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

Robert Bissonnette (), Alice B. Gottlieb, Richard G. Langley, Craig L. Leonardi, Kim A. Papp, David M. Pariser, Jonathan Uy, Kim Parnell Lafferty, Wayne Langholff, Steven Fakharzadeh, Jesse A. Berlin, Emily S. Brouwer, Andrew J. Greenspan and Bruce E. Strober
Additional contact information
Robert Bissonnette: Innovaderm Research, Inc.
Alice B. Gottlieb: Icahn School of Medicine at Mount Sinai
Richard G. Langley: Dalhousie University
Craig L. Leonardi: Saint Louis University Medical School
Kim A. Papp: K. Papp Clinical Research and Probity Research Inc.
David M. Pariser: Eastern Virginia Medical School
Jonathan Uy: Janssen Scientific Affairs, LLC
Kim Parnell Lafferty: Janssen Scientific Affairs, LLC
Wayne Langholff: Janssen Research & Development, LLC
Steven Fakharzadeh: Janssen Global Services, LLC
Emily S. Brouwer: Janssen Research & Development, LLC
Andrew J. Greenspan: Janssen Scientific Affairs, LLC
Bruce E. Strober: Yale University

Drug Safety, 2021, vol. 44, issue 6, No 8, 699-709

Abstract: Abstract Introduction Psoriasis Longitudinal Assessment and Registry (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.

Date: 2021
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DOI: 10.1007/s40264-021-01065-z

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