title: Earlier identification of risks: cumulative probability analysis of time to safety alerts for therapeutic monoclonal antibodies.
abstract: OBJECTIVE
  Previous analysis of US FDA Medwatch safety alerts for monoclonal antibody therapeutics demonstrated that premarketing clinical trials can predict more than half of safety concerns. We expanded this analysis to assess whether the predictable alerts are detected sooner than the unpredictable alerts.
  
  
  METHODS
  Times to alert were compared using Mann-Whitney test, Kolmogorov-Smirnov test, and using curves displaying cumulative frequencies of alerts over time.
  
  
  RESULTS
  Until December 31, 2013 inclusive, 76 Medwatch alerts for therapeutic monoclonal antibodies were reported: 43 predictable vs. 33 unpredictable. Predictable alerts were reported at a median (IQR) of 41 (19-77) months after approval vs. 53 (23-73) months for the unpredictable alerts. The mean (SE) was 52.07 (6.69) months and 55.91 (7.06) months for the predictable and unpredictable, respectively. Although the difference of 12 months between medians of time to alert was observed, the difference was not demonstrated as significant. Cumulative frequency curves show that predictable alerts were detected sooner until month 73 after approval, when ~ 80% of alerts were detected. Immunological reactions (such as infusion reactions, anaphylaxis, and reactions due to antibodies) were identified early; all 12 such alerts were released before the curves of cumulative frequencies cross at month 73. On the other hand, reactions occurring after the curves cross are predominantly late-occurring cancers and opportunistic infections.
  
  
  CONCLUSIONS
  The results imply that focus on predictable reactions defined as potential risks may play a role in early detection of important safety concerns.
authors.forename: Vid
authors.initials: V
authors.lastname: Stanulović
authors.forename: Pavla
authors.initials: P
authors.lastname: Kadlecová
authors.forename: Romána
authors.initials: R
authors.lastname: Zelkó
authors.forename: Sándor
authors.initials: S
authors.lastname: Kerpel-Fronius
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology* / Q000517:prevention & control; D006801:Humans; D053208:Kaplan-Meier Estimate; D061214:Patient Safety; D011336:Probability; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000911:Antibodies, Monoclonal