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Adverse Event Reporting

Session 4: Adverse Event Reporting

Deborah A. Zarin, M.D.

Timeline showing that additional adverse events data is required not later than 18 months after enactment (March 27, 2009).

Adverse Events - Default

  • If the Secretary fails to issue regulation by 24 months after the date of enactment [September 2009]
    • Table of anticipated and unanticipated serious adverse events
    • Grouped by organ system
    • Number and frequency of event in each arm of clinical trial
    • Table of anticipated and unanticipated adverse events
    • Exceed a frequency of 5 percent within any arm of clinical trial
    • Grouped by organ system
    • Number and frequency of event in each arm of clinical trial

Published Adverse Events

Table 4: Adverse Events Occurring With a Frequency of at Least 2.0%

 Esomeprazole (n = 1205)Omeprazole (n = 1200)
No. (%) of Patients
Headache 75 (6.5%) 70 (5.8%)
Diarrhea 47 (3.9%) 56 (4.7%)
Nausea 36 (3.0%) 36 (3.0%)
Abdominal Pain 31 (2.6%) 32 (2.7%)

Results Record

Adverse Events

 Esomeprazole N-1,205*Omeprazole N=1,200
Serious Adverse Events N/A N/A
Frequent Adverse Events (>5%)
Nervous System Disorders
75 (6.2%) 70 (58%)
Gastrointestinal Disorders
67 (5.6%)
61 (5.1%)
66 (5.5%)

*Of the 2.425 patients with erosive esophagitis randomized to study medication, 2,405 patients received at least one dose of either esomeprazole (n = 1,205) or omeprazole (n = 1,200)

Issues in Reporting Adverse Event Data

  • Definitions: AE, serious AE
  • Characteristics to consider
    • Frequency (threshold)
    • Attributable?
    • Statistically significant?
    • # assessed (and time frame)
    • Systematically assessed?
  • How to count and how to report
    • Splitting vs. lumping
    • Recurrent events in same patient


  • US Public Law 110-85 Default: Frequent AEs
    • AEs that exceed a frequency of 5%
    • Poor reporting practice: "Reporting only the adverse events observed at a certain frequency or rate threshold (for example, >3% or >10%)."
  • FDA – Adverse Reactions Section of Labeling – General Principles for Presenting Adverse Events in a Table
    • The frequency cutoff for the listing of common adverse reactions identified from clinical trials (usually the adverse reactions table) must be appropriate to the safety database
      • Factors that could influence selection of a frequency cut-off include the size of the safety database, the designs of the trials in the database, and the nature of the indication.  The frequency cutoff should be noted in the listing or table header, in the text accompanying the listing or table, or in a footnote.

Ann Intern Med. 2004;141:781-788

FDA Guidance for Industry - Adverse Reactions Section of Labeling for Human - Prescription Drug and Biological Products — Content and Format Proposed Approach

Key Implementation Issues

  • Default v. regulation
    • Default as voluntary “pilot” to inform rulemaking?
  • Timing of submissions—relationship to completion date and outcome measures


  • A Phase III, Randomized, Open-Label, Multicenter Study Comparing GW572016 [lapatinib] and Capecitabine (Xeloda) versus Capecitabine in Women with Refractory Advanced or Metastatic Breast Cancer
  • GlaxoSmithKline
  • Sources:
    • GSK clinical trial register
    • New England Journal of Medicine
    • Drugs @ FDA: Lapatinib label
Continuation of listing of any serious adverse events on therapy
Continuation of listing of any serious adverse events on therapy

New England Journal of Medicine

Image of table of adverse events as reported in the related New England Journal article. Timing – Adverse events through November 15, 2005. Frequency – Not specified. Attribution – Not specified. AEs reported by four grade levels and total (any grade). Includes p-value for each type of event

N Engl J Med 2006;355:2733-43

Table 3 shows adverse events through November 15, 2005, according to the treatment received.

FDA Approved Label

Timing – Not specified. Frequency – Occurring in >= 10% of patients. Attribution --  Not specified. Grade 3, Grade 4, and All Grades. Grouped by organ systems (e.g., gastrointestinal, skin and subcutaneous tissue)