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) Patient’s mother actually reads the VIS about rotavirus vaccine

4. Clinical Question Mother asks, “How do we know rotateq will not cause intussusception in my baby? Is it really safe?” Mother is not reassured by CDC’s endorsement http://www.cdc.gov/vaccines/pubs/vis/downloads/vis-rotavirus.pdf

5. PICO Patients: Infants Intervention: Rotateq vaccine Rotateq = Pentavalent human- bovine reassortant live rotavirus vaccine Comparator: No vaccine Outcome: Intussusception Clark HF, et al. “The New Pentavalent Rotavirus Vaccine Composed of Bovine (Strain WC3) –Human Rotavirus Reassortants.” Pedi ID Journal 2006; 25: 577- 583. aapredbook.aappublications.org/week/ 114_01.jpg

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 America’s 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 report’s 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 dose’s 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 1 st dose given 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. 92% of 1 st VSD Doses were given at 6-12 weeks

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 America’s First Polio Vaccine Led to the Growing Vaccine Crisis. New Haven, CT: Yale University Press, 2005. Rennels MB. “The Rotavirus Vaccine Story: A Clinical Investigator’s 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.