1 vaccines and related biological products advisory committee meeting cervarix ® : human...

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


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


(TVC of Naïve Women)*CervarixN=5449


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


(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



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



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


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


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


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


% %

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


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=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=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=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.

49

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).

50

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

51

Pregnancies with Known Outcomes During Entire Study Period [through 8/31/08]

CervarixN=3178


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

52

CervarixN=392


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)

53

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 [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

55

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.

63

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;

64

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.

69

Questions for the Committee4. Please comment on other

recommendations for post-marketing commitments.

1 vaccines and related biological products advisory committee meeting cervarix ® : human...

Documents