# Presentation: 229274

## Slide 1

## Vaccine Safety Research Methods

**  ****Hypothesis generating**
**Vs. **
**Hypothesis testing**

## Vaccine Safety Research Methods

**Hypothesis generating****	**
- Passive surveillance systems
- Vaccine Adverse Event Reporting System (VAERS)
- Active surveillance systems
- Rapid Cycle Analysis (RCA)
- Post-marketing screening studies
- Safety of the Pediatric Trivalent Inactivated Influenza Vaccination (TIV) (I & II)

## Safety of Pediatric TIV (I)

**Objective **
**  **To screen a large cohort of children ages 6 months to 18 years who received the TIV for evidence of medically attended events (MAE) following vaccination

## Safety of Pediatric TIV (I)

- Vaccine Safety Datalink (VSD)
- 5 Managed Care Organizations (MCOs): Kaiser Permanente (KP) Northern California, KP Southern California, Group Health Cooperative, KP Northwest, and KP Colorado
- >3,500,000 children under 18 years of age

## Safety of Pediatric TIV (I)

- Data ranging 1/1/93 – 12/31/99
- Outpatient/ED visits, 1/1/95 – 12/31/99
- Inpatient visits, 1/1/93 – 12/31/99
- Children who received at least one TIV shot were included in the cohort
- 251,600 children who received 438,167 TIV vaccinations

## Safety of Pediatric TIV (I)

- 1,165 diagnosis codes occurred during the 2 weeks following flu vaccination
- Only analyzed those who experienced an event during the follow-up period

## Risk and Control Periods

- Flu
- Vaccination
- Day 0

- Control Group 1:
- Days -28    -15

- Control Group 2:
- Days 15 - 28

- Risk Period:
- Days 1-14

## Inpatient	

**Inpatient****	**

- 438,167 Shots

- Sample 1
- 219,084 Shots

- Sample 2
- 219,083 Shots

-  Confirm against
-  Sample 2

- Remove codes
- not biologically
- plausible

- P < .05 compared to EITHER
- control group

## Final Steps

**ORs > 1 and p < .05 in both samples**
- Medical chart review on the cases to confirm case status
- Reanalyze data with confirmed incident cases

## Conclusions

**No signals of any serious events noted**
- Confirms that a signal has not been missed by VAERS

## Safety of Pediatric TIV (II)

- Same objective as the first study, but the analysis focused on children 6 to 23 months
- 8 MCOs
- Data ranging from 1/1/1991 – 5/31/2003
- Used similar self-control methodology as the first study

## Safety of Pediatric TIV (II)

- Did not randomly split the cohort
- Required a significant association (P < 0.05) against both control periods before and after vaccination
- Conducted an additional self-controlled case series (SCCS) analysis on biologically plausible significant associations, controlling for age and season

## Safety of Pediatric TIV (II)

- Screened more than 45,356 children, representing 69,359 TIV vaccinations
- Analyzed more than 1200 ICD-9 codes and 20,000 MAEs
- Examined MAEs in post-vaccination risk windows of 3, 14, and 42 days

## Conclusions

**Similar conclusions to the first safety of TIV study**
- Possible association with fever and pain crisis in 14 days following vaccination in children with sickle cell anemia
- Case-control study in VSD underway

## Strengths of Screening Studies

- Relatively fast turnaround
- Analyze multiple outcomes
- Denominator data – in contrast to VAERS
- Control for potential confounders
- Can follow-up positive signals with chart review
- Bridges the gap between passive surveillance and formal hypothesis testing studies

## Limitations of Screening Studies

- Multiple comparisons – type 1 error
- Many outcomes not biologically plausible
- Difficult to control for age and seasonal effects
- Biases inherent to administrative data

## Summary

- Good method for screening a large cohort in a relatively short amount of time
- Requires chart review for positive signals
- May have a role in post-licensure safety screening of new vaccines
** **

## Acknowledgments

- Vaccine Safety Datalink
- Co-authors on TIV studies
- Simon J. Hambidge, David McClure, Eric K France, Stanley Xu, Kristi Yamasaki, Lisa Jackson, John P. Mullooly, Kenneth M. Zangwill, S. Michael Marcy, Steven B. Black, Edwin M. Lewis, MPH, Henry R. Shinefield, Edward Belongia, James Nordin, Robert T. Chen, David K. Shay, Robert L. Davis, and Frank DeStefano. ** **

## References

- France EK, Glanz JM, Xu S, et al. Safety of the trivalent inactivated vaccine among children: A population-based study. Arch Pediatr Adolesc Med 2004 Nov;158(11):1031-1036.
- Hambidge SJ, Glanz JM, McClure D, et al. Safety of the trivalent influenza vaccine in infants and young children ages 6-23 months: A population-based study. JAMA 2006 Oct 25;296(16):1990-7.
- Glanz JM, Mcclure DL, Xu S, Hambidge SJ, Lee M, Kolczak MS, et al.  Four different study designs to evaluate vaccine safety were equally valid with contrasting limitations. J Clin Epidemiol 2006; 59:808-18.

## Negative Odds Ratios

**In both studies (I ****&II), there were several significant ORs between 0.40 and 0.90 for common acute illnesses**** **
- URI
- Cough
- Otitis Media
- Pneumonia
- Sinusitis
- Bronchitis

## Why The Negative Odds Ratios?

- “Healthy Vaccinee” Effect
- “Expected Symptoms” Effect
- “Sick of the Clinic” Effect
- “Vaccinated When Sick” Effect

## Risk and Control Periods

- Flu
- Vaccination
- Day 0

- Control Group 1:
- Days -28    -15

- Control Group 2:
- Days 15 - 28

- Risk Period:
- Days 1-14

## Why The Negative Odds Ratios?

- “Healthy Vaccinee” Effect
- “Expected Symptoms” Effect
- “Sick of the Clinic” Effect
- “Vaccinated When Sick” Effect

## Why The Negative Odds Ratios?

- “Healthy Vaccinee” Effect
- “Expected Symptoms” Effect
- “Sick of the Clinic” Effect
- “Vaccinated When Sick” Effect

## Why The Negative Odds Ratios?

- “Healthy Vaccinee” Effect
- “Expected Symptoms” Effect
- “Sick of the Clinic” Effect
- “Vaccinated When Sick” Effect