|
1
|
- Vaccines and Related Biological Products Advisory Committee Meeting
- May 18, 2006
- Nancy B. Miller, M.D.
- CBER, FDA
|
|
2
|
- Chairperson: Gopa Raychaudhuri, Ph.D.
- Regulatory Coordinator: Julienne Vaillancourt, R.Ph., M.P.H.
- Clinical: Nancy Miller, M.D.
-
Joseph Toerner, M.D., M.P.H.
-
Karen Goldenthal, M.D.
-
Antonia Geber, M.D.
-
Douglas Pratt, M.D., M.P.H
- Statistical: Henry Hsu, Ph.D., M.P.H.
-
Lev Sirota, Ph.D.
-
A. Dale Horne, Dr.Ph.
- Product: Robin Levis, Ph.D.
-
Rolf Taffs, Ph.D.
- Gennady
Rezapkin, Ph.D.
- Loris
McVittie, Ph.D.
-
Jerry Weir, Ph.D.
- Non-Clinical: Sally Hargus, Ph.D.
-
Marion Gruber, Ph.D.
- Pharmacovigilance:
Hector Izurieta, M.D.
- Robert Ball, M.D., M.P.H.
- Bioresearch Monitoring: Robert Wesley
- Facility: Susan Yu,
Ph.D.
- Laurie Norwood, Ph.D.
- Advertising/Promotional Labeling:
Maryann Gallagher
|
|
3
|
- Each 0.5 mL dose contains
- 20 mcg HPV 6 L1 VLP
- 40 mcg HPV 11 L1 VLP
- 40 mcg HPV 16 L1 VLP
- 20 mcg HPV 18 L1 VLP
- Adjuvant: 225 mcg aluminum
- Administered 0, 2, and 6 months IM
|
|
4
|
- Prevention of HPV 16/18 related:
- Cervical cancer
- Cervical AIS
- CIN 2 and CIN 3
- Vulvar and vaginal cancer
- VIN 2 and VIN 3
- VaIN 2 and VaIN 3
- Prevention of HPV 6/11/16/18 related:
- CIN grade 1
- Genital warts (condyloma acuminata)
- VIN grade 1 and VaIN grade 1
- HPV infection
|
|
5
|
- Children and adolescents 9 through 17 years of age and women 18 through
26 years of age.
|
|
6
|
- FDA considers the data submitted in the BLA to be supportive of use of
Gardasil in preadolescent and adolescent females 9-17 years of age and
females 18-26 years of age.
|
|
7
|
- 1997: Submission of IND for
monovalent HPV 11 L1
- VLP vaccine (Other INDs for monovalent HPV 16 and 18)
- 2000: Submission of IND for
quadrivalent HPV 6, 11, 16, 18 L1 VLP vaccine
- 2001 (November): VRBPAC
discussion of endpoints for Phase 3 development
- 2002: Product development program
granted fast track status; Initiation of Phase 3 trials
- 2005 (May): Pre-BLA meeting,
agreement to allow rolling BLA and Priority Review
- 2005 (August): Start of rolling
BLA submisssion
- 2005 (December): Last section of
rolling BLA received including Phase 3 study data; 6 month priority
review
|
|
8
|
- November 2001 VRBPAC:
- CIN 2/3 histology, AIS, or
worse with virology.
|
|
9
|
- 001: HPV 11 L1 VLP Vaccine
- 002: HPV 16 L1 VLP Vaccine
- 004: HPV 16 L1 VLP Vaccine
- 006: HPV 18 L1 VLP Vaccine
|
|
10
|
- 005: “Proof of Concept” Phase II
Efficacy Trial (HPV 16)
- 007: Quadrivalent Dose-Ranging
and Efficacy Study
- 013: CIN/Warts Efficacy Study
- 015: CIN 2/3 Efficacy Study
|
|
11
|
- 011: Hepatitis B Concomitant
Use Substudy
- 012: HPV 16 Bridging Substudy
|
|
12
|
- 016: Adolescent/Adult Bridging
and End-Expiry Study
- 018: Adolescent Immunogenicity
and Safety Study
|
|
13
|
|
|
14
|
|
|
15
|
|
|
16
|
|
|
17
|
|
|
18
|
|
|
19
|
|
|
20
|
|
|
21
|
|
|
22
|
|
|
23
|
- Per Protocol Population for Efficacy (PPE): Received all 3 vaccinations, naïve to
relevant vaccine HPV type through Month 7, did not deviate from
protocol; cases counted after Month 7.
- Modified Intent to Treat -1 Population (MITT-1): Same as PPE, but included protocol
violators
- Modified Intent to Treat-2 Population (MITT-2): Received at least 1
vaccination, naïve to relevant vaccine HPV type at Day 1, and had any
follow-up visit after the first vaccination; cases counted from 30 days
after dose 1.
|
|
24
|
- Restricted MITT-2 Population (RMITT-2):
Seronegative and PCR negative to all four vaccine HPV types at
Day 1 and a normal Pap test at Day 1; cases counted 30 days after dose
1.
- All MITT-1 Population: Naïve to
all four vaccine HPV types through Month 7, and cases counted starting
after Month 7.
|
|
25
|
- Modified Intent to Treat-3 Population (MITT-3): Received at least one vaccination and
had any follow-up visit one month after dose 1. Cases were counted from 30 days after
dose 1. Subjects were included
regardless of baseline HPV status.
|
|
26
|
- Squamous intraepithelial lesion (SIL) present at baseline: 12%
- PCR positive and/or seropositive to a vaccine HPV type: 27%
|
|
27
|
- Primary Endpoints:
- HPV 16/18 related CIN 2/3 or worse [015, combined analysis]
- HPV 6/11/16/18 related CIN [013]
- HPV 6/11/16/18 related External Genital Lesions (EGLs) [013]
|
|
28
|
- Other Endpoints of Interest:
- HPV 16/18 related EGLs
- CIN 2/3 due to any HPV type and non-vaccine HPV types
- EGL due to any HPV type and non-vaccine HPV types
|
|
29
|
- Efficacy Against HPV 16/18 CIN 2/3 or Worse
|
|
30
|
|
|
31
|
|
|
32
|
|
|
33
|
- Efficacy Against
- HPV 6/11/16/18 CIN
|
|
34
|
|
|
35
|
|
|
36
|
- Four cases occurred in the Gardasil group for the PP analysis (Protocol
015).
- All four cases had HPV 16 related CIN 1 at Month 12-13.
- One subject had anti-HPV 16 level just below level of detection and
LSIL at Day 1 and HSIL at Mo 7, and possibly had prior exposure to HPV
16; also non-naïve to HPV 18 at Day 1 and colposcopy triggered by the
HSIL at Mo 7, led to a diagnosis of HPV 18 related CIN 3 at Mo 9.
- Three other subjects developed LSIL at Mo 7 and
- Mo 12, which led to
colposcopies with the resulting diagnoses. One had anti-HPV 16 level at Mo 7
higher than GMT seen in Per Protocol Immunogenicity (PPI) population.
|
|
37
|
|
|
38
|
|
|
39
|
|
|
40
|
- Efficacy Against Any HPV Type and Non-Vaccine HPV Type Related CIN
|
|
41
|
|
|
42
|
|
|
43
|
- Efficacy Against HPV 6/11/16/18
- Related External Genital Lesions (EGLs)
|
|
44
|
|
|
45
|
|
|
46
|
|
|
47
|
|
|
48
|
|
|
49
|
|
|
50
|
|
|
51
|
|
|
52
|
|
|
53
|
- Safety Population
- Safety Surveillance
- Deaths
- SAEs
- Pregnancies/Lactation
|
|
54
|
|
|
55
|
|
|
56
|
- Vaccine Report Cards for 14 days after each vaccination (Protocols 005,
007, 013 + NSAE 015)
- Solicited local AEs: Pain,
tenderness, redness for 5 days after vaccination
- Temperatures for 5 days after vaccination
- > 100° F oral
- Solicited and unsolicited
systemic AEs: Sore muscle, sore
joints, headache, rash, diarrhea for 14 days after vaccination
|
|
57
|
- Any SAE for day of consent to 14 days postdose 1, and 14 days postdose 2
and 3 regardless of attribution
- Any death or SAE which resulted in study discontinuation
- Any SAE throughout study which was possibly vaccine or procedure related
or whose relationship was unclear
- Pregnancy related SAEs throughout study
|
|
58
|
- Pre-vaccination
- Study period through Month 7
- Study period after Month 7
|
|
59
|
- All pregnancies were to be followed to outcome
- SAEs were reported for mothers and infants
- Lactation outcomes were followed
|
|
60
|
|
|
61
|
|
|
62
|
|
|
63
|
|
|
64
|
|
|
65
|
|
|
66
|
- A similar pattern and occurrence of SAEs and AEs in pregnancy were
reported in women who were vaccinated with Gardasil (N=40, 4.2%) or
placebo (N=41, 4.3%).
- These events included conditions leading to C-section, premature labor,
and conditions associated with pregnancy.
|
|
67
|
- Higher proportion of children with SAEs in women who received Gardasil
while breastfeeding in the vaccination period (Gardasil N=17, 3.4%;
placebo N=9, 1.8%); the events
were of similar nature in both groups.
- In both the vaccine and placebo groups, these included respiratory
infections, gastroenteritis, and asthma.
|
|
68
|
|
|
69
|
- Although no obvious safety signal was identified, post-marketing
pharmacovigilance activities will continue to collect AEs that occur
post-vaccination in a larger population.
|
|
70
|
- An imbalance was noted regarding the EDCn of infants who had congenital
anomalies (five cases for mothers who received Gardasil vs. none for
mothers who received placebo).
However, there did not appear to be a pattern among the
congenital anomalies.
|
|
71
|
- Bridging immune response in adolescent girls to adult women
- Duration of immune response
- Co-administration with Hepatitis B vaccine
|
|
72
|
- Females naïve to the four vaccine HPV types are expected to benefit most
from the vaccine.
- Efficacy studies cannot be conducted in preadolescent girls.
|
|
73
|
|
|
74
|
|
|
75
|
- Duration of Immune Response
|
|
76
|
|
|
77
|
|
|
78
|
- Anti-HPV 6, 11, 16, and 18 immune responses were non-inferior when
Gardasil was given with or without Recombivax (SC rates, GMT ratios)
- Anti-Hepatitis B immune response was similar when Recombivax was given
with or without Gardasil (SC rates)
- Anti-Hep B GMTs lower in coadministration group
|
|
79
|
- Routine pharmacovigilance
- Phase 4 studies
- Other studies
|
|
80
|
- Passive reporting of adverse events (AEs) including:
- Monthly submission of non-serious AE reports
- Regular FDA-CDC-Sponsor conference calls
- Pregnancy registry
|
|
81
|
- Observational safety surveillance study in large U.S. MCO
- Investigation of serious AEs that occur in close temporal association
with vaccination (60 days follow-up)
- Nordic Long Term Follow-up Study
- Longitudinal evaluation of subjects in Protocol 015 enrolled in Nordic
countries using national registries
|
|
82
|
- HPV-related diseases
- Long term effectiveness and duration of immune response
- Potential safety signals
- Pregnancy outcomes
|
|
83
|
- Evaluation of long term effectivenesss and duration of immune response:
- Extension of protocol 007
- Extension of protocol 018
- Detection of unanticipated safety signals through active surveillance in
all studies.
|
|
84
|
- The efficacy, safety, and “bridging” immune response data submitted to
the BLA support licensure of Gardasil in females 9-26 years of age naïve
to the relevant vaccine HPV type for prevention of the following
diseases/events:
- HPV 16/18 related cervical cancer, CIN 2/3 and AIS.
- HPV 6/11/16/18 related VIN 2, VIN 3, VaIN 2, VaIN 3
- HPV 6/11/16/18 related CIN 1, genital warts, VIN 1 and VaIN 1
|
|
85
|
- Applicant’s Per Protocol HPV type-specific analyses that indicated a
very high level of efficacy in naïve subjects may not reflect the
efficacy of Gardasil for all HPV related disease on a population basis.
- HPV related disease occurred in Gardasil recipients.
- Some vaccine recipients were non-naïve at baseline for one or more
vaccine HPV type(s), and some of these subjects developed HPV disease
related to that HPV type(s).
- Subjects who were naïve to all four vaccine HPV types could still
develop disease related to an HPV type not included in the vaccine.
|
|
86
|
- Modified Intent to Treat analysis (MITT-3) of all vaccinated females
across studies 005, 007, 013, and 015 demonstrate modest efficacy
against CIN 2/3:
- MITT-3: Overall efficacy CIN 2/3
or worse due to HPV6/11/16/18 [39.0% (23.5, 51.7%)]
- MITT-3: Overall efficacy CIN 2/3
or worse due to any HPV type [12.2%
- (-3.2%, 25.3%)].
|
|
87
|
- Longer-term efficacy
- Study 005 results suggest favorable longer term efficacy
- Duration of immune response
- Post-licensure commitments
|
|
88
|
- Do the data from studies 005, 007, 013, and 015 support the efficacy of
Gardasil for the prevention of HPV 16/18 related cervical cancer, cervical AIS, and
CIN 2/3 or worse in females 16-26 years of age?
|
|
89
|
- Do the data from studies 007, 013, and 015 support the efficacy of
Gardasil for the prevention of HPV 6/11/16/18 related VIN 2/3 and VaIN
2/3 in females 16-26 years of age?
|
|
90
|
- Do the data from studies 007, 013, and 015 support the efficacy of
Gardasil for the prevention of HPV 6/11/16/18 related condyloma
acuminata, VIN 1 and
- VaIN 1?
|
|
91
|
- Do the immunogenicity data support bridging of the younger female
population (9-15 years of age) to the efficacy population (females 16-26
years of age)?
|
|
92
|
- Do the safety data from studies 007, 013, 015, 016 and 018 support the
safety of Gardasil for use in females 9-26 years of age?
|
|
93
|
- Please comment on post-marketing commitments.
|
Notes
