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Control Groups in RCTs Supporting Approval of Drugs for Systemic Rheumatic Diseases, 2012-2022
Yang Liu1,2, Yan Xie3, Yunhe Qin4
1Tsinghua Clinical Research Institute, School of Medicine, Tsinghua University, Beijing, China.
Importance:
Randomized clinical trials (RCTs) testing innovative drugs must strive to use optimal control groups to reflect the best available treatments. A comprehensive evaluation of the quality of control groups in pivotal RCTs supporting systemic rheumatic disease (SRD) drug approvals by the Food and Drug Administration (FDA) is lacking.
Objective:
To examine the proportion of pivotal RCTs that used optimal control groups among RCTs supporting newly approved SRD drugs in the US over the past decade.
Design, Setting, And Participants:
In this study, individual RCTs supporting SRD new drug approvals by the FDA between January 2012 and October 2022 were analyzed for design, study duration, control group, and primary end point. The quality of control groups was determined by comparison with published guidelines before and during the trial.
Main Outcomes And Measures:
The primary measure was the proportion of RCTs using optimal control groups. Differences in response rate between investigating and control groups and the response rate of placebo control groups were also examined.
Results:
Between January 2012 and October 2022, the FDA approved 44 SRD drugs, involving 65 pivotal RCTs. Overall, 16 RCTs used optimal control groups. In 55 trials, no active groups were used, and more than 80% of these trials were suboptimal (47 trials [85.5%]). Among 56 trials for systemic arthritis, 49 trials used suboptimal control groups, mainly placebo or dose-response controls (47 trials), with a few active controls (2 trials). Studies of other SRDs frequently used placebo or dose-response controls but were considered optimal controls (8 trials). There was significant improvement in response rates of investigating compared with placebo groups, with relative risk mostly exceeding 1.50 (range, 0.90; 95% CI, 0.69-1.17 for anifrolumab to 11.00; 95% CI, 2.69-44.96 for mepolizumab). In all placebo-controlled trials, the median (IQR) response rate in placebo groups was 26.0% (19.2%-32.3%).
Conclusions And Relevance:
These findings suggest that the quality of control groups in RCTs leading to SRD drug approval needs improvement and that despite challenges in translating scientific theories to clinical scenarios, it is crucial to consistently prioritize efforts to promote appropriate control group selection to ensure the accurate assessment of innovative drug efficacy.
Insights
Most randomized clinical trials for systemic rheumatic disease drugs lack optimal control groups, necessitating improved trial design for accurate efficacy assessment. This highlights a critical need for better control group selection in drug development.
Area of Science:
- Rheumatology
- Clinical Pharmacology
- Drug Development
Background:
- Randomized clinical trials (RCTs) are crucial for evaluating innovative drugs.
- Optimal control groups are essential for accurately assessing drug efficacy.
- A gap exists in evaluating control group quality in pivotal RCTs for systemic rheumatic disease (SRD) drug approvals.
Purpose of the Study:
- To determine the proportion of pivotal RCTs using optimal control groups for newly approved SRD drugs in the US.
- To analyze control group quality in SRD drug approval trials over the past decade.
Main Methods:
- Analysis of pivotal RCTs supporting FDA-approved SRD drugs (January 2012 - October 2022).
- Evaluation of trial design, duration, control group, and primary endpoint.
- Assessment of control group quality against published guidelines.
Main Results:
- Out of 65 pivotal RCTs for 44 SRD drugs, only 16 used optimal control groups.
- 55 trials lacked active control groups, with 85.5% deemed suboptimal.
- 49 of 56 trials for systemic arthritis used suboptimal controls (primarily placebo).
Conclusions:
- The quality of control groups in SRD drug approval RCTs requires significant improvement.
- Prioritizing appropriate control group selection is vital for accurate assessment of innovative drug efficacy.
- Translating scientific advancements into clinical practice necessitates robust trial methodologies.
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