Rotateq and Intussusception

1
Rotateq and Intussusception

• Lee Hampton, MD, MSc
• Advisor Robert Baltimore, MD
• September 29, 2008

2
Overview

• Clinical Scenario and Question
• Search Strategy and Background
• Article Validity
• Article Results
• Clinical Implications

3
Scenario

• 2 month old infant due for routine vaccinations
• Pediarix (DTAP, IPV, HBV)
• Prevnar (PCV7)
• ActHib (Hib)
• Rotateq (Rotavirus)
• Patients mother actually reads the VIS about
  rotavirus vaccine

4
Clinical Question
http//www.cdc.gov/vaccines/pubs/vis/downloads/vis
-rotavirus.pdf

• Mother asks, How do we know rotateq will not
  cause intussusception in my baby? Is it really
  safe?
• Mother is not reassured by CDCs endorsement

5
PICO

• Patients Infants
• Intervention Rotateq vaccine
• Rotateq Pentavalent human-bovine reassortant
  live rotavirus vaccine
• Comparator No vaccine
• Outcome Intussusception

aapredbook.aappublications.org/week/114_01.jpg
Clark HF, et al. The New Pentavalent Rotavirus
Vaccine Composed of Bovine (Strain WC3) Human
Rotavirus Reassortants. Pedi ID Journal 2006
25 577-583.
6
(No Transcript)
7
Search Results

• 26 articles
• 1 randomized control trial
• Rotateq Efficacy and Safety Trial
• 34,000 infants got vaccine, 34,000 got placebo
  (5-10x larger than usual vaccine studies)
• No increased risk of intussusception
• 2 post-licensure surveillance reports
• 1 survey of rotateq vaccine uptake
• 22 commentaries

Vesikari T, et al. Safety and Efficacy of a
Pentavalent Human-Bovine (WC3) Reassortant
Rotavirus Vaccine. NEJM 2006 354 22-33.
8
Vaccine Clinical Trials and Their Limitations

• Pros
• Collection of very detailed data
• Usually blinded, randomized, controlled trials
• Cons
• Limited sample size
• Limited follow-up time
• May not assess every important outcome

Levine M, et al. How to Use an Article About
Harm. JAMA 1994 271 1615-1619. Meyboom RHB, et
al. Pharmacovigilance in Perspective. Drug
Safety 1999 21 429-447.
9
Post-licensure Vaccine Problems

• Significant vaccine associated adverse events may
  not show up until after a vaccine is licensed
• Hepatitis with yellow fever vaccine during WWII
• Paralytic polio with early inactivated polio
  vaccine, aka Salk vaccine (Cutter incident)
• Paralytic polio with live, attenuated polio
  vaccine, aka Sabin or oral polio vaccine
• Guillain-Barré Syndrome with 1976 swine flu
  vaccine
• Guillain-Barré Syndrome with menactra (MCV4)

Farley J. To Cast out Disease A History of the
International Health Division of the Rockefeller
Foundation (1913-1951). New York, NY Oxford UP,
2004. Offit PA. The Cutter Incident How
Americas First Polio Vaccine Led to the Growing
Vaccine Crisis . New Haven, CT Yale University
Press, 2005. Woo EJ, Ball R, Braun M, et al.
Update Guillain-Barré Syndrome Among Recipients
of Menactra Meningococcal Conjugate Vaccine ---
United States, June 2005--September 2006. MMWR
2006 55 1120-1124.
10
Withdrawal of Rotashield

• Rhesus-human reassortant vaccine for rotavirus
• Clinical trials (10,000 got vaccine, 4600 got
  placebo) showed small, statistically
  insignificant increase in intussusception among
  vaccinees
• Approved by FDA in 1998
• 1.5 million doses distributed
• 15 intussusception cases reported to VAERS,
  warning issued, and vaccination suspended in 1999
• 83 more cases reported, case control study showed
  increased risk, product withdrawn

Haber P, et al. Murphy TV, et al. Rennels MB.
Simonsen L, et al.
11
Post-Licensure Surveillance Article

• Haber P, et al. Postlicensure Monitoring of
  Intussusception After RotaTeq Vaccination in the
  United States, February 1, 2006, to September 25,
  2007. Pediatrics June 2008 121 1206-1212.
• Data from
• VAERS (Vaccine Adverse Event Reporting System)
• VSD (Vaccine Safety Datalink)

12
Vaccine Adverse Event Reporting System

• Started in 1990 by CDC and FDA
• Passive detection system
• Patients, health care providers, parents, and
  manufacturers can report any problem that occurs
  after any vaccination
• System is basically voluntary
• Receives 10,000-15,000 reports annually
• Potentially covers entire US population
• Usually used to generate hypotheses

Varricchio F, et al. Understanding Vaccine
Safety Information from the Vaccine Adverse Event
Reporting System. Pedi ID Journal 2004 23
287-294
13
VAERS and Brighton

• Adverse event report descriptions and quality
  vary dramatically
• Brighton Collaboration seeks to define adverse
  events and classify each case reports
  reliability
• Level I intussusception Intestinal invagination
  shown via surgery or radiologically monitored
  enema
• Article only analyzes confirmed level I cases

Bines JE, et al. Acute Intussusception in
Infants and Children as an Adverse Event
Following Immunization Case Definition and
Guidelines of Data Collection, Analysis, and
Presentation. Vaccine 2004 22 569-574. Haber
P, et al. Postlicensure Monitoring of
Intussusception After RotaTeq Vaccination in the
United States, February 1, 2006, to September 25,
2007. Pediatrics June 2008 121 1206-1212.
14
VAERS Event Rates

• Voluntary reporting of problems can lead to
  significant underreporting
• Ca. 1-10 of minor events are reported
• Ca. 70 of serious problems (e.g. paralytic
  poliomyelitis) are reported
• Cannot determine exactly how many children
  vaccinated
• Estimates based on the number of vaccine doses
  distributed can be used for rough rate
  denominators

• Haber P, et al. Postlicensure Monitoring of
  Intussusception After RotaTeq Vaccination in the
  United States, February 1, 2006, to September 25,
  2007. Pediatrics June 2008 121 1206-1212.
• Varricchio F, et al. Understanding Vaccine
  Safety Information from the Vaccine Adverse Event
  Reporting System. Pedi ID Journal 2004 23
  287-294

15
Validity in Studies of Harm

• Clearly identified comparison groups similar in
  important determinants of outcome aside from one
  of interest?
• Outcomes and exposures measured in the same way
  in all comparison groups?
• Follow-up sufficiently long and complete?
• Temporal relationship correct?
• Dose response gradient?

Levine M, et al. How to Use an Article About
Harm. JAMA 1994 271 1615-1619.
16
Comparisons with VAERS

• Cannot determine unvaccinated event rate
• Other databases like VSD can provide estimates
  but use different data collection methods
• Can compare number of VAERS reports for different
  vaccines (e.g. rotashield)
• Same data collection methods but major potential
  confounding
• Reporter bias
• Anti-vaccination groups, media attention
• FDA warning in Feb. 2007 provided media boost

• Haber P, et al. Postlicensure Monitoring of
  Intussusception After RotaTeq Vaccination in the
  United States. Pediatrics June 2008 121
  1206-1212.
• Varricchio F, et al. Understanding Vaccine
  Safety Information from the Vaccine Adverse Event
  Reporting System. Pedi ID Journal 2004 23
  287-294

17
VAERS Validity

• Can sometimes assess temporal association
• Authors reviewed case medical records
• Follow-up potentially indefinite
• Article follow-up varies between 1 and 19 months
• Fixed doses preclude dose-response analysis if
  each doses risk is independent of the others

• Haber P, et al. Postlicensure Monitoring of
  Intussusception After RotaTeq Vaccination in the
  United States. Pediatrics June 2008 121
  1206-1212.
• Varricchio F, et al. Understanding Vaccine
  Safety Information from the Vaccine Adverse Event
  Reporting System. Pedi ID Journal 2004 23
  287-294

18
Results in Studies of Harm

• How strong is the association between risk and
  exposure?
• How precise is the estimate of the risk?

Levine M, et al. How to Use an Article About
Harm. JAMA 1994 271 1615-1619.
19
VAERS Results
Rotateq Rotashield Cases reported
160 98 Doses distributed 9,120,000
1,500,000 Case/Dose 1/57,000 1/15,000
Haber P, et al. Postlicensure Monitoring of
Intussusception After RotaTeq Vaccination in the
United States. Pediatrics June 2008 121
1206-1212.
20
VAERS Observed vs. Expected
Haber P, et al. Postlicensure Monitoring of
Intussusception After RotaTeq Vaccination in the
United States. Pediatrics June 2008 121
1206-1212.
21
VAERS Observed vs. Expected Sensitivity Analysis

• Rotateq would significantly increase risk if
• Only 50 of intussusception cases reported and
• Only 50 of vaccine distributed

Haber P, et al. Postlicensure Monitoring of
Intussusception After RotaTeq Vaccination in the
United States. Pediatrics June 2008 121
1206-1212.
22
Vaccine Safety Datalink

• Database of medical records from eight West Coast
  managed care organizations with 6 million
  members, ca. 2 of US pop.
• Allows calculation of background incidence rate
  of events using ICD-9 codes
• Better characterization of patients and events
  than VAERS
• Less underreporting of events
• Uses unvaccinated children as control group

Chen RT, et al. The Vaccine Safety Datalink
Immunization Research in Health Maintenance
Organization in the USA. Bulletin WHO 2000 78
186-194.
23
VSD Validity

• Similar comparison groups?
• Vaccination 49,902 children received at least
  one dose, 111,521 doses given total
• Control 186,772 children of the same age in the
  same HMOs who did not receive rotateq during the
  same period
• No information on other differences between
  groups
• Analysis of cases 3-7 days after vaccination
  combined REST with VSD data
• Outcomes and exposures measured in the same way
  in all comparison groups?
• Yes Review of HMO vaccination and medical event
  records

Chen RT, et al. The Vaccine Safety Datalink
Immunization Research in Health Maintenance
Organization in the USA. Bulletin WHO 2000 78
186-194. Haber P, et al. Postlicensure
Monitoring of Intussusception After RotaTeq
Vaccination in the United States. Pediatrics
June 2008 121 1206-1212. Levine M, et al. How
to Use an Article About Harm. JAMA 1994 271
1615-1619.
24
VSD Validity

• Follow-up sufficiently long and complete?
• Probably Both groups monitored for 30 days
• Temporal relationship correct?
• Yes All analyzed cases of intussusception
  followed vaccination
• Dose response gradient?
• Maybe Vaccines used fixed dose administration,
  but the system should indicate whether the risks
  of multiple doses are synergistic

Chen RT, et al. The Vaccine Safety Datalink
Immunization Research in Health Maintenance
Organization in the USA. Bulletin WHO 2000 78
186-194. Haber P, et al. Postlicensure
Monitoring of Intussusception After RotaTeq
Vaccination in the United States. Pediatrics
June 2008 121 1206-1212. Levine M, et al. How
to Use an Article About Harm. JAMA 1994 271
1615-1619.
25
VSD Results

• How strong is the association between risk and
  exposure?
• 3 cases (Days 10, 17, 20) in 111,521 vaccinees
• 9 cases among 186,722 non-vaccinees
• RR of 0.84
• No cases 3-7 days after vaccination in combined
  REST/VSD cohort
• How precise is the estimate of the risk?
• 95 CI 0.14-3.92

Haber P, et al. Postlicensure Monitoring of
Intussusception After RotaTeq Vaccination in the
United States. Pediatrics June 2008 121
1206-1212.
26
Age of Vaccination with Rotashield

• Risk of intussusception increases with age at
  which 1st dose given

• 92 of 1st VSD Doses were given at 6-12 weeks

Haber P, et al. Postlicensure Monitoring of
Intussusception After RotaTeq Vaccination in the
United States. Pediatrics June 2008 121
1206-1212. Simonsen L, et al. More on Rotashield
and Intussusception The Role of Age at the Time
of Vaccination. Journal of ID 2005 192 S36-S43.
27
How Do the Results Affect Patient Care?

• Are the results applicable to the PCC?
• VAERS - Yes. The results should apply to all US
  infants
• VSD Very probably. VSD drawn from mostly middle
  class people on the West Coast
• What is the magnitude of the risk?
• Probably no risk. At worst, 4x increase in risk
• Should I attempt to stop the exposure?
• No, but give within recommended time-frame and
  report any post-vaccine intussusception to VAERS

Chen RT, et al. The Vaccine Safety Datalink
Immunization Research in Health Maintenance
Organization in the USA. Bulletin WHO 2000 78
186-194. Levine M, et al. How to Use an Article
About Harm. JAMA 1994 271 1615-1619.
28
Conclusions

• Post-licensure surveillance can help monitor
  drug/vacccine safety
• VAERS and the VSD are useful surveillance systems
  but can have major problems with data accuracy
  and potential confounding
• VAERS and VSD data supports REST results that
  rotateq is not associated with intussusception
• Good case control study better for testing
  vaccine safety hypotheses

29
References

• Bines JE, et al. Acute Intussusception in
  Infants and Children as an Adverse Event
  Following Immunization Case Definition and
  Guidelines of Data Collection, Analysis, and
  Presentation. Vaccine 2004 22 569-574.
• Chen RT, et al. The Vaccine Safety Datalink
  Immunization Research in Health Maintenance
  Organization in the USA. Bulletin WHO 2000 78
  186-194.
• Clark HF, et al. The New Pentavalent Rotavirus
  Vaccine Composed of Bovine (Strain WC3) Human
  Rotavirus Reassortants. Pedi ID Journal 2006
  25 577-583.
• Davis RL, et al. Active Surveillance of Vaccine
  Safety A System to Detect Early Signals of
  Adverse Events. Epidemiology 2005 16 336-341.
• Farley J. To Cast out Disease A History of the
  International Health Division of the Rockefeller
  Foundation (1913-1951). New York, NY Oxford UP,
  2004.
• Haber P, et al. Postlicensure Monitoring of
  Intussusception After RotaTeq Vaccination in the
  United States, February 1, 2006, to September 25,
  2007. Pediatrics 2008 121 1206-1212.
• Levine M, et al. How to Use an Article About
  Harm. JAMA 1994 271 1615-1619.

30
References

• Meyboom RHB, et al. Pharmacovigilance in
  Perspective. Drug Safety 1999 21 429-447.
• Murphy TV, et al. Intussusception Among Infants
  Given an Oral Rotavirus Vaccine. NEJM 2001 344
  564-572.
• Offit PA. The Cutter Incident How Americas
  First Polio Vaccine Led to the Growing Vaccine
  Crisis . New Haven, CT Yale University Press,
  2005.
• Rennels MB. The Rotavirus Vaccine Story A
  Clinical Investigators View. Pediatrics 2000
  106 123-125.
• Simonsen L, et al. More on Rotashield and
  Intussusception The Role of Age at the Time of
  Vaccination. Journal of ID 2005 192 S36-S43.
• Varricchio F, et al. Understanding Vaccine
  Safety Information from the Vaccine Adverse Event
  Reporting System. Pedi ID Journal 2004 23
  287-294.
• Vesikari T, et al. Safety and Efficacy of a
  Pentavalent Human-Bovine (WC3) Reassortant
  Rotavirus Vaccine. NEJM 2006 354 22-33.
• Woo EJ, Ball R, Braun M, et al. Update
  Guillain-Barré Syndrome Among Recipients of
  Menactra Meningococcal Conjugate Vaccine ---
  United States, June 2005--September 2006. MMWR
  2006 55 1120-1124.

31
Intussusception Cases by Day After Rotateq
Administration
Haber P, et al. Postlicensure Monitoring of
Intussusception After RotaTeq Vaccination in the
United States. Pediatrics June 2008 121
1206-1212.