Rising placebo response rates in rheumatoid arthritis trials mirror recruitment shifts

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WASHINGTON — Rising rates of ACR20 response in the placebo arms of rheumatoid arthritis trials may be related to increasingly globalized recruitment patterns, according to data presented at ACR Convergence 2024.

“As many of you might be aware, we have observed a significant increase in ACR response rates in placebo arms across the last 2 decades,” Andreas Kerschbaumer, MD, PhD, of the Medical University of Vienna, told attendees.

“We know that response rates of placebo arms are rising over time, and we could show that recruitment areas have changed over time toward global recruitment,” Andreas Kerschbaumer, MD, PhD, said. Image: Adobe Stock

Furthermore, a study Kerschbaumer had previously co-authored found that placebo-treated patients on background methotrexate demonstrated “better response rates compared to placebo patients without any conventional synthetic DMARD,” he added.

“This observation inspired us to do this analysis, because we know that there is an increased recruiting pressure on sponsors and investigators all over the world in drug development programs,” Kerschbaumer said.

To examine the potential reasons for the rise in placebo responses among RA cohorts, Kerschbaumer and colleagues analyzed geographic recruitment patterns over time, as well as socioeconomic factors of participants involved in clinical trials. Their analysis included the placebo arms of 135 trials, initiated between 1994 and 2019, evaluating biological or targeted synthetic DMARDs among patients with RA on established conventional synthetic DMARDs.

The researchers extracted numbers of recruiting centers per country in each study, and used World Bank data to calculate weighted, per-capita gross national incomes (GNI). For the final analysis, the researchers used a linear mixed model regression, with a random effect on study level, weighted by the number of patients in each study and adjusted for overall rising global GNI.

According to the researchers, recruitment in 1991 was limited to North America and Western Europe. However, expansion into other areas of the globe increased beginning in 2005, with recent studies particularly including patients in less affluent countries.

Week-12 and -24 ACR20 response rates in placebo arms demonstrated a significant positive association with the year studies were started, according to the researchers. Analysis via per-capita GNI showed a strong and significant negative association between placebo response rates and weighted and normalized GNI of study countries, estimated at –3.7% per 10,000 international dollars at week 12 and –3.93% at week 24.

“We know that response rates of placebo arms are rising over time, and we could show that recruitment areas have changed over time toward global recruitment,” Kerschbaumer said. “We could analyze this by showing recent trials recruiting increasingly in less affluent countries and say that globalization of recruitment might be one of the significant contributors to higher placebo response rates observed in more recent trials.

“Why is this? This can only be speculated upon and is to be investigated,” he added. “We believe that access to health care might be one of the primary issues, so patients might be very much incentivized in less affluent countries to get enrolled into a trial while being not able to afford therapy and have lots of out-of-pocket expenses for their conventional synthetic DMARDs while being treated in usual care.”

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