Placebo responses in RA trials extend beyond psychological effects
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Participants in rheumatoid arthritis clinical trials who received a placebo exhibited meaningful gains in objective and subjective outcomes, indicating that placebo responses represent more than a psychological effect, researchers noted.
“Placebo responses in clinical trials can be large and, assuming a ceiling effect — a maximum improvement for a given patient in a given time — can lead to underestimating the effect of the tested drug,” Jan Vollert, PhD, of Brigham and Women’s Hospital and Harvard Medical School, told Healio Rheumatology. “This can lead to promising new drugs not reaching the market. It has been discussed whether this could be avoided by using physiological outcomes, rather than patient-reported ones, assuming this would reduce the placebo response.”
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To analyze whether subjective patient-reported and objective inflammation outcomes differ among placebo responses, Vollert and colleagues conducted a cross-sectional study of data from the placebo arms of five double-blind, randomized clinical trials. According to the researchers, all included trials were international and conducted for at least 24 weeks, between 2005 and 2009. In all, the analysis included 788 patients with RA who had been randomly assigned to receive a placebo.
Using this data, the researchers analyzed the difference in pain severity, C-reactive protein level and erythrocyte sedimentation rate from baseline to weeks 12 and 24, based on a 0- to 100-mm visual analog scale.
According to the researchers, there was a statistically significant decrease in patient-reported pain intensity, with differences of –14 mm at week 12 (95% CI, –12 to –16 mm) and –20 mm at week 24 (95% CI, –16 to –22 mm). There were also significant decreases in C-reactive protein levels, with a difference of –0.51 mg/dL at week 12 (95% CI, –0.47 to –0.56 mg/dL) and –1.16 mg/dL at week 24 (95% CI, –1.03 to –1.30 mg/dL). Similar decreases in erythrocyte sedimentation rate were also observed, with differences –11 mm/h at week 12 (95% CI, –10 to 12 mm/h) and –25 mm/h at week 24 (95% CI, –12 to –26 mm/h).
“In this analysis, we found very similar magnitude of placebo response between physiological and patient-reported outcomes, specifically between blood-based markers of inflammation and patient-reported pain-levels,” Vollert said. “We do not know if this is a phenomenon of regression to the mean or a ‘real’ placebo effect, and it might be a combination of both.”
“Clinical trials need to find better ways to account for high placebo responses and to better distinguish between the response in active and placebo arms,” he added. “Clinically, it adds to the large body of evidence that ‘subjective’, patient-reported outcomes are not in any way unreliable, and we should not trust lab results over what the patients tell us.”
Perspective
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David A. McLain, MD, FACP, FACR
The placebo effect and regression to the mean (RTM) are extremely important in clinical trials. There is an excellent article on RTM that was published in the BMJ by Morton and colleagues. “Improvement” observed after therapeutic intervention may be only a RTM.
Francis Dalton documented this phenomenon in 1886, when he referred to it a “regression to mediocrity” and is now termed RTM. The universal phenomenon of RTM is most marked when patients have been selected for high initial scores, namely DAS. If the disease has natural fluctuations, like RA, patients selected for high disease activity will inevitably show reductions in disease activity with time.
The word ‘placebo’ has been used since 1811 to mean a “medicine given more to please than to benefit the patient”. It appears the RTM is a bigger effect than the true placebo effect. Symptoms seem to improve in a similar pattern in clinical trials following a wide variety of active, as well as inactive, treatments. The common pattern of responses could, for a large part, be explained by the natural history of the disease.
In order to eliminate this effect, it is essential to do a proper RCT with control and treatment groups tested in parallel. When that is done, the control group shows the same regression to the mean as the treatment group. This is the reason that the placebo response is so strong in many trials. Any additional response in the active treatment group can be confidently attributed to the treatment. Anything short of that is whistling in the wind.
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