Factors associated with placebo response rate in randomized controlled trials of antiseizure medications for focal epilepsy, 2024, French et al

[rvallee]

Factors associated with placebo response rate in randomized controlled trials of antiseizure medications for focal epilepsy
https://onlinelibrary.wiley.com/doi/10.1111/epi.18197

Abstract

Objective
Randomized controlled trials (RCTs) are necessary to evaluate the efficacy of novel treatments for epilepsy. However, there have been concerning increases in the placebo responder rate over time. To understand these trends, we evaluated features associated with increased placebo responder rate.

Methods
Using individual-level data from 20 focal-onset seizure trials provided by seven pharmaceutical companies, we evaluated associations with change in seizure frequency in participants randomized to placebo. We used multivariable logistic regression to evaluate participant and study factors associated with differing rates of 50% reduction in seizure frequency during blinded placebo treatment, as compared to pre-randomization baseline seizure frequency. In addition, we focused on the association of placebo responder rate with pre-randomization baseline seizure frequency and country of recruitment.

Results
In the pooled analysis of 1674 participants randomized to placebo, a higher 50% responder rate (50RR) was associated with a shorter duration of epilepsy (p = .006), lower baseline seizure rate (p = .002), fewer concomitant antiseizure medications (p = .004), absence of adverse events (p < .001), more trial arms (p = .006), and geographic region (p < .001). Mixture modeling indicated a significantly higher 50RR in Bulgaria, Croatia, India, and Canada (42% in the higher group vs 22% in the lower group comprising all 40 other countries, p < 10−15). In addition, there was a significantly higher 50RR in participants with a baseline seizure frequency of six or fewer seizures per 28 days (29% vs 21%, p = .00018).

Significance
These results can assist future RCTs in estimating the expected placebo responder rate, which may lead to more reliable power estimates. Higher placebo responder rate was associated with markers of less-refractory epilepsy. There were concerning significant differences in placebo responder rate by country and geographic region as well as an elevated placebo responder rate in participants with baseline seizure frequency close to the minimum eligibility criteria.


Key points

• Clinical features associated with refractory epilepsy were associated with lower placebo responder rate.
• Placebo responder rate was higher in 4 of 44 countries.
• Placebo responder rate was significantly higher in participants with six or fewer baseline seizures per month.
• Higher placebo responder rate was associated with fewer adverse effects.

 

[rvallee]

Not super interesting in itself, the first author is interested in "functional seizures" and as we have seen over recent years, there is a growing problem in all clinical trials over loosened criteria and lowered standards to try and blend in conditions that medicine poorly understands.

The study doesn't really provide useful insights other than showing the difficulty the discipline is facing over its constantly diminishing performance and quality. Obviously there is no more "placebo response" anywhere or at any time, rather as the clinical trial industry is used to prove psychosomatic models, standards have to be loosened to the point of being meaningless, and carefully putting their thumbs on the scale has become common practice, they get more noise than ever.

This is obviously going to grow as a problem, since every solution the industry has to its growing mass of failures is to do worsen everything, to maximize noise over science. It has essentially become normal to explicitly try to amplify this noise, so obviously they get more of it. But they can't reconcile the fact that they have loosed standards and normalized influencing outcomes to produce fake results as the problem.

One way the response to this problem being trying to amplify it as much as possible is that it feeds on itself:

To overcome these reduced effect sizes, the number of participants in trials has increased. This can contribute to increases in the cost of developing the novel treatments that are critical to improving the care of patients with epilepsy.6

Since the objective is to create as much noise as possible, they need more power to see the signal. This demands more expensive trials, even though clinical trials already are massively expensive because of an extreme case of the redundancies, except as we see in the psychobehavioral industry the approach has instead been to have more trials of even less quality, which is far more expensive while adding nothing at all.

This industry is not about to fix itself. Not even close.

 

[Yann04]

Tangentially related but it really feels like the psychosomatic rehabilitation industry exists as an effect of a Foucaultian Diapositif, forming a whole series of “official truths” that are not grounded in data, but through which the system (which Foucault called “regime of truth”) can assert biopower and control people who they judge as abnormal and a threat to productivity/cohesion in their system.