Intussusception Following Use of RotaShield , A Summary

1. Intussusception Following Use of RotaShield, A Summary Hector S. Izurieta Vaccine Safety Branch Division of Epidemiology Office of Biostatistics and Epidemiology

2. Clinical trials • Findings of pre-licensure clinical trials: • In multiple trials, a total of 5 intussusception (IT) cases were found in 10,054 vaccinees (0.05%) vs. 1 case in 4,633 controls (0.02%) • Difference not statistically significant • All 5 cases occurred after second or third dose • Two occurred with the final vaccine formulation

3. Licensure of RotaShield • Package insert • IT described as potential adverse reaction • August 31, 1998, licensure of RotaShield • FDA/CDC monitor passive reporting of IT to Vaccine Adverse event reporting System (VAERS) • Post licensure phase 4 study planned • March, 1999, ACIP recommended RotaShield for routine use

4. Recommendation for Routine Use Suspended (MMWR, July 1999) • 15 IT cases in VAERS (11 during first week). • Expected number for first week based on doses administered: 14-16 • Population-based studies find high (non-significant) rates of IT within one week following vaccination • ranging between 292 and 314 cases per 100,000 • MMWR stimulates VAERS reporting

5. Withdrawal of RotaShield • October 15, 1999: Wyeth voluntarily withdraws RotaShield • Decision based in part on preliminary results from CDC’s Case Control and Case series studies • October 22, 1999: ACIP withdraws recommendation for vaccine use • License revoked, November 15, 2002

6. Main Study Results • Case-control study and case series analysis find significant results* • Observational cohort (VSD) study also finds significant results** • The effect of age at vaccination is being debated# * Murphy et al.., N Engl J Med. 2001 ** Kramarz et al., Pediatr Infect Dis J. 2001 # Simonsen et al, 2005; Paul Gargiullo, CDC, unpublished

7. Population Attributable Risk for IT • Studies differed in methodology, strengths and limitations • Consensus estimate of population attributable risk* : • 1 IT case per 10,000 vaccinees • high estimate=1 per 5,000 • low estimate=1 per 12,000 * Peter G and Myers M. Pediatrics, 2002

8. Evidence of Possible Association With Natural Rotavirus Infection • Lack of clear evidence that natural rotavirus infection causes IT* • Rotavirus infection associated with increased distal ileum wall thickness and lymphadenopathy** * Rennels et al, Pediatrics, 1998 ** Robinson et al, JID 2004

9. Possible Mechanisms for Association Between RotaShield and IT • RotaShield contains a simian (strain RRV) backbone • “Unique strain” hypothesis* • RRV shed predominantly after first dose • RRV might be evading recognition by passively acquired specific antibodies * Paul Offit, personal communication

10. Summary • Evidence indicates existence of causal association between RotaShield and IT • Association identified post-licensure • Precise mechanisms debated • Consensus estimate of population attributable risk* ~1 per 10,000 vaccinees * Peter G and Myers M. Pediatrics, 2002

11. Acknowledgements Miles Braun, OBE/CBER/FDA Robert Ball, OBE/CBER/FDA Mary Foulkes, OBE/CBER/FDA Douglas Pratt, OVRR/CBER/FDA Paul Gargiulo, NIP/CDC Trudy Murphy, NIP/CDC

12. Outline of Pharmacovigilance Plans for Rotateq® Hector S. Izurieta VSB/DE/OBE/CBER/FDA

13. Justification • Both FDA and CDC are committed to ensure the safety of all vaccines • Rotateq is a live vaccine • Evidence of an association between a prior rotavirus vaccine (Rotashield) and intussusception • The association was confirmed after licensure

14. Pharmacovigilance for Rotateq®:Main Resources • Main government resources • Vaccine Adverse Events Reporting System (VAERS) • Vaccine Safety Datalink (VSD) Project • Sponsor’s role (Pharmacovigilance plan ) • Accelerated reporting of adverse events to FDA • Reports could be sent in monthly batches • Phase 4 study • Other

15. Vaccine Adverse Events Reporting System (VAERS) (1) • National passive surveillance system for reporting vaccine adverse events • Co-managed by FDA and CDC • Voluntary, easy to report • Nationwide reach • Useful for signal detection

16. VAERS (2) • VAERS will receive accelerated reporting by Sponsor • Daily review of all serious reports and of • Confirmed and suspected intussusception (IT) • Gastrointestinal symptoms

17. VAERS, Main Limitations • Absence of denominator data • Underreporting • Missing/wrong data • Usually, causality cannot be established

18. Vaccine Safety Datalink (VSD) • Collaboration between CDC and Health Maintenance Organizations (HMOs) • As needed, feedback from FDA • Approximately 8 million members (4% of U.S. population) • Birth cohort ~96,000

19. VSD, Main Characteristics • Large, well defined populations • Computerized linkable databases • Initial plan under development contemplates working with automated data • Chart reviews available, if needed • Can determine strength of an association

20. VSD, Potential Limitation • Full uptake of a new vaccine by HMOs could take a few years • Many years could be required to detect increased risk of a rare event • Alternatively, participation of additional HMOs may be needed

21. Considerations on Sponsor’s Phase 4 study • Clinical trials • large (~35,000 vaccinees) • population studied does not necessarily represent those who will use the vaccine after licensure • Proposed Phase 4 study has sample size of ~25,000 vaccinees

22. Sponsor’s Phase 4 Study: Location • Location, a VSD site? • If so: • Overlap with Government-sponsored study? • Duplication of efforts? • CDC-FDA-Sponsor conference to discuss plans?

23. Acknowledgements Miles Braun, CBER/FDA Robert Ball, CBER/FDA Douglas Pratt, CBER/FDA Rose Tiernan, CBER/FDA Frank Destefano, CDC Penina Haber, CDC