title: Using epidemiological registry data to provide background rates as context for adverse events in a rheumatoid arthritis drug development program: a coordinated approach.
abstract: OBJECTIVE
  Observational studies can provide context for adverse events observed in clinical trials, especially for infrequent events or long-term risks. We developed methods to improve safety contextualization for a rheumatoid arthritis drug development program through coordinated analyses of multiple registries.
  
  
  METHODS
  We identified and characterized differences and similarities across five registries (Swedish Rheumatology Quality of Care Register, Consortium of Rheumatology Researchers of North America [CORRONA], Norfolk Arthritis Register, Institute of Rheumatology Rheumatoid Arthritis, and the new CORRONA International), harmonized outcome definitions, and investigated whether restricted subcohorts improved comparability with trial populations. To address confounding, we identified risk predictors for outcomes of interest (mortality, cardiovascular disease, infection, and malignancy). We used patient-level analyses at each registry and central analysis of standardized group-level data.
  
  
  RESULTS
  Despite data differences, the coordinated approach enabled consistent variable definitions for key baseline characteristics and outcomes. Selection of restricted subcohorts (e.g., using active joint count criteria) improved baseline comparability with trial patients for some rheumatoid arthritis disease activity measures, but less for other characteristics (e.g., age and comorbidity); however, such selection decreased sample size considerably. For most outcomes, age was the most important risk predictor, emphasizing the importance of age/sex standardization to address confounding. The prospective approach enabled use of recent relevant data; the distributed analysis safeguarded confidentiality of registry data.
  
  
  CONCLUSIONS
  Compared with reliance on published data alone, a forward-looking coordinated approach across multiple observational data sources can improve comparability and consistency and better support sensitivity analyses and data interpretation, in contextualizing safety data from clinical trials. This approach may have utility to support safety assessments across diverse diseases and drug development programs and satisfy future regulatory requirements.
authors: Medical Evidence & Observational Research Centre, Global Medicines Development, AstraZeneca R&D, Mölndal, Sweden.|Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Fredrik
authors: F
authors: Nyberg
authors: Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.|Department of Rheumatology, Karolinska University Hospital, Stockholm, Sweden.
authors: Johan
authors: J
authors: Askling
authors: Biometric & Information Sciences, Global Medicines Development, AstraZeneca R&D, Mölndal, Sweden.
authors: Niklas
authors: N
authors: Berglind
authors: Biometric & Information Sciences, Global Medicines Development, AstraZeneca R&D, Mölndal, Sweden.
authors: Stefan
authors: S
authors: Franzén
authors: Clinical, Global Medicines Development, AstraZeneca R&D, Macclesfield, UK.
authors: Meilien
authors: M
authors: Ho
authors: Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors: Marie
authors: M
authors: Holmqvist
authors: Medical Evidence & Observational Research Centre, Global Medicines Development, AstraZeneca, Wilmington, DE, USA.
authors: Laura
authors: L
authors: Horne
authors: Clinical, Global Medicines Development, AstraZeneca, Wilmington, DE, USA.
authors: Kathy
authors: K
authors: Lampl
authors: University of Nebraska Medical Center, Omaha, NE, USA.|National Data Bank for Rheumatic Diseases, Wichita, KS, USA.
authors: Kaleb
authors: K
authors: Michaud
authors: The College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
authors: Dimitrios A
authors: DA
authors: Pappas
authors: University of Massachusetts Medical School, Worcester, MA, USA.
authors: George
authors: G
authors: Reed
authors: NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.|Arthritis Research UK Centre for Epidemiology, The University of Manchester, Manchester, UK.
authors: Deborah
authors: D
authors: Symmons
authors: Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan.
authors: Eiichi
authors: E
authors: Tanaka
authors: MedImmune, Gaithersburg, MD, USA.
authors: Trung N
authors: TN
authors: Tran
authors: Arthritis Research UK Centre for Epidemiology, The University of Manchester, Manchester, UK.
authors: Suzanne M M
authors: SM
authors: Verstappen
authors: Patient Safety, GRAPSQA, Global Medicines Development, AstraZeneca R&D, Macclesfield, UK.
authors: Eveline
authors: E
authors: Wesby-van Swaay
authors: Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan.
authors: Hisashi
authors: H
authors: Yamanaka
authors: NYU School of Medicine, New York, NY, USA.|Corrona LLC, Southborough, MA, USA.
authors: Jeffrey D
authors: JD
authors: Greenberg
mesh_terms: D000368:Aged; D000631:Aminopyridines; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000503:physiopathology; D015195:Drug Design; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D010078:Oxazines / Q000009:adverse effects / Q000627:therapeutic use; D011446:Prospective Studies; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use; D011743:Pyrimidines; D012042:Registries / Q000706:statistics & numerical data*; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D000631:Aminopyridines; D018501:Antirheumatic Agents; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; C523665:fostamatinib
keywords: adverse events; clinical trials; methodology; observational data; pharmacoepidemiology; registries; rheumatoid arthritis