In a new retrospective study presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held November 1-4, in Phoenix, Arizona, a majority of patients with anti-acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (gMG) treated in routine care did not meet criteria for a potential phase 3 clinical trial. These results suggest that broader inclusion criteria are needed to increase eligibility in clinical trials and from doing that, study results would be more likely to be generalizable to a more diverse patient population with gMG.1
During the study period, investigators identified 67 patients with AChR+ MG who had a total of 330 visits between January 2021 and June 2023. At the conclusion of the analysis, 89.5% of patients(n = 60) and 95% (n = 315) of clinic visits did not meet the inclusion criteria for the clinical trial participation. The most common reason for not meeting the criteria, occurring in 77.5% of visits, was having a Myasthenia Gravis Activities of Daily Living (MGADL) score of less than 5. In the subgroup of symptomatic patients with an MG-ADL score of more than 5, the most common reasons for not meeting the criteria were complement inhibitor use, intravenous immunoglobulin use in the last 4 weeks, and recent medication changes.
- The recent study highlights that a significant proportion of patients with generalized myasthenia gravis (gMG) in routine care do not meet the strict criteria for phase 3 clinical trials, indicating the need for more inclusive standards.
- Among the reasons for failing to meet criteria, having a low Myasthenia Gravis Activities of Daily Living score and recent medication changes were notable factors.
- The study underscores the importance of considering broader eligibility criteria in MG clinical trials to improve research inclusivity and the applicability of findings to a more diverse patient population.
"It was quite astonishing to discover that the majority of the patients treated in routine care would not have satisfied the eligibility requirements for recently approved medications," lead author Nakul Katyal, MD, assistant professor of neurology at the University of Kentucky, told NeurologyLive®. "Our next step is to collect data over an extended period at our institution and partner with other institutions to gather more extensive data for evaluating the applicability of our initial results."
In this analysis, Katyal and colleagues evaluated the percentage of MG patients receiving routine clinical care who meet clinical trial eligibility criteria and the main reasons for failure to meet study criteria. In the study, included patients with AChR+ve gMG with documented MG-ADL scores had clinical data assessed that comprised of MG history, concomitant treatment(s), and MG-ADL score from both new and follow-up visits through June 2023 to determine the eligibility for clinical trials.
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The authors noted that recent and ongoing phase 3 clinical trials for assessing potential therapeutics for patients with gMG use strict inclusion and exclusion criteria. The current structured criteria lacks the opportunity to include diverse patients and also leads to difficulty in recruiting patients for trials as well as potentially limiting the generalizability of their results to a heterogenous clinic population.
Previously, completed clinical trials have had a variety of designs but also were potentially structured in less explicit ways. A study published in 2018 highlighted the extent to which the eligibility criteria of clinical trials can impact the characteristics of the study population.2 In this analysis, the authors reflected on clinical trials in their design, conduct, and outcome to identify what lessons can be learned to potentially help design future trials and therefore improve therapeutic development efforts. Study design, including treatment duration, strategies for steroid tapering, and selection of outcome measures, were found to similarly influence the ability of a trial to demonstrate a therapeutic effect.
Investigators also noted that trial eligibility criteria may inadvertently select for incidents compared with prevalent cases or patients with relatively mild versus more severe cases of the disease. In addition, the authors noted that trial enrichment for patients who have relatively mild disease may limit the sensitivity of the study for identifying a therapeutic effect. Additionally, enrichment for patients with more severe disease may show confounds caused by regression toward the mean, and overly narrow eligibility may limit the generalizability of results. Notably, the study authors added that an exclusive focus on incident cases may set back recruitment because of factors such as access to treatment outside of the trial or after the completion of the double-blind treatment period.
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1. Katyal N, Clifford K, Goyal N, Muppidi S, et al. Effect of Applying Inclusion and Exclusion Criteria of Phase 3 Trials to Myasthenia Gravis Patients in Routine Clinical Care. Presented at: American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting; November 1-4, 2023; Phoenix, AZ. Abstract 63.
2. Benatar M, Howard JF Jr, Barohn R, Wolfe GI, Cutter G. Learning from the past: reflections on recently completed myasthenia gravis trials. Ann N Y Acad Sci. 2018;1412(1):5-13. doi:10.1111/nyas.13501