Listening to the elephant in the room: response-shift effects in clinical trials research.

Background: While a substantial body of work postulates that adaptation (response-shift effects) may serve to hide intervention benefits, much of the research was conducted in observational studies, not randomized-controlled trials. This scoping review identified all clinical trials that addressed response shift phenomena, and characterized how response-shift effects impacted trial findings.

Methods: A scoping review was done of the medical literature from 1968 to 2021 using as keywords "response shift" and "clinical trial." Articles were included if they were a clinical trial that explicitly examined response-shift effects; and excluded if they were not a clinical trial, a full report, or if response shift was mentioned only in the discussion. Clinical-trials papers were then reviewed and retained in the scoping review if they focused on randomized participants, showed clear examples of response shift, and used reliable and valid response-shift detection methods. A synthesis of review results further characterized the articles' design characteristics, samples, interventions, statistical power, and impact of response-shift adjustment on treatment effect.

Results: The search yielded 2148 unique references, 25 of which were randomized-controlled clinical trials that addressed response-shift effects; 17 of which were retained after applying exclusion criteria; 10 of which were adequately powered; and 7 of which revealed clinically-important response-shift effects that made the intervention look significantly better.

Conclusions: These findings supported the presumption that response shift phenomena obfuscate treatment benefits, and revealed a greater intervention effect after integrating response-shift related changes. The formal consideration of response-shift effects in clinical trials research will thus not only improve estimation of treatment effects, but will also integrate the inherent healing process of treatments.

Key Points: This scoping review supported the presumption that response shift phenomena obfuscate treatment benefits and revealed a greater intervention effect after integrating response-shift related changes. The formal consideration of response-shift effects in clinical trials research will not only improve estimation of treatment effects but will also integrate the inherent healing process of treatments.