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
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 > 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
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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 > 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
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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’)
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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 Issues
Serologic 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 Issues
Serologic 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.
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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 noncases

Results:
Infants
Toddlers
Pre School

Clinical
Efficacy
92.5
90.0
100.0
Predicted VE with Level At
%> 4
100.0
95.0
100.0
%> 8
98.0
90.0
100.0
%>16
98.0
86.0
97.0
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.
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: 195196.
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