Gold-standard clinical trials fail to capture how personal behaviour affects treatment

A recent study shows that people who felt confident that they received a trial drug changed their behaviour in ways that improved their health outcomes and also made the drug itself more effective

Double-blind clinical trials for new drugs are considered to be the ‘gold standard’ of medical research because, free from doctor and participant bias, they're designed to determine the efficacy of a treatment. But one effect these trials fail to measure is how a medication’s performance can vary based on patients' lifestyle choices, especially if patients change their habits because they are anticipating treatment, according to a new study published in PLOS ONE.

A recent meta-analysis of six clinical trials, led by researchers from Princeton University, the California Institute of Technology and Cambridge University, shows that people who felt confident that they received the drug changed their behaviour in ways that not only improved their health outcomes but also made the drug itself more effective. They also were less likely to bow out of a clinical trial.

The researchers propose a new trial design – a two-by-two blind trial – that can measure such interactions between behaviour and treatment. Unlike current double-blind clinical trials, the new model works by randomising not only the treatment status of patients but also the probability with which they receive treatment. This helps to determine how behavioural changes, such as changes in diet and exercise, influence treatment outcomes.

‘Our proposed design has the potential to better evaluate the effectiveness of treatments targeting conditions related to mental health, substance abuse and smoking cessation, in which behaviour is known to play an important role,’ said co-lead author Sylvain Chassang, a professor of economics and public affairs at Princeton's Woodrow Wilson School of Public and International Affairs.

The researchers propose a new clinical trial design that varies the probability of treatment across participant groups. Instead of having a 50/50 chance of receiving treatment, participants are placed in high- and low-probability treatment groups. In the high-probability group, there is a 70% chance of receiving treatment whereas the low-probability group would have only a 30% chance of receiving treatment.

To test their hypothesis that treatment and behaviour interact, the researchers conducted a meta-analysis of data from six clinical trials involving two antidepressants, paroxetine and tricyclic imipramine. By changing the variation in the likelihood of treatment across trials, they were able to determine how much of the overall effect is attributable to behaviour change alone, the treatment alone and the interaction between the treatment and behaviour.

First, the researchers evaluated whether participants behaved differently based on whether they had a high or low probability of receiving the treatment. They found that in trials where participants had a high probability of treatment, around 70%, the dropout rate was significantly lower than in trials with participants who had a lower probability of treatment (around 50%).

They then wanted to evaluate how behaviour affected treatment outcomes. In the case of paroxetine, they found that the effectiveness of treatment increased with the likelihood of being treated. This change, the researchers argue, can be interpreted as an interaction effect between drugs and changes in behaviour. While specific patient behaviours were not directly observable, the analysis shows that participants who feel confident about receiving treatment change their behaviour in a way that makes the drug more effective.

‘Our work indicates that clinical trials underestimate the efficacy of a drug whenever there are complementarities between drugs and changes in behaviour,’ said Chassang. ‘It may be the case that the 50% probability isn't high enough for people to change any of their behaviours, especially if it's a really uncertain new treatment. Then it's just going to look like that drug doesn't work, and that isn't the case.’ The paper, ‘Accounting for Behavior in Treatment Effects: New Applications for Blind Trials,’ is available online.

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