Title: Robert C. Kohberger, Ph.D. VP Planning and Project Management
1Licensing 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
2Correlates 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
3Meningococcal 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
4What 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
5Why 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
6Why 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
7How 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
8Trial 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
9Results 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)
10Results 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 !
11Other 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
12Other 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.
13Other 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
14Lessons 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
15Lessons 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.
16References
- 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.