# Presentation: 689553

## Session 4Adverse Event Reporting

- Deborah A. Zarin, M.D.

## Expanded Clinical Trial Registry

**Enactment**

- 1 yr

- 2 yr

- 3 yr

- 18 m

- Linking to existing results information at FDA and NIH

- Launch Basic Results Database

- Expansion by Rulemaking: Final Rule

- Additional Adverse Events Data

**REGISTRY**

**RESULTS**

- 90 d

- Public Meeting

**9/27/07**

- Pilot Quality Control Project
- Recommendation to Secretary – Narrative Summaries

**12/26/07**

**9/27/08**

**3/27/09**

**9/27/10**

- New Administration
- Transition Phase

## Adverse Events - Default

- If the Secretary fails to issue regulation by 24 months after the date of enactment [September 2009]
- SERIOUS ADVERSE EVENTS
- Table of anticipated and unanticipated serious adverse events
- Grouped by organ system
- Number and frequency of event in each arm of clinical trial
- FREQUENT ADVERSE EVENTS
- 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

## Results RecordAdverse Events

- Results RecordAdverse Events

**Adverse Events**

**Serious Adverse Events****	****	****          **N/A		 N/A
**Frequent Adverse Events (>5%)**
- Nervous System Disorders
-   Headache			      75 (6.2%)	          70 (58%)
- Gastrointestinal Disorders
-   Diarrhea			      67 (5.6%)	          66 (5.5%)
-   Nausea			      61 (5.1%)	          57 (4.8%)

_**Esomeprazole**_
**N=1,205*******

_**Omeprazole**_
**N=1,200**

*****

- 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

## Frequency

- US Public Law 110-85 Default:  Frequent AEs
- AEs that exceed a frequency of 5%
- CONSORT
- 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

## Key Implementation Issues

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

## Example

- 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

## GSK Clinical Trial Register

- http://ctr.gsk.co.uk/Summary/lapatinib/studylist.asp

**Frequency:**             Most frequent 10 events in each group

**Attribution:**        Not specified

**Timing:**             AEs collected from first dose ... to 30 days after last dose

**Most Frequent Adverse Events on Therapy**

## GSK Clinical Trial Register

**Any Serious Adverse Events on Therapy**

**Timing:**             On-Therapy (first dose of study medication to last day of study medication)

**Frequency:**             Any (i.e., all)

**Attribution:** related – considered by the investigator to be related to study medication

## Slide 12

## Slide 13

## New England Journal of Medicine

**Timing:**             Adverse events through November 15, 2005

**Frequency:**             Not specified

**Attribution:**           Not specified

- N Engl J Med 2006;355:2733-43

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

## FDA Approved Label

**Attribution**:       Not specified

**Timing:**              Not specified

**Frequency:**             Occurring in _> _10% of patients