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3 Cervarix: Applicant’s Proposed Indications In females years of age, prevention of cervical cancer (squamous cell carcinoma and adenocarcinoma) by protecting against the following precancerous or dysplastic lesions and infections caused by oncogenic human papillomaviruses (including types 16 and 18 and some non- vaccine HPV types) CIN grade 2 and CIN grade 3 and AIS CIN 1 Abnormal cytology (ASC-US, LSIL, HSIL) Persistent infection Incident infection AIS = Adenocarcinoma in situ; CIN = Cervical Intraepithelial Neoplasia; ASC-US = atypical squamous cells of undetermined significance; LSIL = low grade squamous intraepithelial lesion; HSIL = high grade squamous cell intraepithelial lesion.
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1
Vaccines and Related Biological Products Advisory Committee Meeting
Cervarix®: Human Papillomavirus Bivalent
(Types 16 and 18) Vaccine, Recombinant
Applicant: GlaxoSmithKline Biologicals (GSK)
Nancy Miller, M.D.FDA/CBER/OVRR/DVRPA
September 9, 2009
2
Presentation Topics Proposed Indication Efficacy Immunogenicity Safety Post-Marketing Studies Questions for Committee
3
Cervarix:Applicant’s Proposed Indications
In females 10-25 years of age, prevention of cervical cancer (squamous cell carcinoma and adenocarcinoma) by protecting against the following precancerous or dysplastic lesions and infections caused by oncogenic human papillomaviruses (including types 16 and 18 and some non-vaccine HPV types)
CIN grade 2 and CIN grade 3 and AIS CIN 1 Abnormal cytology (ASC-US, LSIL, HSIL) Persistent infection Incident infection
AIS = Adenocarcinoma in situ; CIN = Cervical Intraepithelial Neoplasia; ASC-US = atypical squamous cells of undetermined significance; LSIL = low grade squamous intraepithelial lesion; HSIL = high grade squamous cell intraepithelial lesion.
4
Efficacy Endpoint for Preventive HPV Vaccines (Cervical Cancer)
November 2001 VRBPAC: CIN 2/3 histology, AIS, or worse with
virologic identification of HPV type.
5
Cervarix: Efficacy HPV 16/18 related CIN2+ HPV 16/18 related CIN1+, persistent
infection (6- and 12-month definition), abnormal cytology
CIN2+ irrespective of HPV type Cervical disease related to non-vaccine
HPV types
6
HPV-008: Primary Efficacy Endpoints Study design: randomized, double-blind controlled trial (Havrix)
[HAV/Al(OH)3] Primary endpoint: CIN2+ associated with
HPV-16 and/or HPV-18 (fixed event study design) Final analysis when at least 36 cases of HPV 16/18 related
CIN2+ were detected in the ATP cohort for efficacy, including at least 15 cases of CIn2+ associated with HPV-18.
At time of analysis, 60 cases identified in ATP cohort.
CIN2+=CIN2, CIN3, AIS or invasive cervical cancer; CIN1+=CIN1, CIN2, CIN3, AIS or invasive cancer
7
HPV-008: Secondary Efficacy Endpoints Secondary endpoints:
Persistent infection with HPV 16 and/or 18 (6- and 12-month)
CIN1+ associated with HPV 16 and/or 18 Persistent infection with High Risk HPV types CIN2+ associated with High Risk HPV types
High Risk HPV=16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68
6-month persistent infection-relevant HPV type detected on 2 consecutive swabs 6 months apart;
12-month persistent infection-relevant HPV type detected on 2 consecutive swabs 12 months apart.
8
HPV-008: Distribution of Subjects by Geographical Region
Region Cervarix Control (Havrix)
Total (%)
Asia-Pacific 3175 3177 6532 (34.1%)Europe 3224 3224 6448 (34.%)Latin America 1388 1386 2774 (14.9%)
North America 1532 1538 3070 (16.5%)Totals 9319 9325 18644 (100%)
9
HPV-008: Baseline CharacteristicsCharacteristic Cervarix
N=9319Value or %
HavrixN=9325
Value or %Age (mean in years) 20.0 20.0
Abnormal cytology Low grade cytology High-grade cytology
9.3%0.5%
8.8%0.5%
PCR status Day 1 Positive for HPV-16 Positive for HPV-18
5.6%2.4%
5.2%2.3%
Serostatus Day 1 Positive for HPV-16 Positive for HPV-18
16.7%11.7%
16.8%11.6%
Positive by serology &/or PCR to HPV 16 Positive by serology &/or PCR to HPV 18
19.2%13.1%
19.3%12.8%
10
HPV-008: Efficacy Analysis PopulationsPopulation Pap test baseline Serostatus
D0 PCR status Doses/cases counted when
According to Protocol cohort(ATP)
Normal or low-grade (a)
Negative relevant HPV
Negative through M6 for relevant HPV
type
3 doses/1 day after dose 3
Total Vaccinated
Cohort (TVC)*Any Any Any 1 dose/1 day
after dose 1
TVC naïve Total
Vaccinated Cohort Naïve
Women(TVC Naïve)*
Normal (b)
Negative for HPV 16 and
18
Negative for all HR HPV D0 1 dose/1 day
after dose 1
(a) Normal or low-grade cytology = negative or ASC-US or LSIL; (b) normal = negative or ASC-US HCII negative; HR HPV=16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68; *TVC and TVC naïve include subjects with data available for analysis.
11
Study HPV-008: Analysis of Efficacy AgainstCIN2+ Associated with HPV 16/18
(ATP Cohort)*CervarixN=8093
Control (Havrix)N=8069
No. of subjects
No. of cases
No. of subjects
No. of cases
Efficacy(96.1% CI)
HPV 16/18 7344 4 7312 5692.9%
(79.9%, 98.3%)
HPV 16 6303 2 6165 4695.7%
(82.9%, 99.6%)
HPV 18 6794 2 6746 1586.7%
(39.7%, 98.7%)*ATP cohort = subjects received 3 doses vaccine, were seronegative for HPV 16 or 18 at Month 0, were PCR negative for HR HPV DNA at Month 0, and negative for HPV 16 or 18 at Month 6; cases counted 1 day after dose 3.
12
Study HPV-008: Analysis of Efficacy AgainstCIN2+ Associated with HPV 16/18 (TVC)*
CervarixN=8667
Control (Havrix)N=8682
No. of subjects
No. of cases
No. of subjects
No. of cases
Efficacy(96.1% CI)
HPV 16/18 8667 82 8682 174
52.8% (37.5%, 64.7%)
HPV 16 8667 75 8682 15250.6%
(33.5%, 63.6%)
HPV 18 8667 8 8682 3375.7%
(44.4%, 90.8%)TVC*=Total vaccinated cohort (Includes subjects who may be naïve OR non-naïve for the relevant HPV type, received one dose vaccine, with data available, cases counted after dose 1.
13
Study HPV-008: Analysis of Efficacy AgainstCIN2+ Associated with HPV 16/18
(TVC of Naïve Women)*CervarixN=5449
Control (Havrix)N=5436
No. of subjects
No. of cases
No. of subjects
No. of cases
Efficacy(96.1% CI)
HPV 16/18 5449 1 5436 6398.4%
(90.4%, 100%)
HPV 16 5449 1 5436 5698.2%
(89.1%, 100%)
HPV 18 5449 0 5436 12100%
(61.3%, 100%)*TVC cohort of naïve women: subjects PCR negative for HR HPV types Month 0, seronegative for HPV 16 and 18 M0, and Pap normal at baseline, with data available; cases counted 1 day after dose 1.
14
Study HPV-008: Analysis of Efficacy AgainstCIN2+ Associated with HPV 16/18
(Subjects Seropositive and/or PCR Positive Baseline)*Cervarix Control (Havrix)
No. of subjects
No. of cases
No. of subjects
No. of cases
Efficacy(96.1% CI)
PCR(+) orSero (+ or -)
617 62 567 580.5%
(-47.7%, 32.9%)
PCR (+)Sero (-)
303 18 285 2737.8%
(-20.9%, 68.8%)
PCR (+)Sero (+)
315 43 289 31-32.5%
(-123.1, 20.4%)
*Subjects have normal or low-grade cytology
15
Cervarix: Efficacy HPV 16/18 related CIN2+ HPV 16/18 related CIN1+, persistent
infection (6- and 12-month definition), abnormal cytology
CIN2+ irrespective of HPV type Cervical disease related to non-vaccine
HPV types
16
HPV-008: Summary of Vaccine Efficacy Against CIN1+, Abnormal Cytology, Incident Infection,
and Persistent Infection (6 and 12 Month) Related to HPV 16 and/or 18 (ATP Cohort for Efficacy)
Cervarix Control (Havrix)
Endpoint No. of subjects
No. of cases
No. of subjects
No. of cases
Efficacy(96.1% CI)
CIN1+ 7344 8 7312 96 91.7%(82.4%, 96,7%)
Incident infection 7346 263 7320 1074 76.7%(73.2%, 79.9%)
6-month persistent infection 7177 32 7122 497 93.8%
(91.0%, 95.9%)12-month persistent infection
7035 21 6984 233 91.2%(85.9%, 94.8%)
ASC-US, LSIL, HSIL 7340 51 7312 434 88.5%
(83.3%, 92.4%)
17
Cervarix: Efficacy HPV 16/18 related CIN2+ HPV 16/18 related CIN1+, persistent
infection (6- and 12-month definition), abnormal cytology
CIN 2+ irrespective of HPV type Cervical disease related to non-vaccine
HPV types
18
Study HPV-008: Analysis of Efficacy AgainstCIN2+ Irrespective of HPV type (TVC)*
CervarixN=8667
Control (Havrix)N=8682
No. of subjects
No. of cases
No. of subjects
No. of cases
Efficacy(96.1% CI)
8667 224 8682 32230.4%
(16.4%, 42.1%)
*TVC=Total vaccinated cohort (Includes subjects who received one dose vaccine, any Pap test, any serostatus, any baseline PCR, data available, cases counted after dose 1)
19
Study HPV-008: Analysis of Efficacy AgainstCIN2+ Irrespective of HPV type
(TVC of Naïve Women)*CervarixN=5449
Control (Havrix)N=5436
No. of subjects
No. of cases
No. of subjects
No. of cases
Efficacy(96.1% CI)
5449 33 5436 11070.2%
(54.7%, 80.9%)
(*TVC Naive=subjects DNA negative for all HR HPV types Month 0, seronegative/PCR negative for HPV 16 and 18, negative cytology M0, data available, cases counted 1 day after dose 1)
20
Cervarix: Efficacy HPV 16/18 related cervical CIN2+
HPV 16/18 related CIN1+, persistent infection (6- and 12-month definition), abnormal cytology
CIN2+ irrespective of HPV type
CIN2+ related to non-vaccine HPV types
21
CIN2+ Related to Non-Vaccine HPV Type(s) (Statistical Considerations)
One of the 7 secondary efficacy endpoints is defined as “Histopathologically-confirmed CIN2+ associated with the following oncogenic HPV types (or combination of types): HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 (by PCR) detected within the lesional component of the cervical tissue specimen (by PCR).”
This is a composite endpoint including 14 HPV types. None of these types was pre-specified as an individual endpoint. Results of the individual analyses on these 12 non-vaccine HPV types are based on post-hoc evaluation.
No multiplicity adjustments for the Type I error probability have been considered in the evaluation of each of the 12 non-vaccine HPV types.
22
CIN2+ Related to Non-Vaccine HPV Type(s) (ATP Cohort for Efficacy)
CervarixN=7863
Control (Havrix)N=7853
No. of cases No. of cases
Efficacy(96.1% CI)
HR-HPV 54 14261.9%
(46.7%, 73.2%)
HRW-HPV 50 10954.0%
(34.0%, 64.0%)
12 HR HPV types 48 7737.4%
(7.4%, 58.2%)Subjects DNA negative for at least one HPV type at Month 0 and Month 6 (subjects were in the analysis of at least one single type)HRW-HPV = All high-risk (oncogenic) HPV types excluding HPV-16 and HPV-18HR-HPV= High-risk (oncogenic) HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68
23
GSK Analysis of Efficacy for CIN2+ Associated with HR HPV Types [ATP Cohort for Efficacy]
Cervarix N=7363-7782
Control (Havrix)N=7352-7764
HPV type Total cases Total Vaccine Efficacy (96.1% CI)31 2 25 92.0% (66.0%, 99.2%)33 12 25 51.9% (-2.9%, 78.9%)35 1 6 83.3% (-49.1%, 99.7%)
39 3 10 69.8% (-24.2%, 95.2%)
45 0 4 100% (-67.8%, 100%)51 10 27 62.9% (18.0%, 84.7%)52 12 14 14.3% (-108.1%, 65.4%)56 4 10 59.9% (-47.1%, 91.5%)58 6 17 64.5% (1.5%, 89.2%)59 1 4 74.9% (-178.6%, 99.6%)66 4 10 60.0% (-46.7%, 91.6%)68 5 11 54.4% (-49.8%, 88.4%)
24
GSK Analysis of Efficacy of CIN2+ Associated with HR HPV types [TVC of Naïve Women]
Cervarix N=5449
Control (Havrix) N=5436
HPV type Total cases Total Vaccine Efficacy (96.1% CI)
31 0 20 100% (78.3%, 100%)
33 5 18 72.3% (19.1%, 92.5%)
35 1 4 75.1% (-176.3%, 99.6%)
39 3 9 66.8% (-41.4%, 94.8%)
45 0 5 100% (-19.5%, 100%)
51 2 17 88.3% (47.9%, 98.9%)
52 7 11 36.5% (-88.4%, 80.3%)
56 0 4 100% (-67.1%, 100%)
58 3 11 72.8% (-8.9%, 95.6%)
59 0 2 100% (-514.5%, 100%)
66 1 6 83.4% (-48.0%, 99.7%)
68 2 7 71.5% (-60.3%, 97.5%)
25
Analysis of Efficacy of CIN2+ Associated with HR HPV types [GSK Analysis with CBER Modifications]
[TVC of Naïve Women]Cervarix N=5449 Control (Havrix) N=5436
HPV type Total cases Total-# cases with 16/1831 0 20-7=13
33 5 18-3=15
35 1 4-2=2
39 3 9-5-4
45 0 5-4=1
51 2 17-14=3
52 7 11-8*=3
56 0 4 -4=0
58 3 11-6*=559 0 2-1*=1
66 1 6-3=3
68 2 7-5=2Cases may contain different HPV types and may be listed more than once because of this. [cases] include HPV 16/18; cases may include other non-vaccine HPV types; *includes 1 case where different lesions collected at same time are considered.
26
HPV-001/007 HPV-001: randomized, double-blind controlled
trial (aluminum hydroxide control) Primary Efficacy Endpoint: Prevention of HPV-
16 and/or HPV-18 incident infection after three doses of vaccine in naïve* subjects.
Secondary Efficacy Endpoints: Prevention of persistent infection and abnormal cytology associated with vaccine HPV types and with non-vaccine HPV types.
HPV-007 (extension of HPV-001) evaluated long-term immunogenicity and efficacy. *Naïve=seronegative for HPV 16/18 baseline, PCR negative for HPV 16/18 through M6, HR HPV negative by HCII testing, normal cytology.
27
HPV-007: Efficacy for 16/18 Related Outcomes Within 6 Years After Vaccination
Cervarix Control
(aluminum hydroxide)
Endpoint No. of subjects
No. of cases
No. of subjects
No. of cases
Efficacy(95% CI)
Incident infection with HPV 16 &/or 18 (ATP cohort)
303 2 267 4796.7%
(87.4%, 99.6%)
6-month persistent infection with HPV 16 &/or 18 (ATP cohort)
304 0 277 24100%
(85.9%, 100%)
12-month persistent infection with HPV 16 &/or 18 (ATP cohort)
304 0 285 15100%
(75.0%, 100%)
CIN2+ associated with HPV 16/18 (Total Cohort) 358 0 342 6
100% (19.7%, 100%)
Infection determined by PCR of cervical samples
28
Immunogenicity Bridging immunologic response from
females 15-25 years of age to females 10-14 years of age
HPV-012 and HPV-013 Duration of immune response
29
HPV-012: Non-Inferiority of Antibody Response at Month 7
(15-25 Year Old Females Compared to 10-14 Year Old Females)
15-25N=116-118
10-14N=141-143
Difference inSeroconversion
Rates [15-25] minus [10-14]
15-25N=116-118
10-14N=141-143 GMT Ratio
[15-25]/[10-14]
IgG by ELISA (%) (%) % (95% CI) GMT GMT Ratio
(95% CI)
Anti-HPV 16 100% (100%) 0.00%(-3.15%, 2.62%) 7438.9 17272.5 0.43
(0.35, 0.53)
Anti-HPV 18 100% (100%) 0.00%(-3.21%, 2.65%) 3070.1 6863.8 0.45
(0.36, 0.55)
Seropositivity rate = UL of the 95% CI <10%; GMT ratio=UL of the 95% CI < 2. N=number of subjects with available results, subjects seronegative prior to Dose 1. Seroconversion: initially seronegative subject prior to vaccination with and became seropositive. Seropositive for anti-HPV 16 ≥8 EU/mL; Seropositive for anti-HPV 18 ≥7 EU/mL.
30
HPV-013: Seropositivity Rates and GMTs in 15-25 Year Old Females From HPV-001 Compared to 10-14 Year Old Females
[ATP Cohort for Immunogenicity] [Month 7]Seropositivity Rate
15-25 N=362
Seropositivity Rate10-14
N=655-656
GMT15-25N=362
GMT10-14
N=655-656
IgG by ELISA%
(95% CI)%
(95% CI)GMT
(95% CI) GMT (95% CI)
Anti-HPV 16 100%(99%,100%)
100%(99.4%, 100%)
4378.5(3956.2, 4845.7)
20018.1(18799.3,21315.9)
Anti-HPV 18 100%(99%,100%)
100%(99.4%, 100%)
3459.8(3162.8, 3784.8)
8359.4(7820.8, 8935.1)
15-25 = subjects 15-25 years of age study HPV-001; 10-14 = 10-14 years of age; n=number of subjects with prevaccination samples available.
Seropositive for anti-HPV 16 ≥8 EU/mL; Seropositive for anti-HPV 18 ≥7 EU/mL.
31
HPV-001/007: Immune Response in Cervarix Recipients Month 75-76
(IgG by ELISA) [ATP Cohort for Immunogenicity]
IgG by ELISA Seropositivity Rates GMTs
Anti-HPV 16N=52
100%(93.2%, 100%)
463.6(360.8, 595.5)
Anti-HPV 18N=52
100%(93.2%, 100%)
279.8(218.0, 359.1)
N=number of Cervarix recipients with available results;
Seropositive for anti-HPV 16 ≥8 EU/mL; Seropositive for anti-HPV 18 ≥7 EU/mL.
32
HPV-004/005: Effect of AS04 on Antibody Response at Year 4
Seropositivity Rate
AS04-adjuvanted
N=27
Seropositivity Rate
Aluminum-adjvanted
N=11
GMTAS04-
adjuvantedN=27
GMTAluminum-adjuvanted
N=11
IgG by ELISA%
(95% CI)%
(95% CI)GMT
(95% CI) GMT (95% CI)
Anti-HPV 1696.3%
(81.0%, 99.9%)100%
(71.5%, 100%)858.5
(496.3, 1485.2)488.8
(261.1, 915.0)
Anti-HPV 1896.3%
(81.0%, 99.9%)100%
(71.5%, 100%)455.5
(262.9, 789.0)189.9
(108.0, 333.7)
ELISA Version 2 used in pooled analysis;
Seropositive for anti-HPV-16 ≥ 8 EL.U/mL; Seropositive for anti-HPV 18 ≥ 7 EL.U/mL
33
Safety Solicited and Unsolicited Adverse Events Deaths Serious Adverse Events Adverse Events leading to discontinuation
from studies New Onset Chronic Diseases and
Autoimmune Diseases Musculoskeletal/Autoimmune events Neuroinflammatory events
Pregnancies and Pregnancy outcomes
34
Study HPV-008: Number of Subjects in Safety Populations
(15-25 year old females)Safety Population Cervarix Control
(Havrix*) Total
Total Vaccinated Cohort for Safety
9319 9325 18644
Safety Diary Card Subset 3184 3187 6371
35
Study HPV-013: Number of Subjects in Safety Population (10-14 year old females)
Safety Population Cervarix Control
(Havrix) Total
Total Vaccinated Cohort
1035 1032 2067
*Havrix formulation for 10-14 year old females contains 360 EL.U/0.5 mL HAV antigen and 250 mcg Al(OH)3
36
HPV-008: Solicited Adverse Events (7 days after Vaccination) [Safety Diary Card Subset]
Females 15-25 Years of AgeSolicited symptom Cervarix
N=3077Control (Havrix)
N=3080% %
Local Symptoms 91.2% 79.8% Pain 90.5% 78.0%General symptoms 78.9% 74.8% Fatigue 57.6% 53.6% Headache 54.1% 51.3% Myalgia 52.2% 44.9%
37
HPV-013: Solicited Adverse Events (7 days after Vaccination) [Total Vaccinated Cohort]
Females 10-14 Years of AgeSolicited Symptom Cervarix N=1029 Control (Havrix) N=1027
% %Local Symptoms 87.5% 68.1% Pain 86.4% 64.2%General symptoms 79.7% 71.1% Headache 50.1% 45.2% Myalgia 49.5% 33.1% Fatigue 48.5% 42.3% Gastrointestinal 25.8% 24.6% Arthralgia 25.2% 19.9%
38
HPV-008: Unsolicited Adverse Events (30 days after Vaccination) [Safety Diary Card Subset]
Females 15-25 Years of AgeCervarixN=3184
Control (Havrix)N=3187
% %
At least one unsolicited AE 42.5% 43.6%
Headache 6.8% 7.6%Influenza 4.9% 5.6%GYN Chlamydia 4.1% 4.4%Nasopharyngitis 3.5% 3.4%
Pharyngolaryngeal pain 3.0% 2.7%
Dizziness 2.8% 2.6%
39
HPV-013: Unsolicited Adverse Events(30 days after Vaccination)
[Total Vaccinated Cohort]-Females 10-14 Years of AgeCervarixN=1035
Control (Havrix)N=1032
At least one unsolicited AE 37.3% 41.4%Infections and Infestations URI Nasopharynitis
21.8%5.8%5.4%
23.3%6.7%5.9%
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain
6.5%
2.7%
5.2%
2.1%Nervous system disorders 5.2% 6.0%Gastrointestinal disorders 2.7% 3.7%
40
Deaths Reported in All Studies Involving Cervarix
Cervarix N=33623(Total=20, 0.06%)
Control N=23700 (Total=17, 0.08%)
Trauma 7 6Suicide 2 5Neoplasms 3 2 Infections 4 1Cardiac disorders 1 0Gastrointestinal disorders 2 0Death not specified 0 2Endocrine disorders 0 1PE with lung mass (CA or TB) 1 0
41
Percentage of Subjects Reporting the Occurrence of at Least One Serious Adverse Event in the Updated Pooled
Safety Analysis in the BLA Submission (Total Vaccinated Cohort)
Follow-up periodHPV
N=16142Pooled Control
N=13811Vaccination period (Month 0 - Month 7)
206 (1.3%) 180 (1.3%)
Entire observation period(Range: 7 -76 months)
851 (5.3%) 805 (5.9%)
Studies HPV-001, HPV-003, HPV-004, and HPV-005, HPV-007 [final analysis], HPV-008 [final analysis], HPV-012, HPV-013, HPV-013 Ext [Month 18 analysis], HPV-014, HPV-014 Ext [Month 18 analysis], HPV-015 [Month 7 safety interim analysis] and HPV-016 Age groups: HPV = [10-14], [15-25] and [25+], ALU = [15-25] and [25+], HAV360 = [10-14] and HAV720 = [15-25]N = number of subjects with at least one administered dose; n/% = number/percentage of subjects reporting at least one symptom
42
AEs/SAEs Leading to Discontinuations
*Study discontinuations due to adverse events for studies included in BLA [Studies HPV-001, 003, 004, 005, 007, 008, 009, 012 (including extension), 013 (including extension), 014 (including extension), 015, 016] classified by MedDRA Primary System Organ Class and Preferred Term (Total vaccinated cohort, through August 31, 2008)
Follow-up periodHPV
N=16142Pooled Control
N=13811
Entire Study Period(through 8/31/08)
43 (0.27%) 29 (0.21%)
43
New Onset Chronic Diseases and New Onset Autoimmune Diseases in
Pooled Safety Population
Follow-up periodHPV
N=16142Pooled Control
N=13811
Vaccination period (Month 0 - Month 7)
1.2% (95% CI: 1.0, 1.4%)
1.0% (95% CI: 0.9, 1.3%)
Entire observation period (through 8/31/08)
2.4% (95% CI: 2.2, 2.7)
2.6% (95% CI: 2.4, 2.9%)
44
New Onset Autoimmune Diseases
Follow-up periodHPV
N=13591Pooled Control
N=11341
Vaccination period (Month 0 - Month 7)
0.2% (95% CI: 0.1%, 0.3%)
0.2% (95% CI: 0.1%, 0.3%)
Entire observation period (through 8/31/08)
0.7% (95% CI: 0.6%, 0.8%)
0.8% (95% CI: 0.6%, 0.9%)
45
Musculoskeletal /Autoimmune Events In response to request from CBER, GSK provided
comparison of events related to musculoskeletal system (e.g., arthritis, fibromyalgia) in subjects (meta-analysis for MPL containing products).
Cases reviewed in blinded manner by panel of expert rheumatologists (GSK).
The overall relative risk for HPV-AS04 containing products in controlled studies over entire study period was 1.31 (95% CI: 0.79, 2.20).
The most frequently reported musculoskeletal events were arthritis, fibromyalgia, rheumatoid arthritis, systemic lupus erythematosus and arthropathy.
46
Musculoskeletal/Autoimmune Events (cont.)
In extended analysis recommended by expert panel using additional MedDRA terms, RR for entire study period for HPV-AS04 vaccines in controlled trials was 1.08 (95% CI: 0.68, 1.72).
Expert panel assessed some events as uncertain etiology, and when diagnoses combined (confirmed and uncertain), RR = 1.67 (95% CI: 0.73, 3.87) for HPV-MPL vaccines in controlled trials. *Time at risk = 1 to 6 months after last vaccinationSiegrist C et al. HPV immunization in Adolescent and Young Adults: A Cohort Study to Illustrate What Events Might be Mistaken for Adverse Reactions. Pediatric Infectious Disease Journal 2007; 26:979-984.
47
Musculoskeletal/Autoimmune Events (cont.)
Time to onset analysis provided by GSK including additional blinded expert. During time at risk*, RR=3.0 (95% CI = 0.24, 157.41) and at anytime at risk, RR=1.00 (95% CI: 0.30, 3.34). Time at risk: 2 reactive arthritis HPV, 1 control; 1
RA in each treatment group. Difficulty in ascribing cause in this age group
[Siegrist et al (2007)] *Time to risk = 1 to 6 months from last vaccination
Siegrist C et al. HPV immunization in Adolescent and Young Adults: A Cohort Study to Illustrate What Events Might be Mistaken for Adverse Reactions. Pediatric Infectious Disease Journal 2007; 26:979-984.
48
Neuroinflammatory Events (Controlled and Uncontrolled HPV-AS04 studies)
(through 12/31/08)Event HPV-MPL N=34466 Control N=27742
Demyelinating disease1
*129 days after dose 2 [CIS][U]0
Multiple sclerosis3
*25 days after dose 2 [CIS] [U]2 other cases >2 years after dose 3
1*60 days after dose 1
Myelitis2
*47 days after dose 2 [insuff. Dx]22 months after dose 3 [TM]
0
Optic neuritis
3*9 days after dose 1 [CIS] [U]*15 months after dose 3 [CIS]
1 other case > 2 years after dose 3
2*134 days after dose 3 [CIS]
*23 months after dose 3 [CIS]
Optic neuritis/multiple sclerosis
1*17 months after dose 3 [CIS]
0
*events were reviewed at time of original review; CIS=clinically isolated syndrome; TM=transverse myelitis; [U] = uncontrolled studies; cases highlighted in blue occurred within 12 weeks of vaccination.
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Neuroinflammatory events GSK’s meta-analysis for HPV-AS04 products:
RR = 2.33 (95% CI: 0.5, 13.97). External expert neurology panel (blinded as
to treatments) (GSK) No increased risk of neuroinflammatory disorders
following vaccination with MPL-containing vaccines (review included events through 12/31/07).
Neurologist (outside FDA) Data not sufficient to establish a link, but further
monitoring recommended (post-marketing studies).
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Pregnancies During Entire Study Period and Around Time of Vaccination
(through 8/31/08)CervarixN=19871
Pooled Control N=17548
N (%) of subjects with pregnancies during entire study period
3696 (18.6%) 3580 (20.4%)
N (%) of subjects with pregnancies around vaccination (-30 to +45 days)
396 (2.0%) 365 (2.1%)
*
Studies HPV-001, 003, 004, 005, 007, 008 009, 012, 012EXT 013, 013EXT, 014, 014EXT, 015, 016 and 023
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Pregnancies with Known Outcomes During Entire Study Period [through 8/31/08]
CervarixN=3178
Pooled Control N=3093
Normal infant 2300 (72.37%) 2240 (72.40%)
Premature birth 73 (2.3%) 62 (2.0%)
Abnormal infant (excl cong. anomaly)
105 (3.3%) 114 (3.69%)
Elective termination 216 (6.80%) 217 (7.02%)
Therapeutic abortion 4 (0.13%) 4 (0.13%)
Ectopic pregnancy 22 (0.69%) 21 (0.68%)
Spontaneous abortion 408 (12.84%) 388 (12.54%)
Stillbirth 20 (0.63%) 19 (0.61%)
Congenital anomaly 30 (0.94%) 28 (0.91%)
Studies HPV-001, 003, 004, 005, 007, 008 009, 012, 012EXT, 013, 013EXT, 014, 014EXT, 015, 016 and 023
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CervarixN=392
Pooled Control N=359
Normal infant 258 (65.82%) 253 (70.47%)Premature birth 10 (2.55%) 9 (2.51%)Abnormal infant (excl cong. anomaly)
20 (5.10%) 17 (4.74%)
Elective termination 39 (9.95%) 39 (9.75%)Therapeutic abortion 1 (0.26%) 1 (0.28%)Ectopic pregnancy 2 (0.51%) 1 (0.28%)Spontaneous abortion 54 (13.78%) 35 (9.75%)Stillbirth 1 (0.26%) 3 (0.84%)Congenital anomaly 7 (1.79%) 5 (1.39%)
§Time around vaccination = -30 to +45 days from day of vaccination
Studies HPV-001, 003, 004, 005, 007, 008 009, 012, 012EXT, 013, 013EXT, 014, 014EXT, 015, and 016
Pregnancies with Known Outcomes Around Time of Vaccination§ (through 8/31/08)
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Number (%) Spontaneous Abortions for All Pregnancies with Known Outcome
(by Age and Treatment)Cervarix
Control (Havrix)
Control [Al(OH3)]
15-25 years of ageN (%)
367/2985 (12.29%)
323/2736 (11.81%)
21/191 (10.99%)
25+ years of ageN (%)
40/169 (23.67%) -
44/151 (29.14%)
N (%)=number and percentages of pregnancies which resulted in spontaneous abortion.
54
Number (%) Spontaneous Abortions for Pregnancies with Known Outcomes Around Time of Vaccination§
(by Age and Treatment)
CervarixN=374
Control (Havrix)N=319
Control [Al(OH3)]
N=12
15-25 years of ageN(%)
50/374 (13.37%)
28/319 (8.78%)
1/12(8.33%)
25+ years of ageN (%)
4/21(19.05%)
- 6/31(19.35%)
N (%) = Number and percentages of pregnancies which resulted in spontaneous abortions. §Time around vaccination = -30 to +45 days from day of vaccination
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Limitations in Assessment of Spontaneous Abortion
Spontaneous abortion not a pre-specified outcome. Clinical trials not designed to study spontaneous
abortions. Post-hoc selection of time window. The rates in treatment groups are within expected
background rates (9-21%) In pregnancies around time of vaccination, no difference
in mean time to spontaneous abortion in each group. Pre-clinical reproductive toxicology studies without
signal.
56
NCI Analysis of Spontaneous Abortions
The 1-sided P-value for the primary permutation test was 0.16 using the nearest vaccination as the reference date.
Among pregnancies with estimated conception date between day 0 and 89 from nearest vaccination, the miscarriage rate was 15.4% (58) miscarriages in the treatment arm and 9.6% (34) in the control arm (1-sided P-value of 0.036, did not meet the standard threshold for significance.
The secondary analysis could neither deny nor confirm an increased discrepancy in spontaneous abortion rates among vaccine recipients.
57
Safety in Post-Marketing Period Worldwide
Cervarix was licensed for use in Australia in 5/07, and many other countries in the EU, South America, and Asia.
From 5/18/07 – 5/18/09, 1706 reports of adverse events tabulated by CBER
793 (64%) non-serious 450 (36%) serious: One death reported in
12 year old girl related to Group A strep septicemia at 3 weeks after dose 2.
58
Frequency of 10 Most Reported Adverse Events per 100,000 Doses Distributed [May 2007 through May 2009]
Event PT Number of Events Reported frequency per 100,000 doses distributed
Headache 249 3.65Injection site pain 246 3.61
Pyrexia 223 3.27Dizziness 188 2.76Nausea 163 2.39
Pain in extremity* 162 2.38Malaise 119 1.75
Rash 115 1.69Product quality issue 110 1.61
Syncope 101 1.48
*Description of individual cases similar to pain at injection site
59
Post-marketing Commitments(Proposed)
Routine pharmacovigilance Post-marketing studies Other studies
60
Routine Pharmacovigilance Passive reporting of adverse events
(AEs) including: Monthly submission of non-serious
AE reports Regular FDA-CDC-Sponsor
conference calls Submission of SAEs within 15 days
Pregnancy registry
61
Post-Marketing Studies CBER and GSK in discussions re:
post-marketing study in US Phase III/IV community randomized study
(HPV-040) will use Medical Birth Registry in Finland for the follow-up of pregnancies and pregnancy outcomes.
62
Summary of Efficacy: HPV 16/18 Related Disease
The data submitted to the BLA demonstrate efficacy of Cervarix in females 15-25 years of age naïve to the relevant vaccine HPV type for prevention of HPV 16/18 related cervical cancer, CIN2+ and CIN1+.
Immunologic bridging provides a basis for inferring effectiveness in females 10-14 years of age.
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Summary of Efficacy: Non-Vaccine HPV Related Disease
In TVC of naïve women, point estimate of efficacy ~ 70% in prevention of CIN2+ irrespective of HPV.
May be predominantly due to prevention of HPV 16/18 related disease, but also possible contribution from prevention of other HPV types, (e.g., HPV-31) when HPV 16 and 18 excluded from analyses.
No immunologic bridge available to girls 10-14 years of ageTVC naïve = Total Vaccinated Cohort naïve women;
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Summary of Cervarix Safety Musculoskeletal/autoimmune events
Overall, no statistically significantly increased relative risk in meta-analysis.
Neuroinflammatory events Overall, elevated relative risk though not
statistically significant in meta-analysis. Spontaneous abortions
Imbalance in spontaneous abortions in women 15-25 years of age around vaccination in studies 008 and 009, but many limiting factors.
65
Questions for the Committee1A. Do the data support the efficacy of
Cervarix for the prevention of HPV 16/18 related cervical cancer,
CIN2+, AIS, and CIN1+in females 15-25 years of age?
66
Questions for the Committee1B. Do the immunogenicity bridging
data support effectiveness for prevention of HPV 16/18 related cervical cancer, CIN2+, AIS, and CIN1+in in adolescent females10-14 years of age?
67
Questions for the Committee2. Please comment on the strength of the
data to support the efficacy of Cervarix for the prevention of any non-vaccine HPV related CIN2+ in females 10-25 years of age.
68
Questions for the Committee3. Do the safety data support the safety
of Cervarix for use in females 10-25 years of age?
a. Please comment on imbalance noted in spontaneous abortions in 15-25 year old females around the time of vaccination.
b. Please comment on findings for neuroinflammatory events and diseases of potential autoimmune etiology.
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Questions for the Committee4. Please comment on other
recommendations for post-marketing commitments.