Title: FDA/CBER VRBPAC Meeting
1- FDA/CBER VRBPAC Meeting
- February 27, 2007 Gaithersburg, MD
- NIAID H5N1 Vaccine Clinical Research Program
Overview - and
- Protocol 04-063 Study Results
-
- Linda C. Lambert, Ph.D.
- Division of Microbiology and Infectious Diseases
- National Institute of Allergy and Infectious
Diseases - NIH/DHHS
2NIAID
To serve public health by conducting and
supporting research on infectious and allergic
diseases
- DHHS Pandemic Influenza Research Plan
- NIAID - research on control, prevention, and
treatment of seasonal and pandemic influenza - Assess basic biology, immunology, host response
- Characterize newly emerging strains, molecular
basis of virulence/transmission - Develop and clinically evaluate of new
diagnostics, drugs, and vaccines
coordinate/collaborate with DHHS, NVPO, FDA, CDC
and other Public Health Service efforts - Generate information to further inform ongoing
global pandemic preparedness efforts
3(No Transcript)
4NIAID H5N1 Vaccine Clinical Research Program
Objectives I
- Obtain H5N1 vaccine from manufactures with
licensed products as quickly as possible - May 2004 award contracts to Aventis Pasteur
(sanofi pasteur) - Produce a pilot-scale lot of H5N1 vaccine using
scaled-down processes similar to those for their
licensed vaccines - 2 formulations 30 mcg/ml, 90 mcg/ml
- Gain experience overcoming technical and
logistical issues - USG and sanofi pasteur - Demonstrate use of reverse genetics to generate
H5 vaccine reference viruses and obtain USDA
Select Agent exemption - Produce reagents to measure vaccine potency
- Develop assay capacity to measure vaccine
responses - Prepare for commercial-scale manufacturing
5NIAID H5N1 Vaccine Clinical Research Program
Objectives II
- Rapidly implement well controlled Phase I/II
clinical trials to obtain data on the safety and
immunogenicity of the vaccine - Provide initial data on the comparative
dose-ranging immune responses to form the basis
of additional clinical trials - Assess multiple study populations adults,
elderly, and pediatric populations - Support H5N1 hemagglutinin (HI) and
microneutralization (MN) immunoassays, data
collection/analysis
6NIAID H5N1 Vaccine Clinical Research Program
sanofi pasteur
- June 2004 NIAID provided clade 1 H5N1 reference
virus to sanofi pasteur - rgA/Vietnam/1203/2004 with neuraminidase (NA)
and genetically modified hemagglutinin (HA) gene
6 PR8 genes - March 2005 sanofi pasteur delivered vaccine
- April 2005 NIAID initiated H5N1 vaccine trial in
adults - 3 VTEU sites fully enrolled May 20th
- NIAID transfers preliminary and final data sets
for 04-063 to sanofi pasteur for BLA submission - John Treanor results adult study (NIAID
Protocol 04-063 published NEJM 3/2006) and
brief overview of follow-on studies
7NIAID evaluation of sanofi subvirion inactivated
rgA/Vietnam/1203/04 x PR8 H5N1 Vaccine
Presentation to the FDA VRBPAC Meeting 27
February 2007
J. Treanor, J. Campbell, and K. Zangwill for the
DMID 04-063 study team
8NIAID approach to evaluation of sanofi subvirion
H5N1 vaccine
Protocol 04-063
Protocol 04-076
Protocol 04-077
904-063 sanofi subvirion inactivated H5N1
vaccine in healthy adults
- Published data up to and including day 56 (NEJM
354 (13) 1343-51, March 30, 2006) - Healthy adults ages 18 to 64
- Prospective, multicenter, randomized, double
blind clinical trial - Interventions dose ranging, two IM doses of H5
vaccine or placebo separated by 28 days - 7.5 mcg, 15 mcg, 45 mcg, 90 mcg, (n100/group)
- Endpoints
- Safety solicited and unsolicited AEs
- Co-primary Immunogenicity neutralizing and HAI
antibody - Determined proportion achieving titer of gt 140
28 days after 2nd dose - Correlation of either assay with protection
against H5N1 infection or disease is unknown
10Demographics of enrolled subjects Protocol
04-063
Demographics of enrolled subjects Demographics of enrolled subjects Demographics of enrolled subjects Demographics of enrolled subjects Demographics of enrolled subjects Demographics of enrolled subjects
Number of subjects () in the following dose groups Number of subjects () in the following dose groups Number of subjects () in the following dose groups Number of subjects () in the following dose groups Number of subjects () in the following dose groups
Characteristic Placebo (n48) 7.5 mcg (n101) 15 mcg (n101) 45 mcg (n98) 90 mcg (n103)
White 39 (81.3) 81 (80.2) 78 (77.2) 75 (76.5) 84 (81.6)
Black 3 (6.3) 5 (5.0) 6 (5.9) 12 (12.2) 11 (10.7)
Asian 4 (8.3) 13 (12.9) 13 (12.9) 10 (10.2) 8 (7.8)
Pacific Islander 0 (0.0) 0 (0.0) 1 (1.0) 0 (0.0) 0 (0.0)
Multiracial 2 (4.2) 2 (2.0) 2 (2.0) 1 (1.0) 0 (0.0)
Hispanic 4 (8.3) 13 (12.9) 11 (10.9) 6 (6.1) 13 (12.6)
Female 22 (45.8) 51 (50.5) 65 (64.4) 42 (42.9) 55 (53.4)
Previous vaccine 20 (41.7) 39 (38.6) 42 (41.6) 42 (42.9) 44 (42.7)
Age (median, range) 38 (21-62) 39 (18-64) 40 (22-64) 38 (19-63) 38 (18-64)
11Summary of safety, Protocol 04-063
- Dose-related pain and tenderness at injection
site (0 severe, 7 moderate, 53 mild at 90 mcg,
dose 1) - Rates are similar after dose 1 and dose 2
- No difference in rates of systemic side effects
between any dose and placebo - 1 SAE not related to vaccine occurred within 56
days of dose 1
12Reverse cumulative distribution of MN antibody at
day 56 (28 days after dose 2)
54 (43,64)
Percent at or above indicated titer
NEJM 3541343-51, 2006
Reciprocal titer
13Reverse cumulative distribution of HAI antibody
at day 56 (28 days after dose 2)
58 (47, 67)
Percent at or above indicated titer
NEJM 3541343-51, 2006
Reciprocal titer
14Protocol 04-063 reanalysis
- Changes in analysis were suggested after study
completion and publication (March 06) based on
FDA guidance document (March 06) and discussions
with FDA (April 21, 2006). - HAI became primary focus of immunogenicity
evaluation. - FDA recommended redefining the value assigned for
the first dilution from 120 (as published) to
110 - HAI seroresponse redefined with FDA consultation
as requiring 1 four-fold increase over baseline
and 2 titer of 140 or greater. - Reanalysis involves recalculations using 110
definition of the starting dilution, and reduces
all reported titers by one dilution. - No retesting of sera was performed. Only
recalculations of results based on new
definitions were done.
15Reverse cumulative distribution of HAI antibody
at day 56 (28 days after dose 2)
FIRST WELL dilution defined as 120
58 (47, 67)
Percent at above indicated titer
NEJM 3541343-51, 2006
Reciprocal HAI titer
16Reverse cumulative distribution of HAI antibody
at day 56 (28 days after dose 2)
17Current cumulative experience with sanofi vaccine
at 90 mcg
Number of subjects receiving one, two, or three
90 mcg doses of sanofi vaccine
Studies Randomized trials 04-063/05-090
04-076 Open label studies 05-0043 05-0129
05-0130 Total 90 mcg recipients
Populations Healthy adults Elderly
adults Previous rH5 Manufacturers Lab workers
One 103 105 37 83 35 363
Two 99 94 - 76 35 304
Three 86 80 - - - 166
18NIAID evaluation of 90 mcg dose in open label
populations safety
- Protocols 05-043, 05-129, 05-0130
- No SAE related to vaccine to date
- Rates of local and systemic solicited adverse
events are similar to rates at 90 mcg in Protocol
04-063
19NIAID controlled evaluation of sanofi H5N1
vaccine in additional populations
- Elderly adults (N259)
- Children 2-9 years old (45 mcg, N125)
- Database is not locked and only aggregate
analysis available - No vaccine related serious adverse events
- Local and systemic reactogenicity mostly reported
as mild or moderate, rarely (1 or less) reported
as severe