Meta-data analysis results in recommendation of “two-by-two” design
An article on the website of British publication Pharmaceutical Journal says a group of researchers have found that clinical drug trials with a single probability of treatment are inadequate. The scientists’ report, in the American publication PLoS One, says these tests fall short especially in estimating the additional benefits that arise from such interactions and propose “the use of two-by-two blind trials, which randomise both treatment and behaviour by varying the probability of receiving active treatment across different participants. This allows the effects of treatment and behaviour, and the interaction between them, to be assessed.”
They add that “some treatments can be more effective when patients alter behavioural patterns, such as exercise levels or food intake. And the impact of behavioural effects varies according to how strongly the patient believes that they are receiving the active treatment.”
The Pharmaceutical Journal reports that the researchers, led by Sylvain Chassang, a professor of economics and public affairs at Princeton University conducted a meta-analysis of data from six blinded antidepressant trials in which participant-level data were available. The six trials included three for the selective serotonin re-uptake inhibitor paroxetine and three for the tricyclic imipramine. Three of the studies had a high probability of treatment (>65%).
“The results provide strong evidence that the belief that their condition is being treated affects the behaviour of trial participants; in this case, specifically the decision to drop out of a trial. In the case of paroxetine, but not imipramine, there was an interaction between treatment and behavioural changes that enhanced the effectiveness of the drug–patients who were more confident that they were being treated changed their behaviour in a way that made the drug more effective,” the Journal says.
“These data show that standard blind trials can fail to account for the full value added when there are interactions between a treatment and behaviour,” say the researchers. Known as the “Hawthorne effect,” the phenomenon involves the motivations and behaviors of patients who know they are being observed.
The Pharmaceutical Journal article notes that “In their meta-analysis, the researchers highlight behavioural changes, ‘whereby a patient’s optimistic belief in the therapeutic benefit of a treatment may translate into a potentially observable change in their daily activity.'”
The writers of the paper concede, however, that placebo effects can manifest physiologically. “For example, in chronic pain, placebo effects involve activation of endogenous analgesic (opioidergic) mechanisms. In Parkinson’s disease, they involve activation of the dopamine system. In both cases, placebos affect the molecular mechanisms targeted by pharmacological agents,” says the Journal.
“In all these cases, two-by-two trials can help evaluate plausible interaction effects between treatment and the patient’s physiological response to anticipation of treatment,” the researchers write. “In addition, in a number of these domains, especially depression and pain, recent research has identified ‘nocebo’ effects. These effects are often associated with clinician comments that emphasise the side effects of treatments.”
The researchers recommend strongly for obscuring from clinicians a patient’s probability of treatment, as well as whether they will actually receive it, during two-by-two trials. In PLoS One, they note that “this ensures both types of trial participant are subject to the same emphasis on possible side effects in discussions with their doctor.”