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

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

3. 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

4. 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

5. 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

6. 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 > 4 while 444/540 non-cases had hSBA > 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

7. 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 > 4 • safety demonstration • follow-up after licensure for efficacy • PHLS primary responsibility for clinical trials, immunogenicity evaluation, and follow-up

8. 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 >80% (age dependent - infants vs ‘catch-up’)

10. 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 !

11. 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

12. 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 <8 predicted susceptibility and > 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.

13. Other IssuesValidation of Protective Level (2003) • Population based correlates • ratio of % vax subj. > protective level / % control subj. > 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

14. 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

15. 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.

16. 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. 10:780-786. • Farrington, CP. Estimation of vaccine effectiveness using the screening method. 1995 Int. J. Epidemiol. 22:742-746. • Maslanka SE, et al. Standardization and a multilaboratory comparison of N. meningitidis serogroup A and C serum bactericidal assays. 1997. Clin. Diagn. Lab. Immun. 4:156-167. • 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 20:S58-S67. • Ramsey ME et al. Efficacy of meningococcal serogroup C conjugate vaccine in teenagers and toddlers in England 2001 The Lancet 357: 195-196.