and (3) drug exposure time trends at the population and individual levels.

In the context of the case example on the design of a study to estimate the effects of antidiabetic medications on hip fracture risk, we consider aspects (1) and (2) particularly important when defining a biologically plausible exposure risk window, exposure measurement, and a set of potential confounders. Further, we highlight the importance of aspect (3) drawing attention to time trends in the use of antidiabetic medications that may be due to changes in drug markets and policies at the population level, and in healthcare needs at the individual level, which may result in significantly biased effect estimates.

Conclusions: Careful consideration and transparent reporting of the three key study design aspects emphasized, and of study design and analytic approaches in general, will improve the validity of reported evidence from observational studies. This will also allow for the conduct of more effective and efficient critical appraisal, ultimately reducing the risk of misleading clinical decision-makers about the comparative effectiveness and safety of long-term drug exposure.