Robert C. Kohberger, Ph.D. VP Planning and Project Management

1
Licensing a New Vaccine on the Basis of Surrogate
Endpoints A Practical Example

• Robert C. Kohberger, Ph.D.VP Planning and
  Project Management

19 September, 2003
2
Correlates and Surrogates?
Nomenclature In the relatively small universe of
vaccine researchers, statisticians have tried to
to emphasize the difference between a surrogate
and a correlate. But this effort has not always
been successful. Not clear if vaccines will ever
have, in the strict definition, a surrogate of
efficacy Correlates and surrogates often used
interchangeably
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Meningococcal C Conjugate Vaccine U.K.Timeline

• 1994 discussions began within the U.K.
  Department of Health. Included public health,
  academic, regulatory, and manufacturers
  representatives
• 1995 assay standardized (to U.K. standards) and
  trials began
• 1998 Trials completed and reported
• 1999 Vaccine licensed on basis of surrogate
  endpoints
• 2002 Clinical efficacy reported
• 2003 Protective levels reported

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What Was the Efficacy Surrogate?

• Primary - hSBA
• Serum Bactericidal Antibody Assay using human
  complement
• a measure of the ability of the antibody to kill
  the organism.
• Secondary - avidity
• binding ability of antibodies
• considered by many to be a measure of the memory
  of the antibodies elicited by the vaccine
• memory ability of immune system to recognize and
  respond to an organism when antibody levels in
  serum are essentially zero

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Why Was It Chosen?

• Thought to be fastest route to licensure
• meningococcal C disease serious problem in U.K
• estimated in 1999 there would be 1,500 cases and
  150 deaths
• clinical trial in U.K. would be time consuming
  and expensive
• would any manufacturer consider such a trial for
  U.K. licensure?
• incidence rates
• population
• U.K. pricing policies. Difficult to justify
  expense considering UK reimbursement policies.
• needed information for different age groups on
  schedule and number of doses
• infants, toddlers, school age

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Why Was It Chosen?

• Vaccinologists and immunologists considered hSBA
  to have validity as efficacy surrogate
• 1969 study demonstrated with naturally acquired
  antibody hSBA levels correlated with protection
• In military recruits 3/54 cases had hSBA gt 4
  while 444/540 non-cases had hSBA gt 4. A value of
  4 in hSBA then considered as a protective level.
• Experience with H. influenza vaccine demonstrated
  immunogenicity measurements correlated with
  clinical efficacy.
• Vaccine highly effective worldwide
• Both IgG (ELISA) and OPA related to protection.
• A memory response has been clinically
  demonstrated
• MnC a similar vaccine in that a polysaccaride is
  conjugated to a carrier

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How was the Surrogate Chosen?

• Consultative Group
• PHLS - Public Health Laboratory Surveillance
• NIBSC - National Institute of Biological
  Standards and Control
• CAMR - Center for Applied Microbiology and
  Research
• ICH - Institute for Child Health
• MCA - Medicines Control Agency
• Manufacturers Wyeth, Chiron, NAVI (Baxter)
• Agreements Reached
• MCA would license vaccine on the basis of
  immunology - sufficient proportion of subjects
  obtain hSBA gt 4
• safety demonstration
• follow-up after licensure for efficacy
• PHLS primary responsibility for clinical trials,
  immunogenicity evaluation, and follow-up

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Trial Implementation

• PHLS primary responsibility for clinical trials
  and immunogenicity evaluation
• assay development
• trial design - joint with manufacturers
• trial implementation - joint with manufactures
• site selection, monitoring, data management
• routine serology evaluation
• trial reporting - joint with manufacturers
• License submission - manufacturers
• including CMC and Clinical sections
• Cost Sharing Department of Health and
  manufacturers

9
Results Licensed in 1999

• Meningococcal C disease (0-19 years of age)
• 1999 incidence - 700
• 2001 incidence - 100
• reduction 87
• Meningococcal C disease deaths (0-19 years of
  age)
• 1999 incidence - 109
• 2001 incidence - 51
• reduction 53
• Vaccination coverage gt80 (age dependent -
  infants vs catch-up)

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Results Licensed in 1999

• Disease incidence compared temporally and with
  meningococcal B disease. Reduction determined to
  be real
• Approximately 90 Vaccine Efficacy
• Screening Method (Farrrington)
• Disease Incidence Through 2003 remains low
• Success !

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Other IssuesSerologic Assay

• WHO coordinated consultation on standardization
  of hSBA assay.
• Meetings 1995-1996 (during the trial)
• because of extensive experience, led by U.K.
• included worldwide participants
• agreement reached and published in 1997
• With an increasing number of meningococcal assays
  being done, became clear there was a problem with
  human complement
• variability in key characteristics
• reliable and sufficient source of supply
• baby rabbit complement proposed as alternative

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Other IssuesSerologic Assay

• WHO coordinated consultation on standardization
  of rSBA assay, comparison with hSBA, value of
  protective level with hSBA
• Meetings 2000-2001
• Agreement on assay procedures
• Disagreement on protective level
• General consensus that with rSBA lt8 predicted
  susceptibility and gt 128 predicted protection.
• Could not agree on titers between 8 - 128
• Note that original basis of hSBA (done in 1969)
  as surrogate never had such precision.

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Other IssuesValidation of Protective Level (2003)

• Population based correlates
• ratio of vax subj. gt protective level /
  control subj. gt protective level should be
  similar to the clinical efficacy relative risk
• individual correlates requires all subjects to
  have serology done after vaccination. Or at least
  a sufficient (and random) sample of cases and
  non-cases
• Results
• Conclusion 4 overestimates, 16 underestimates VE
  and 8 is mostly likely the protective level

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Lessons Learned

• Compelling Need for Product Licensure on the
  Basis of Surrogates
• disease incidence or inability to do clinical
  efficacy trials
• safety must be demonstrated
• risk for efficacy is assumed. In this case
  primarily by regulators (UK Department of
  Health), but also manufacturers (because this is
  UK, a lesser extent)
• Clear understanding and agreement on surrogate
  immunologic assay(s)
• worldwide
• regulators, academics, and manufacturers
• WHO Vaccine Division is a useful coordinating
  group

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Lessons Learned

• Efficacy evaluation after field use critical
• Obtaining agreement on immunological measurements
  is time and effort consuming
• WHO consultative meetings lasted over two years
  with significant work done by all parties
• Value lies in cost and the speed in time to
  market of a product.

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References

• Andrews N, et al. Validation of serological
  correlate of protection for meningococcal C
  conjugate vaccine by using efficacy estimates
  from postlicensure surveillance in England. 2003
  Clin. Diagn. Lab. Immun. 10780-786.
• Farrington, CP. Estimation of vaccine
  effectiveness using the screening method. 1995
  Int. J. Epidemiol. 22742-746.
• Maslanka SE, et al. Standardization and a
  multilaboratory comparison of N. meningitidis
  serogroup A and C serum bactericidal assays.
  1997. Clin. Diagn. Lab. Immun. 4156-167.
• Miller E et al. Planning, registration, and
  implementation of an immunisation campaign
  against meningococcal serogroup C disease in the
  UK a success story 2002 Vaccine 20S58-S67.
• Ramsey ME et al. Efficacy of meningococcal
  serogroup C conjugate vaccine in teenagers and
  toddlers in England 2001 The Lancet 357 195-196.