Robert C. Kohberger, Ph.D. VP Planning and Project Management Licensing a New Vaccine on the Basis of Surrogate Endpoints: A Practical Example 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 incidence reduction = 87% Meningococcal C disease deaths (0-19 years of age): 1999 incidence 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 Issues Serologic Assay WHO coordinated consultation on standardization of hSBA assay. Meetings (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 Issues Serologic Assay WHO coordinated consultation on standardization of rSBA assay, comparison with hSBA, value of protective level with hSBA Meetings Agreement on assay procedures Disagreement on protective level General consensus that with rSBA 128 predicted protection. Could not agree on titers between Note that original basis of hSBA (done in 1969) as surrogate never had such precision.

13 Other Issues Validation 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 Clin. Diagn. Lab. Immun. 10: Farrington, CP. Estimation of vaccine effectiveness using the screening method Int. J. Epidemiol. 22: Maslanka SE, et al. Standardization and a multilaboratory comparison of N. meningitidis serogroup A and C serum bactericidal assays Clin. Diagn. Lab. Immun. 4: 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: