Intussusception Following Use of Rota Shield A

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

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 2

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

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 (nonsignificant) rates of IT within one week following vaccination – ranging between 292 and 314 cases per 100, 000 • MMWR stimulates VAERS reporting 4

Withdrawal of Rota. Shield • October 15, 1999: Wyeth voluntarily withdraws Rota. Shield – 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 5

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 , Pediatr Infect Dis J. 2001 # Simonsen et al, 2005; Paul Gargiullo, CDC, unpublished 6

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 7

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 8

Possible Mechanisms for Association Between Rota. Shield and IT • Rota. Shield 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 9

Summary • Evidence indicates existence of causal association between Rota. Shield 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 10

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 11

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

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 13

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 14

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 15

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

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

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 18

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 19

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 20

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 21

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? 22

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