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

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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

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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

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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

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Withdrawal of RotaShield

• October 15, 1999 Wyeth voluntarily withdraws
  RotaShield
• Decision based in part on preliminary results
  from CDCs Case Control and Case series studies
• October 22, 1999 ACIP withdraws recommendation
  for vaccine use
• License revoked, November 15, 2002

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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unpublished
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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 estimate1 per 5,000
• low estimate1 per 12,000

Peter G and Myers M. Pediatrics, 2002
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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
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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
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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
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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

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Outline of Pharmacovigilance Plans for Rotateq

• Hector S. Izurieta VSB/DE/OBE/CBER/FDA

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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

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Pharmacovigilance for RotateqMain Resources

• Main government resources
• Vaccine Adverse Events Reporting System (VAERS)
• Vaccine Safety Datalink (VSD) Project
• Sponsors role (Pharmacovigilance plan )
• Accelerated reporting of adverse events to FDA
• Reports could be sent in monthly batches
• Phase 4 study
• Other

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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

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VAERS (2)

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

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VAERS, Main Limitations

• Absence of denominator data
• Underreporting
• Missing/wrong data
• Usually, causality cannot be established

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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

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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

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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

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Considerations on Sponsors 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

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Sponsors 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?

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Acknowledgements

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