Transcript Clinical Evaluation of Preventive Vaccines: Use of Bridging Studies Marion F. Gruber, Ph.D. 2006 FDA/Industry Statistics Workshop Washington D.C., September 29, 2006

Clinical Evaluation of Preventive
Vaccines: Use of Bridging Studies
Marion F. Gruber, Ph.D.
2006 FDA/Industry Statistics Workshop
Washington D.C., September 29, 2006
Objectives

Approval Process for Preventive Vaccines
 Applicable laws & regulations
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Clinical endpoint efficacy studies
Correlates of Protection
Bridging studies, e.g.,
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New population
 Foreign trials
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Age Group
Comparison of two products
Considerations for successful bridging studies
Acts & Regulations Pertinent to
Vaccine Development
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PHS Act (42 USC 262-63) Section 351
FD & C Act (21 USC 301-392)
FDAMA, November 12, 1997
21 CFR
 21 CFR 600-680 Biological Product Standards
 21 CFR 314.126 Adequate and well-controlled trials
 21 CFR 312 Investigational New Drug Application
 21 CFR 210-211 Good Manufacturing Practices
 21 CFR 58 Good Laboratory Practices
 21 CFR 56 Institutional Review Boards
 21 CFR 50 Protection of Human Subjects
 21 CFR 25 Environmental Impact Considerations
Stages of Review and Regulation
Clinical Investigational Plan
IND
BLA
Phase 1
Phase 2
Phase 3
Safety
Immunogenicity
Safety
Immunogenicity
Dose
Ranging
Safety
Efficacy
Immunogenicity
Data to
support
approval;
Inspection
Phase 4
Inspection
Safety
Efficacy
Lot Release
BLA
Supplement
Post-approval
Changes:
New Indications
Dosing
Manufacture
Equip./Facilities
IND =Investigational New Drug Application; BLA=Biologics License Application
Clinical Endpoint Efficacy Studies
 Clinical trials demonstrating preventive efficacy for clinical
endpoints provide the greatest scientific rigor for evaluating
vaccines
 Prospective, controlled, randomized
 Primary endpoint: prevention of disease
 Necessary in situations when
 Vaccine is novel
 First of its kind administered to target population
 No accepted immune response correlate of protection

Example: NCKP efficacy trial of the heptavalent pneumococcal
conjugate vaccine: ~ 38,000 infants
 Prevention of invasive pneumococcal disease
Correlate of Protection
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
Generally, a laboratory parameter that has been
shown to be associated with protection from clinical
disease
 Adequate and well-controlled trials
An immunological correlate of protection is most
useful if clear qualitative and quantitative
relationships can be determined
Correlate of Protection (cont.)
May also be suggested by other sources:
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Population-based studies of vaccines
Trials using
 Specific immune globulins
 Immune globulin with specific Ab
 e.g. polio
Animal challenge/protection studies
Phase 2 clinical data
Protection thought to be conferred to infants by
maternal antibody
Correlate of Protection (cont.)
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Example of licensed vaccines with an identified
correlate of protection:
 Hep B
However, identification of correlate not a
requirement for licensure
Examples of licensed vaccines without an identified
immune correlate of protection:
 Acellular pertussis, Typhoid, Tuberculosis (BCG)
Immune correlate(s) useful for interpreting trials
with immune response endpoints,
 E.g., “bridging studies”
Bridging Studies

A clinical trial in which a parameter of
interest for a product - e.g., manufacturing
process, formulation, dosing schedule – is
directly compared with a changed version of
that parameter with respect to the effect of
the change on the product’s clinical
performance.

Purpose: To determine effect of change(s) on
product’s clinical performance
 e.g., immune response for vaccines
Types of Bridging Studies
To address:
 New population (foreign studies)
 Age group
 New product to standard of care
 New schedule
 Manufacturing changes
 If immune response/safety profile are similar, then
efficacy can be inferred
Population Bridging Studies
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Clinical endpoint efficacy trial not possible in
certain regions
 Disease endemic in limited areas
 Existing vaccines in some countries
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Approach: conduct clinical efficacy trial
where disease rate is high, then “bridge” to
US population with single-arm study in US
Population Bridging Studies (cont.)
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Not possible to randomize region, ethnic group
Thus, not randomized but controlled
 Compare immune/safety endpoints in region where clinical
efficacy shown to those endpoints observed in US bridging
study
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Try to keep comparison group similar
 Demographic factors, e.g., age, gender
 Medical practice, e.g., concomitant vaccines, schedule & ROA,
 Conduct of trial, e.g., inclusion/exclusion criteria, surveillance
for AEs, timing of blood draws, etc.
Population Bridging Study (cont.)
Design:

Comparison of immune responses is often the
primary objective
 Percent responders achieving an immune
response above threshold considered
protective
 Ratio of geometric mean concentration or titer
of antibodies
Population Bridging Study (cont.)
Design:
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Prospective statistical analysis plan
Studies designed to have sufficient power to rule out
important difference in parameters of immune
response
Provide confidence limits on differences between
comparison groups for immune response parameters
 e.g., seroconversion rates and geometric mean
titers
Safety outcomes also measured – rates of common
AEs, SAEs
Statistical Evaluation:
Non-inferiority criteria (Current)
Percent responders or sero-protected:
UL of 2-sided 95% CI for difference
(efficacy pop -target pop) <5-10%
GMTs/GMCs:
UL of 2-sided 95% CI for ratio
(or 1-sided 97.5% CI)
(GMC efficacy pop./GMC target pop.) <1.5-2.0
Other immunologic parameters
Opsonophagocytic activity
Foreign Trials of Preventive Vaccines
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Examples where foreign field trials may play an
important role in vaccine development in the future
(U.S.)
 Vaccines where epidemiology precludes or limits
efficacy trials in U.S. e.g.,
 Malaria,

ETEC, Cholera
Past examples where foreign field trials played an
important role in vaccine development
 E.g.,
DTaP, oral polio, typhoid Vi PS, Hep A
Considerations for Foreign Trials
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Efficacy (and Immunogenicity) differences between
populations may result from differences in factors
such as genetics, nutritional status, & background
infections
 e.g., OPV in developed vs. developing countries
Obtain safety and immunogenicity data using
candidate vaccine in specific population in which
efficacy trial will be performed
Case definition
Adequate sample size
Schedule (changes)
Considerations for Successful “Bridging”
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Validated immune response assays (vaccines)
Foreign clinical data should meet standards of the new
region
 Study design, conduct & regulatory requirements (ICH
E5)
 Determine vaccine’s sensitivity to ethnic factors (ICH
E5)
Study should meet local and international standards
 ICH E6: Good Clinical Practices
 ICH E8: General Considerations for Clinical Trials
 Other Documents (CFR, etc.)
Generous banking of sera from efficacy trial
 SOPP for storing sera
Population Bridging Study
Foreign Trial/New Age Group
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Boostrix: Tetanus Toxoid, reduced Diphtheria
Toxoid and Acellular Pertussis Vaccine adsorbed
(Tdap)
Active immunization against tetanus, diphtheria and
pertussis as a single dose in individuals 10 through
18 years of age
Boostrix: Basis for Licensure
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Demonstration of safety
Demonstration of non-inferiority of anti-tetanus and
anti-diphtheria seroprotection and booster response
vs. Td
Demonstration of booster response to pertussis
antigens
Demonstration of serologic bridge to pertussis
efficacy
Boostrix™ formulation per 0.5mL/dose
comparison with Infanrix®
BOOSTRIX™
INFANRIX®
Tetanus Toxoid
Diphtheria Toxoid
5.0 Lf
2.5 Lf
10 Lf
25 Lf
Pertussis Toxoid (PT)
Filamentous
Hemagglutinin (FHA)
Pertactin (PRN)
8.0 µg
25 µg
8.0 µg
2.5 µg
25 µg
8.0 µg
0.3 mg
(as AlOH3)
< 0.625 mg (as AlOH3)
COMPONENT
Aluminum
Preservative
2.5 mg 2-PE
None
Serologic Bridge to Clinical Efficacy Study

German Household Contact Study (Infanrix®)
 3-dose series at 3, 4, and 5 months of age
 Efficacy 89% (95% CI: 77- 95%) against WHO-defined
pertussis
 > 21 days of paroxysmal cough with positive culture and/or
serologic testing
 Serologic bridge
 Non-inferiority to Infanrix®, administered as a 3-dose
primary series
 GMCs one month post Boostrix (single dose)
compared to GMCs one month after completing
infant series with Infanrix®
Serologic bridge: Testing of Study Samples
 German household Contact Study
 Subjects who had serologic data for at least one
pertussis antigen
 Majority had anti-PT toxoid serological data only
 Serologic assays performed in 1994
 Boostrix Immunogenicity study
 Serologic assays performed in 2003
 Used same assays and same laboratory
Endpoints for Serologic Bridge
Pertussis
antigens
Endpoint
(EU/mL)
Ratio
Infanrix®/Boostrix™
anti-PT
GMC
UL 95% CI < 1.5
anti-FHA
GMC
UL 95% CI < 1.5
anti-PRN
GMC
UL 95% CI < 1.5
Ratios of GMCs between Boostrix™ and Infanrix®
one month post-vaccination (TVC)
Antigen
Infanrix®
N
Boostrix™
GMC*
N
Infanrix®/ **
Boostrix™
GMC*
Ratio (95% CI)
anti-PT
2884
45.7
2941
86.9
0.53 (0.50,0.55)
anti-FHA
685
83.6
2979
614.8
0.14 (0.13,0.15)
anti-PRN
631
112.3
2978
470.7
0.24 (0.21,0.27)
* ELISA units / mL
** pre-specified non-inferiority criteria met
Bridging Study: Age Group
Human Papillomavirus (Types 6, 11, 16, 18) vaccine
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Indication: prevention of HPV 6, 11, 16, 18 related
cervical cancer, cervical dysplasia, vulvar or vaginal
dysplasias, or genital warts
Children & adolescents 9-17 yrs and women 18-26 yrs
CIN 2/3 and AIS served as surrogate markers for
prevention of cervical cancer in efficacy trials
conducted in females 16 – 26 years of age
Bridging Study: Age group
Human Papillomavirus (Types 6, 11, 16, 18) vaccine
 Efficacy assessed in 4 placebo controlled,
double blind, randomized Phase II and III clinical
trials (n = 20,541 females (16 - 26 yrs))
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Phase II*:
Phase II:
Phase III:
Phase III:
n = 2391
n = 551
n = 5,442
n = 12, 157
VE for HPV 16/18-related disease:
 CIN3 or AIS: 100% (95% CI: 87.9%, 100.0%)
 VIN 2/3/ or VaIN 2/3: 100% (95% CI: 55.5%, 100.0%)
*HPV 16 component of Gardasil only
Statistical Analysis of Non-Inferiority of HPV GMTs
Comparing 10-15 yr old females to 16 -23 yr old females
10-15 yr old females
Comparison grp A
N = 506
Assay
16-23 yr old females
Comparison grp B
N = 511
Estimated
fold
difference
Grp A/B
(95% CI)
N
Estimated
GMT
(mmU/ml)
N
Estimated
GMT
(mmU/ml)
Anti HPV 6
426
960.0
320
574.9
1.67
(1.46,1.91)
Anti HPV 11
426
1224.8
320
705.9
1.74
(1.50,2.00)
Anti HPV 16
427
4713.3
306
2548.0
1.85
(1.55, 2.21)
Anti HPV 18
429
918.4
340
452.9
2.03
(1.72, 2.39)
Analysis of non-inferiority comparing seroconversion
rates in 10-15 yr old females with 16-23 yr old females
10-15 yr old females
Comparison grp A
N = 508
Assay
16-23 yr old females
Comparison grp B
N = 511
Estimated
percentage
Point
difference
Grp A-B
(95% CI)
N
Estimated
response
(%)
N
Estimated
GMT
(mmU/ml)
Anti HPV 6
426
100 %
320
100 %
0.0
(-0.9,1.3)
Anti HPV 11
426
100 %
320
100 %
0.0
(-0.9,1.3)
Anti HPV 16
427
100 %
306
100%
0.0
(-0.9,1.3)
Anti HPV 18
429
100 %
340
100 %
0.8
(-0.2, 2.5)
Immunogenicity Bridging between 9-15 year old
females, adolescents and 16-26 year old adult women
9-15 year old female adolescents
16-26 year old adult women
Assay
(cLIA)
n
GMT
mMU/mL
95% CI
n
GMT
mMU/mL
95% CI
Anti-HPV
6
927
931.3
876.9,
989.2
2827
542.4
526.6,
558.7
Anti-HPV
11
927
1305.7
1226.2,
1390.4
2827
766.1
740.5,
792.6
Anti-HPV
16
929
4944.9
4538.5,
5334.8
2707
2313.8
2206.2,
2426.7
Anti-HPV
18
932
1046.0
971.2,
1126.5
3040
460.7
443.8,
478.3
Bridging study: Comparison of 2 Products
Menactra and Menomune
 Indication: Prevention of invasive
meningococcal disease caused by N.
meningitidis (A, C, Y and W-135)
 Menomune (another meningococcal vaccine
licensed and available in the US)
 Comparison to Menomune
Inferred efficacy
Immune correlate: serum bactericidal antibody
Other parameters: SBA GMT, seroconversion
rate, IgG (ELISA)
Non-inferiority to Menomune
Comparison of SBA responses to Menactra & Menomune
28 days after vaccination for participants (11-18 yrs)
Menactra
Menomune
(n = 423)
(n = 423)
(95% CI)
Serogroup
(95% CI)
A
% = 4 fold rise
GMT
92.7
5483
(89.8, 95.0)
(4920,6111)
92.4
3246
(89.5, 94.8)
(2910,3620)
C
% = 4 fold rise
GMT
91.7
1924
(88.7, 94.2)
(1662, 2228)
88.7
1639
(85.2, 91.5)
(1406, 1911)
Y
% = 4 fold rise
GMT
81.8
1322
(77.8, 85.4)
(1162, 1505)
80.1
1228
(76.0, 83.8)
(1088, 1386)
W-135
% = 4 fold rise
GMT
96.7
1407
(94.5, 98.2)
(1232, 1607)
95.3
1545
(92.8, 97.1)
(1384, 1725)
Concluding Remarks
 Preventive vaccines have unique considerations
for product & clinical development
 Overall planning and coordination:
 Accumulate sufficient safety, immunogenicity
& efficacy data during development
 Anticipate the need for clinical bridging
studies
 Utilize available FDA documents & resources
Concluding Remarks
Similar study design
Evaluation of similar endpoints
appropriate for assessment of treatment
Validated immune response assays
(vaccines)
Prospective statistical analysis
Study/population to meet regulatory
requirements in new region
CBER Guidance
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Web: www.fda.gov/cber/reading.htm
Email: [email protected]
Fax: 1-888-CBER-FAX
Phone
 DVRPA: 301- 827-3070
 OCTMA: 301- 827- 1800 or 800-835-4709
Acknowledgments
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Karen Farizo, M.D.
Theresa Finn, Ph.D.
Antonia Geber, M.D.
Karen Goldenthal, M.D.
Amelia D. Horne, Dr.P.H.
Lucia Lee, M.D.
Nancy Miller, M.D.
Douglas Pratt, M.D.