Study Examines Use of Optimal Control Groups in Randomized Clinical Trials for Systemic Rheumatic Diseases

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A study recently posted in JAMA Network Open examined the proportion of pivotal randomized controlled trials (RCTs) that used optimal control groups supporting newly approved drugs for systemic rheumatic diseases (SRDs) in the United States. The study authors analyzed RCTs specific to this therapeutic area between January 2012 and October 2022 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 trials.¹

SRDs are heterogenous groups of diseases characterized by systemic inflammation and dysregulation of the autoimmune system. Interactions between genetic and environmental factors may lead to the triggering of immune pathways, producing multiple autoantibodies and inflammatory factors, and finally, causing damage to multiple organs.^2-4 While there have been advances in RCT execution, they are still lacking considering the global disease burden that SRDs carry, according to the investigators.

“Given the potential of severe and widespread organ damage, SRDs are associated with a considerable disease burden globally despite advances in the treatment landscape of SRDs,” the study authors wrote. “There is an urgent need for changes in current therapies and the development of new approaches.”

The investigators observed that a comprehensive evaluation of the quality of control groups in pivotal RCTs supporting SRD drug approvals by the FDA is lacking. As such, they noted that RCTs must strive to use optimal control groups to reflect the best available treatments.¹ According to the Himmelfarb Life Sciences Library at George Washington University, an RCT is: “A study design that randomly assigns participants into an experimental group or a control group. As the study is conducted, the only expected difference between the control and experimental groups in a randomized controlled trial is the outcome variable being studied.”⁵

Among 65 pivotal RCTs supporting 44 FDA-approved SRD drugs, only 16 (24.6%) utilized optimal control groups, while 55 trials (84.6%) lacked active treatment groups, 47 of which (85.5%) were considered suboptimal. Notably, trials for systemic arthritis, including rheumatoid arthritis (RA) and psoriatic arthritis (PSA), predominantly employed suboptimal control groups. Investigating drug groups generally exhibited significant improvement in response rates compared to placebo groups, emphasizing the potential biases introduced by suboptimal controls.

“From an ethical standpoint, it is not acceptable to subject patients to placebos or therapies that are ineffective for a prolonged period, especially for diseases that warrant early control. It is important to avoid such practices at all costs,” the authors wrote. “From an ethical standpoint, it is not acceptable to subject patients to placebos or therapies that are ineffective for a prolonged period, especially for diseases that warrant early control. It is important to avoid such practices at all costs.”¹

The findings suggest a need for improvement in the quality of control groups in pivotal clinical trials supporting SRD drug approvals, with potential implications for regulatory decision-making and patient outcomes, according to the authors. Based on the results, they recommend consistently prioritizing efforts toward promoting appropriate control groups for pivotal clinical trials.

“When planning a pivotal RCT, it is important to use the best treatments available as the control group while carefully selecting inclusion and exclusion criteria,” the authors wrote. “At least from the operational perspective, informed consent should reflect all the available choices for participants to review.”

References

1. Liu, Y., Xu, Y., & Cheng, X. (2023). Quality of Control Groups in Randomized Clinical Trials Supporting Systemic Rheumatic Disease Drug Approvals by the US Food and Drug Administration. JAMA Network Open, 6(11), e2231743. https://doi.org/10.1001/jamanetworkopen.2022.31743.
2. Gourley M, Miller FW. Mechanisms of disease: environmental factors in the pathogenesis of rheumatic disease. Nat Clin Pract Rheumatol. 2007;3(3):172-180. doi:10.1038/ncprheum0435PubMedGoogle ScholarCrossref
3. Wang L, Wang FS, Gershwin ME. Human autoimmune diseases: a comprehensive update. J Intern Med. 2015;278(4):369-395. doi: 10.1111/joim.12395PubMedGoogle ScholarCrossref.
4. Bossuyt X, De Langhe E, Borghi MO, Meroni PL. Understanding and interpreting antinuclear antibody tests in systemic rheumatic diseases.Nat Rev Rheumatol. 2020;16(12):715-726. doi:10.1038/s41584-020-00522-wPubMedGoogle ScholarCrossref.
5. Study Design 101: Randomized Controlled Trial. (n.d.). Himmelfarb Health Sciences Library. Retrieved from https://guides.himmelfarb.gwu.edu/studydesign101/randomized-controlled-trial.