Pragmatic randomized clinical trials, designed to evaluate interventions under real-world conditions, frequently encounter deviations from pre-specified outcome assessment times. This irregularity can significantly affect the estimation of unbiased treatment effects, particularly in trials focused on chronic diseases and socioeconomically disadvantaged populations. A project funded by the Patient-Centered Outcomes Research Institute (PCORI) is addressing this challenge by developing statistical methodologies to account for these irregular assessment times.
The Impact of Irregular Assessment Times
Irregular assessment times, whether off-schedule or completely missed, can be influenced by factors linked to the outcomes of interest. For instance, a participant's health status may dictate their ability or willingness to adhere to the assessment schedule. As noted in Trials Journal, differences between health status at observed assessment times and pre-specified times can lead to over or underestimation of the benefits or harms of study interventions.
PCORI's Initiative and Pragmatic Trials
PCORI values pragmatic randomized trials for their ability to generate practical evidence that directly impacts patient care and improves health outcomes. The current project focuses on trials evaluating interventions for patients with chronic diseases and limited socioeconomic resources. Investigator groups conducted four pragmatic randomized clinical trials, including studies on asthma (ARC and HAP2), emergency department visits for uncontrolled asthma in children (CHICAGO Plan), and hospitalizations for heart failure, myocardial infarction, pneumonia, COPD, or sickle cell disease (PArTNER). These trials experienced substantial missingness and irregularity of assessment times.
Stakeholder Advisory Board Insights
To gain first-hand insights, a Stakeholder Advisory Board (SAB) was formed, comprising individuals from affected populations, clinicians, clinical trialists, implementation scientists, a qualitative researcher, and biostatisticians. The SAB identified numerous reasons for off-schedule or missed assessments, categorized using the Consolidated Framework for Implementation Research 2.0 (CFIR2.0). This framework considers factors such as the outer setting, inner setting, innovativeness of the trial, individuals involved, and implementation process.
Modifiable Determinants and Mitigation Strategies
The SAB's analysis revealed that timely completion of outcome assessments depends on multiple determinants, not solely on participants' health status. Importantly, several determinants of irregular assessment times can be modified during the protocol design stage. For example, developing study protocols that are feasible for both participants and study implementers. During protocol implementation, investigators can reassess barriers and enact flexible mitigation plans, such as collecting outcomes via home visits rather than requiring travel to clinics or study sites.
Generalizability and Future Research
While preliminary observations stem from localized behavioral trials, researchers conjecture that these findings are generalizable to other pragmatic trials, including geographically diverse and international studies, as well as those involving pharmaceutical treatments. Further research is warranted to formally evaluate this conjecture and to assess multi-level strategies for reducing off-schedule or missed assessments.
