Abstract
Masking (or blinding) of treatment assignment is routinely implemented in classical randomized clinical trials (RCTs) to isolate the effect of the intervention itself and to minimize the potential for bias that could occur with traditional trials. Such biases could be introduced with the conduct, assessment of endpoints, management of conditions, analysis, and reporting when the treatment assignments are known. However, masking of treatments is not only complex but it hinders how generalizable the findings are to the “real world” clinical setting. Pragmatic RCTs (pRCTs) are intended to evaluate the effects of interventions within routine medical care, and as such, do not typically mask treatment groups; moreover, pRCTs assess comparators that are available in routine medical practice, not masked placebos. Whether pRCTs should be masked if intended for regulatory or other purposes has recently been questioned. The literature on pRCTs, while extensive, does not address how much actual benefit is gained from masking outcomes and how masking may affect the “real world” nature of a study. Here, we propose an approach to evaluate sources of bias, describe stakeholders in the conduct of pRCTs who are most likely affected, and offer a framework for considering how masking may be implemented effectively while maintaining generalizability.
Highlights
Clinical trialists have conceptualized the masking of interventions as “all or nothing” for randomized clinical trials (RCTs)
Given the real world nature of Pragmatic RCTs (pRCTs), we propose adopting a mentality of whether the primary endpoint will be significantly influenced by knowledge of treatment assignment, and if so, how such influence may be mitigated
Masking is most desirable when outcome measures involve a great deal of judgment and where decision choices, clinical workup, and reporting may be meaningfully influenced by knowledge of the treatment assignment
Summary
Randomize after patient eligibility assessment and enrollment is complete to minimize selection bias and differential enrollment (a tenet of all RCTs) Masking may not be needed if outcomes can be objectively assessed Include and analyze those initiating therapies (new users) vs those continuing usual care therapies to minimize survival and reporting bias. PRCTs that evaluate other objective clinical events, like myocardial infarction or hospitalizations, may require more clinical evaluation and interpretation than mortality as an outcome, but the degree that knowledge of treatment assignment influences the measurement of these events is likely small and the impact, if any, can potentially be evaluated through quantitative methods.[16] This small bias can be mitigated through the use of masked assessment of endpoints, without the complexity and expense of masking the entire trial. For pRCTs that examine more subjective outcomes as primary outcomes or where such outcomes may be significantly influenced by behaviors due to knowledge of treatment assignment, masking of the patient and/or the health care provider to the treatment intervention may be helpful to minimize the potential bias, if the treatment effects being studied are expected to be meaningful but small. No May be desirable to mask clinician depression, pain perceive one treatment as better this is a depending on his or her perception of primary treatment benefit, if interacting with patients endpoint frequently during study avoids patient report, and reserving potentially subjective endpoints for secondary and exploratory analyses
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