Signal Detection and Methodological Limitations in a Real-World Registry: Learnings from the Evaluation of Long-Term Safety Analyses in PSOLAR

• Published in: Drug safety 2021-06, Vol.44 (6), p.699-709
• Main Authors: Bissonnette, Robert, Gottlieb, Alice B., Langley, Richard G., Leonardi, Craig L., Papp, Kim A., Pariser, David M., Uy, Jonathan, Lafferty, Kim Parnell, Langholff, Wayne, Fakharzadeh, Steven, Berlin, Jesse A., Brouwer, Emily S., Greenspan, Andrew J., Strober, Bruce E.
• Format: Article
• Language: English
• Subjects: Analytical methods; Annual reports; Biological products; Cardiovascular disease; Cardiovascular diseases; Clinical trials; Confidence intervals; Drug Safety and Pharmacovigilance; Enrollments; Health risks; Infliximab; Medicine; Medicine & Public Health; Methods; Monoclonal antibodies; Original; Original Research Article; Patients; Pharmacology/Toxicology; Psoriasis; Regression models; Regulatory approval; Risk; Safety; Signal detection; Statistical analysis; Tumor necrosis factor-α
• ISSN: 0114-5916; 1179-1942
• DOI: 10.1007/s40264-021-01065-z

Introduction Pso riasis L ongitudinal A ssessment and R egistry (PSOLAR) was designed in 2007 as the first disease-based registry for patients with psoriasis. Objective The aim of this study was to discuss methodological limitations and post hoc analyses in long-term safety registries using learnings from analyses of a potential safety risk for major adverse cardiovascular events (MACE) in PSOLAR. Methods PSOLAR is an international observational study of over 12,000 psoriasis patients that was conducted to meet postmarketing safety commitments for infliximab and ustekinumab. A recent annual review of registry data indicated a potential MACE risk for ustekinumab vs. non-biologics based on prespecified COX model regression analyses, which yielded an adjusted hazard ratio (HR) of 1.533 (95% confidence interval [CI] 1.103–2.131). Therefore, we conducted a comprehensive review of key statistical methodology and implemented post hoc analytical methods to address specific limitations. Results The following limiting factors were identified: (1) inclusion of both prevalent and incident (new) users of biologics; (2) unanticipated imbalances in patient characteristics between treatment cohorts at baseline; (3) limited availability of relevant clinical data after enrollment; and (4) divergence of characteristics associated with outcomes among comparator groups over time. The analysis was modified to include only incident users, propensity scores were used to weight HRs, and adalimumab was deemed a more clinically appropriate comparator. The revised HR was 0.820 (95% CI 0.532–1.265), indicating no meaningful increase in MACE risk for ustekinumab. Conclusion Our results, which do not support a causal association between ustekinumab exposure and MACE risk, underscore the need for ongoing assessment of analytical methods in long-term observational studies.