Research: relapse rate dropping on placebo

#MSBlog: As the annual relapse rate continues to go down, trials will get bigger and longer and the price of DMTs will continue to soar! That’s what I call economics.

Stellmann et al. Placebo Cohorts in Phase-3 MS Treatment Trials – Predictors for On-Trial Disease Activity 1990-2010 Based on a Meta-Analysis and Individual Case Data. PLoS One. 2012;7(11):e50347. doi: 10.1371/journal.pone.0050347.

BACKGROUND: Annualized relapse rates (ARR) in the placebo cohorts of phase-3 randomized controlled trials (RCT) of new treatments for relapsing remitting multiple sclerosis (RRMS) have decreased substantially during the last two decades. The causes of these changes are not clear. We consider a better understanding of this phenomenon essential for valuing the effects of new drugs and by designing new trials.

OBJECTIVES: To identify predictive factors of on-study ARR in early and recent MS trials.

METHODS: ARR, rate of relapse-free patients, trial start dates, baseline demographics, relapse definitions and the use of McDonald criteria were retrieved by literature research of the placebo cohorts from RRMS phase-3 trials. Predictors were estimated by univariate and multivariate regression analyses and random-effects meta-regression. In addition, regression models were calculated by the Sylvia Lawry Centre’s (SLC), including individual case data from clinical trials performed until 2000. The most reliable meta-analytic results can be gained from pooled individual case data. In lack of this, random-effects meta-analyses are recommended.

RESULTS: Data from 12 published and one unpublished trial show a decrease of ARR from 1988 to 2012 (adjR(2) = 0.807, p<0.0001). Regression models identified McDonald criteria followed by baseline mean age and the pre-study relapse rate as predictors of the ARR. The pooled individual case data (n = 505) confirmed a decrease of ARR over time. The pre-study relapse rate was the best predictor for on-study relapses. Lacking individual case data after implementation of the McDonald criteria excludes a direct comparison concerning McDonald criteria.

CONCLUSION: Pre-study relapse rate was the best predictor for on-study relapse rate but failed to explain the decrease of the ARR over time alone. Higher age at baseline and the implementation of McDonald criteria were associated as well with a lowered relapse rate in the random-effects meta-regression.

“Reasons for the change in relapse rate in clinical trials are complex and probably related to the change in diagnostic criteria making the disease more benign, the so called Will Rogers Phenomenon. Other factors that contribute are more benign MSers volunteering for placebo-controlled trials because the more active MSers are already on treatment. Increasing age of trial subjects, i.e. relapse rates go down with age. Stricter definitions of relapses in trials; about 50% of relapses in trials don’t fulfil the protocol definition because they don’t cause objective changes in the neurological exam. This a problem for trialists; the lower the relapse rates in trials the larger and longer the trials. To get a positive result in a trial is driven by events, i.e. relapses. To get enough relapses you have to increase the size of the trials this increases  the number of participating sites and extends the recruitment period. This is one of the drivers of why it has become so expensive to do clinical trials and why the price of emerging DMTs are increasing. Pharma companies have to make a return on investment and their profit within the lifetime of the patent. Anything that reduces the patent life such as a longer development programme has knock-on effects on the price when the drug comes to market.”

2 thoughts on “Research: relapse rate dropping on placebo”

  1. Maybe the drugs don't actually do anything other than make money for Big Pharma?It's perhaps only a matter of time before NICE smells the Starbucks and realises they've been taken for a ride by greedy corporations wanting to make a fast quid.MSers don't need drugs, they need love, respect, exercise, mobility aids, physiotherapy and money to ease their suffering. They may also need counselling to come to terms with their disease. All of these things are safer and more reliable than DMTs.

  2. ARR<1 during a trial means that relapses are rather infrequent and affect only a fraction of the participants. Therefore, a handful of relapses can make a difference, giving room to chance to transfigure the final results and conclusions.

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