A 1 GlaxoSmithKline’s Human Rotavirus Vaccine ROTARIX ® Vaccines and Related Biological Products Advisory Committee February 20, 2008

A A 11

GlaxoSmithKline’s GlaxoSmithKline’s Human Rotavirus VaccineHuman Rotavirus Vaccine

ROTARIXROTARIX®®

Vaccines and Related Biological Products Advisory Committee

February 20, 2008

A A 22

GlaxoSmithKline PresentationGlaxoSmithKline Presentation

Clare Kahn, Ph.DVice PresidentNorth America, Regulatory Affairs

Introduction

Leonard Friedland, M.D. Executive Director - Clinical R&DNorth America, Vaccines

Clinical Development PlanClinical Trial Results

Thomas Verstraeten, M.D.Director Head Worldwide Safety, Vaccines

Post-marketing Safety DataPharmacovigilance Plan

Clare Kahn, Ph.D Conclusion

A A 33

Proposed NamesProposed Names

Proprietary Name

Rotavirus Vaccine, Live, Oral

Trade Name Rotarix®

A A 44

Human RV Vaccine - Human RV Vaccine - RotarixRotarix

• Lyophilized vaccine + liquid diluent (CaCO3) – 1 mL per dose

– Each dose: ≥106 CCID50 of live, attenuated HRV strain

• Orally administered

• 2 doses– 1st dose beginning at 6 weeks of age

– 2nd dose at ≥4 weeks after first dose; completed by 24 weeks of age

A A 55

Proposed IndicationProposed Indication

ROTARIX is indicated for the prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (including G2, G3, G4 and G9) when administered as a 2-dose series to infants 6 to 24 weeks of age.

A A 66

Risk by 5th BirthdayAnnual Burden

1 : 5

1 : 1

1 : 205

1 : 50

610,000

2.4 million

24 million

114 million

Estimated Global Prevalence Estimated Global Prevalence of Rotavirus Diseaseof Rotavirus Disease

Deaths

Hospitalizations

Outpatient Visits

RV Episodes

Glass RI, et al. Lancet 2006;368:323-332

A A 77

Estimated US Prevalence Estimated US Prevalence of Rotavirus Diseaseof Rotavirus Disease

1 : 7

4 : 5

20-60

55,000-70,000

1 : 100,000

1 : 80

600,000

2.7 million

Deaths

Hospitalizations

Outpatient Visits

RV Episodes

Risk by 5th BirthdayAnnual Burden

Glass RI, et al. Lancet 2006;368:323-332

A A 88

Distribution of Rotavirus Strains by Distribution of Rotavirus Strains by Region between 1973 and 2003Region between 1973 and 2003

Latin America (n=2,950)

2%

3%

73%

11%

11%

G1 TypeG2 TypeG3 TypeG4 Type

G9 TypesOther Types

North America (n=2,892)

1%

7%

4%

11%

77%

Europe (n=17,475)

2%

4%

9%58%

9%

18%

n= number of RV infections analyzedSantos et al. Rev Med Virol 2005;15:29-56

A A 99

Rotavirus VirionRotavirus Virion

Figure adapted from Cunliffe et al, Lancet 2002;359:640–642

• 11 segments of dsRNA encased by 3 protein capsids

• VP6 common to all RV strains

• Outer capsid proteins VP7 (G protein) and VP4 (P protein) induce neutralizing antibodies involved in disease protection

• Human RV classified into 10 G (VP7) and 11 P (VP4) types

• 5 G-P combinations constitute 90% of worldwide strains:G1P[8], G2P[4], G3P[8], G4P[8], G9P[8]

• P[4] and P[8] share cross-reactive epitopes

A A 1010

33 passages in cell culture

Limiting dilution cloning in Vero cells and further passage in tissue culture

Initial Safety and Efficacy studies1

Live-Attenuated Human Rotavirus Vaccine

(RIX4414 - Rotarix®)

Human rotavirus strain circulating in Cincinnati in 1989

Human RV Vaccine - Human RV Vaccine - RotarixRotarix

1Bernstein et al, Lancet, 1999; 354:287-290

G1P[8]

G1P[8]

A A 1111

Basis for Vaccination with Human StrainBasis for Vaccination with Human Strain

010

20304050

607080

90100

Percent Efficacy

moderate to severe diarrhea

mild diarrhea

asymptomatic infection

Natural RV infection attenuates severity of subsequent infections, regardless of serotype1-3

1 Velazquez et al, N Eng J Med 1996 335 1022–10282 Bernstein DI, et al. JID. 1991; 164(2); 277-833 Velazquez et al, J Infect Dis 2000 182 1602–1609

Two Previous RV infectionsOne Previous RV infection

A A 1212

• Development of live attenuated rotavirus vaccines derived from animal hosts began in 1970s

• RotaShield®: rhesus-human reassortant vaccine licensed in the US in 1998

– Withdrawn in 1999 due to causal link with intussusception

• RotaTeq®: human-bovine reassortant vaccine licensed in 2006

• Rotarix®: live attenuated human RV vaccine

Large scale placebo-controlled safety trials required to refute intussusception related to vaccination

Rotavirus Vaccines - HistoryRotavirus Vaccines - History

A A 1313

Global Strategy for Global Strategy for RotarixRotarix Vaccine Vaccine Development Development

Following RotaShield withdrawal in 1999:

• Need for very large studies to assess risk of possible vaccine-induced intussusception (60,000 subjects)

• WHO recommendation to manufacturers to extend their development programs to countries with high medical need

• Majority of deaths resulting from RV gastroenteritis occur in South East Asia, Africa and Latin America

• Other considerations:

- Availability of sound epidemiology data on RV disease and intussusceptions rates

- a healthcare infrastructure to conduct very large trials

A A 1414

RotarixRotarix BLA Development BLA DevelopmentFinland

Mexico

Honduras

Nicaragua

Panama

Brazil

Venezuela

Colombia

Peru

Chile

ArgentinaPhase III – Study 023

Dominican Rep.

Other BLA Studies

CanadaUSA

South Africa

Thailand

Singapore

Phase III – Study 036

France

Germany

Spain

Czech Rep

Italy

A A 1515

Global Clinical DevelopmentGlobal Clinical Development

Non US clinical studies were pivotal for US licensure as all complied with the following criteria defined byFDA for acceptance of foreign clinical data (21 CFR §312.120, § 314.106; ICH E5)

• Circulating serotypes and IS background rates are similar to the US

• Objectivity of pivotal endpoints– Identification of IS

– Case definition for RV GE

– Use of internationally accepted and widely used scoring system for severity of GE

• Study design and conduct in compliance with GCPs

A A 1616

Registration Status for Registration Status for RotarixRotarix

ArgentinaArubaBoliviaBrazilChileColombiaCosta RicaCuracaoDom RepublicEcuadorEl SalvadorGuatemalaHondurasJamaicaMexicoNicaraguaPanamaParaguayPeruSurinameTrinidadVenezuela

Angola Benin Burkina Faso Cameroon Congo DRC Egypt Gabon Guinea Ivory Coast Kenya Madagascar Malawi Mali Mauritania Mauritius Mozambique Namibia Niger Nigeria RCA Senegal South Africa Togo

BangladeshHong KongMacauMalaysiaMyanmar PhilippinesSingaporeSri Lanka TaiwanThailandVietnam

BahrainIsraelJordanKuwaitMoroccoOmanPakistanQatarSaudi TurkeyUAEYemen

EU CanadaNorwayIcelandKazakhstanSwitzerland

AustraliaNew Zealand

• WHO prequalification – Feb 2007

• 12 million doses distributed

A A 1717


Clare Kahn, Ph.D.Vice PresidentNorth America Regulatory Affairs

Introduction



Thomas Verstraeten, M.D.DirectorHead, Worldwide Safety, Vaccines


Clare Kahn, Ph.D. Conclusion

A A 1818

Phase III

Immuno, Safety

Study 039 Thailand

n=174 n=52

Immuno US coadvaccines, Safety

Study 060 US

n=459

Efficacy, Safety (IS), Immuno

Study 023 Latin America, Finland

n=31673 n=31552

Lot consistency,Safety, Immuno

Study 033 Latin American=730 n=124

Efficacy, Safety,Immuno

Study 036 Europe

n=2646 n=1348

Phase II

Study 004 Finland

n=270 n=135

Study 006 Latin America

n = 1139 n=570 n=567

Study 007 Singapore

n = 1158 n=653 n=653

Safety, Immuno

Study 005 US, Canada

n=212 n=209 n=108

Immuno OPV Coad, Safety

Study 014S. Africa

n=297 n=150

Immuno,Safety

Study 048Finland

n=100 n=50




Summary of Clinical Studies in BLASummary of Clinical Studies in BLA

Rotarix <106.0 CCID50

n = 3076

Rotarix>106.0 CCID50

n = 37214Placebon =34739

Total Exposure = 75029 subjects

Phase II

Study 004 Finland

n=270 n=135

Study 006 Latin America

n = 1139 n=570 n=567

Study 007 Singapore

n = 1158 n=653 n=653

Safety, Immuno

Study 005 US, Canada

n=212 n=209 n=108

Immuno OPV Coad, Safety

Study 014S. Africa

n=297 n=150

Immuno,Safety

Study 048Finland

n=100 n=50




Phase III

Immuno, Safety

Study 039 Thailand

n=174 n=52

Immuno US coadvaccines, Safety

Study 060 US

n=459

Efficacy, Safety (IS), ImmunoStudy 023

Latin America, Finlandn=31673 n=31552

Lot consistency,Safety, Immuno

Study 033 Latin American=730 n=124

Efficacy, Safety,ImmunoStudy 036 Europe

n=2646 n=1348

Rotarix <106.0 CCID50

n = 3076

Rotarix>106.0 CCID50

n = 37214

Placebon =34739

Total Exposure = 75029 subjects

A A 1919

RotarixRotarix Clinical Development Clinical DevelopmentPivotal & Supportive Studies Pivotal & Supportive Studies

• Randomized, blinded, prospective, placebo-controlled (10 of 11 studies)

• Healthy infants, range 5 to 17 weeks at 1st dose (ph III 6 to 14 weeks); 2nd dose 1-2 months later

• Efficacy evaluated through 2 years/RV seasons after vaccination

• Safety evaluated in all studies (study 023 powered for IS assessment)

• Immunogenicity typically evaluated one month after 2nd dose

• Coadministration of routine infants vaccines: allowed in 9 of 11 studies

A A 2020

Clinical Trial Data to be PresentedClinical Trial Data to be PresentedEfficacy• Phase III Latin America • Phase III Europe

Immunogenicity• Seroconversion and Vaccine Take• Coadministration with US licensed Vaccines• Fecal Antigen and Live Virus Shedding

Safety• Intussusception• Integrated Summary of Safety: SAEs• Events of Clinical Interest• Integrated Summary of Safety: Reactogenicity• Reactogenicity: Europe, US & Canada

A A 2121



Safety• Intussusception• Integrated Summary of Safety: SAEs• Events of Clinical Interest• Integrated Summary of Safety: Reactogenicity• Reactogenicity: Europe, US & Canada

A A 2222

Dominican Republic4056 (6.4%)

Mexico13245 (20.9%)

Brazil3218 (5.1%)

Nicaragua4057 (6.4%)

Honduras4195 (6.6%)

Panama4061 (6.4%)

Chile3458 (5.5%)

Argentina4671 (7.4%)

Venezuela4250 (6.7%)

Colombia3910 (6.2%)

Peru12044 (19.0%)

Finland2060 (3.3%)

Study 023: Phase III Study in Latina & FinlandStudy 023: Phase III Study in Latina & Finland18 sites in 12 countries ~63,000 infants

• LA: efficacy & safety• Finland: safety only

A A 2323

N=63,225infants age 6-13 weeks

randomized (1:1)

month 0

Placebo N=31,552

Rotarix N=31,673

1st D

ose

2nd D

ose

Month 1-2 Month 2-4Safety

surveillance(N=63,225)

Month 9-10

1 yr Efficacy analysis

(ATPN=17,867)

Routine immunizations were co-administered according to local regulations

Study 023: Phase III Safety & Efficacy Study 023: Phase III Safety & Efficacy Study in Latin America and FinlandStudy in Latin America and Finland

Month 21-22


(ATPN=14,237)

Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354:11-22

A A 2424

Efficacy Latin America (Study 023)Efficacy Latin America (Study 023)

Primary Efficacy Objective

• To determine if 2 doses of Rotarix can prevent severe RV GE caused by circulating RV strains starting from 2 weeks after dose 2 until 1 year of age

Secondary Efficacy Objectives

• Efficacy against G1 and non-G1 serotypes

• Efficacy using Vesikari severity scale

• Efficacy through 2 years of age

A A 2525

Efficacy Latin America (Study 023)Efficacy Latin America (Study 023)

RV GE Case Definition

• “Severe GE”: diarrhea (≥3 loose stools in 24 hrs) with or without vomiting that required hospitalization and/or re-hydration therapy in a medical facility [Clinical Case Definition]

• RV detection by ELISA

• Type determination by RT-PCR followed by reverse hybridization assay (or optional sequencing as needed)

– Discrimination between G1 vaccine virus and wild-type G1 RV

A A 2626

Efficacy Endpoints

• Severe RV GE during 1st year efficacy period

– Clinical Case Definition

– Vesikari scale: based on intensity and duration of diarrhea, vomiting, fever, dehydration and type of treatment; score ≥11 = “severe”

• Efficacy against RV hospitalizations, all-cause severe GE

• Type-specific efficacy

• Second year efficacy

Efficacy Latin America (Study 023) Efficacy Latin America (Study 023)

A A 2727

0102030405060708090

100

Severe RV GEClinical

Severe RV GEVesikari

RV GEHospitalization

All-causeSevere GE

Vac

cin

e ef

fica

cy (

%)

From 2 weeks post-dose 2 until 12 months of age (ATP cohort)

85%[72;92]

85%[71;93]

85%[70;94]

40%[28;50]

12V:77P 11V:71P 9V:59P 183V:300P

Efficacy Latin America (Study 023) Efficacy Latin America (Study 023)

randomization 1:1

A A 2828

0102030405060708090

100

Severe RV GEClinical

Severe RV GEVesikari

RV GEHospitalization

All-cause SevereGE

Vac

cin

e ef

fica

cy (

%)


81%[71;87]

82%[73;89]

83%[73;90]

39%[30;47]

32V:161P

22V:127P

28V:154P

342V:551P

85%[72;92]

85%[72;93]

85%[70;94]

40%[28;50]

randomization 1:1

Efficacy Latin America (Study 023)Efficacy Latin America (Study 023)From 2 weeks post-dose 2 until 12 months of age (ATP cohort)

A A 2929

01020

3040506070

8090

100

G1P[8] G2P[4] G3P[8] G4P[8] G9P[8]

Va

cc

ine

eff

ica

cy

(%

)


*Not statistically significant

82% [65;92]

79% [25;96]

87% [73;94]

39%* [-112;84]

62% [4;87]

10V:55P 3V:14P+ 7V:18P 9V:66P5V:8P

+ one episode was P[6]

Type-specific Type-specific Efficacy Latin America Efficacy Latin America (Study 023) - severe RV GE(Study 023) - severe RV GE

randomization 1:1

A A 3030

StudyStudy 036: Phase III 036: Phase III StudyStudy in Europe in Europe124 Sites in 6 EU Countries ~4000 Infants124 Sites in 6 EU Countries ~4000 Infants

Spain7.5%Spain7.5%

Germany7%

Germany7%

France3.7%France3.7%

Italy0.6%Italy0.6%

Finland74%

Finland74%

CzechRepublic7.5%

CzechRepublic7.5%

A A 3131

Study 036: Phase III Safety & Study 036: Phase III Safety & Efficacy Study in EuropeEfficacy Study in Europe

Month 0

Placebo N=1,348

Co-administered with DTaP-HepB-IPV/Hib (all), PCV7 (subset), MenC (subset)

Rotarix N=2,646

1st d

ose

2nd d

ose

Months 1–2Months 7-9

Season 1 Efficacy analysis

(ATP N=3,874)

Months 19-21

Season 2 Efficacy analysis

(ATP N=3,848)

N=3,994infants age 6-14 wks

randomized (2:1)

Vesikari T et al. Lancet 2007;370:1757-63

A A 3232

Primary Efficacy Objective

• To determine if 2 doses of Rotarix can prevent any RV GE caused by circulating RV strains starting from 2 weeks after dose 2 until end of the first RV season post-vaccination

Secondary Efficacy Objectives

• Efficacy against severe RV GE

• Efficacy against G1 and non-G1 serotypes

• Efficacy against RV hospitalizations

• Efficacy against medically-attended RV GE

• Efficacy through 2 RV seasons post-vaccination

Efficacy Europe (Study 036)Efficacy Europe (Study 036)

A A 3333


RV GE Case Definition

• GE: diarrhea (≥3 loose stools in 24 hrs) with or without vomiting

• Severity assigned using Vesikari scale; score ≥11 = “severe”

• RV detection by ELISA

• Type determination by RT-PCR followed by reverse hybridization assay (or optional sequencing as needed)

– Discrimination between G1 vaccine virus and wild-type G1 RV

A A 3434


Efficacy Endpoints

• Any and Severe RV GE during 1st RV season

• Efficacy against RV hospitalizations, medically-attended RV, all-cause GE hospitalizations

• Type-specific efficacy

• Second RV season efficacy

• Efficacy from dose 1 to dose 2

A A 3535

0

10

20

30

40

50

60

70

80

90

100

Any RV GE Severe RV GE RV GE Hosp Medically-attended RV

GE

All-cause GEHosp

Vac

cin

e ef

fica

cy (

%)

From 2 weeks post-dose 2 until end of the 1st RV season (ATP cohort)

87% [80;92]

75% [46;89]

92% [84;96]

100% [82;100]96%

[90;99]


24V:94P 5V:60P 0V:12P 10V:62P 11V:22P

randomization 2:1

A A 3636

0

10

20

30

40

50

60

70

80

90

100

Any RV GE Severe RV GE RV GE Hosp Medically-attended RV

GE

All-cause GEHosp

Vac

cin

e ef

fica

cy (

%)

79% [73;84] 72%

[53;83]

84% [77;89]

96% [84;100]90%

[85;94]

85V:204P

24V:127P

2V:25P

41V:128P

27V:48P

From 2 weeks post-dose 2 until end of the 1st RV season (ATP cohort)From 2 weeks post-dose 2 until end of the 2nd RV season (ATP cohort)

87% [80;92]

96% [90;99]

100% [82;100] 92%

[84;96]

75% [46;89]

randomization 2:1


A A 3737

0

10

20

30

40

50

60

70

80

90

100

Any RV GE Severe RV GE

Vac

cin

e ef

fici

acy

(%)

100%[-23;100]

90%[9;100]

From Dose 1 up to before Dose 2 (Total Vaccinated Cohort)


1V:5P 0V:3P

TVC = all subjects who received at least one dose regardless of protocol adherence

randomization 2:1

A A 3838

0

10

20

30

40

50

60

70

80

90

100

G1P[8] G2P[4] G3P[8] G4P[8] G9P[8]

Vac

cin

e ef

fica

cy (

%)

From 2 weeks post-dose 2 until end of the 2nd RV season (ATP cohort)

96% [90;99]

86% [24;99]

85% [72;93]

95% [68;100]

94% [53;100]

4V:57P 1V:8P 1V:11P 13V:44P+

* P genotype not typable for one episode, + P[8] genotype not detected for one episode

2V:7P*

Type-specific Type-specific Efficacy Europe Efficacy Europe (Study 036) - Severe RV GE(Study 036) - Severe RV GE

randomization 2:1

A A 3939

Summary of EfficacySummary of Efficacy

• Rotarix prevents:– Severe RV GE disease (96% EUR; 85% LA)

– Any RV GE disease (87% EUR)

– RV GE hospitalizations (100% EUR: 85% LA)

– Medically attended RV GE (92% EUR)

– RV GE as early as dose 1 (90% EUR)

• Rotarix prevents RV GE caused by G1, G2, G3, G4 and G9 strains

• Rotarix efficacy persists through 2 years/seasons after vaccination

A A 4040



Safety• Intussusception• Integrated Summary of Safety: SAEs• Events of Clinical Interest• Integrated Summary of Safety: Reactogenicity

• Reactogenicity: Europe, US & Canada

A A 4141

Immunogenicity – SeroconversionImmunogenicity – Seroconversion

Serum anti-Rotavirus IgA Response

• Seroconversion = ≥20 U/mL in subjects RV negative prior to 1st dose

• Seroconversion after dose 2 in phase III pivotal efficacy studies:

– study 036 (Europe): 681/787 = 87%– study 023 (Latin America): 302/393 = 77%

Efficacy against severe RV GE paralleled, but always higher compared to antibody response

A A 4242

Immunogenicity – “Vaccine Take”Immunogenicity – “Vaccine Take”

• Vaccine take: Seroconversion and/or RV stool antigen detection in subjects RV negative prior to 1st dose (≥106 CCID50)

Study N tested Vaccine Take (%)

005 (US-CA) 150 88

006 (Latin America) 106 76

007 (Singapore) 46 98

033 (Latin America) 26 73

039 (Thailand) 167 88

048 (Finland) 94 89

A A 4343

Immunogenicity – Coadministered VaccinesImmunogenicity – Coadministered VaccinesUS Study 060 US Study 060

• Randomized 1:1, controlled, open label

• 1º Objective: Non-inferiority immunogenicityRotarix + coads vs. coads alone

• N=484 (1:1)

Month of Age

2 3 4 5 6 7

Co-Ad group

RotarixPediarix PrevnarActHIB

RotarixPediarix PrevnarActHIB

Pediarix PrevnarActHIB

Blood Sample

Serology Testing

Sep-Ad group

Pediarix PrevnarActHIB

Rotarix Pediarix PrevnarActHIB

Rotarix Pediarix PrevnarActHIB

Blood Sample

Serology Testing

A A 4444

Pre-specified non-inferiority criteria met for all 17 coadministered antigens:

• anti-PRP, anti-HBsAg, anti-poliovirus 1, 2 & 3, anti-D and anti-T: LL of 95% CI for the treatment difference in seroprotection rate -10%

• anti-PT, anti-FHA and anti-PRN: LL of 95% CI for the GMC ratios 0.67

• S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F & 23F: LL of 95% CI for the GMC ratios 0.5

Immunogenicity – Coadministered VaccinesImmunogenicity – Coadministered VaccinesUS Study 060 US Study 060

A A 4545

Viral SheddingViral Shedding

• RV antigen excretion is a feature of natural RV infection

• Following vaccination antigen excretion is expected; indication of vaccine activity

• Methodology– Stool RV antigen detected by ELISA– Stool live attenuated RV detected by cell culture

A A 4646

Fecal Antigen* Shedding Study Rota-033Fecal Antigen* Shedding Study Rota-033++

Columbia, Mexico, PeruColumbia, Mexico, Peru

0

10

20

30

40

50

60

70

80

90

100

Day 0 Day 3 Day 7 Day 10 Day 15 Day 30 Day 45 Day 60

% S

ub

ject

s R

V A

g S

hed

din

g

Dose 1 (n=24-26)

Dose 2 (n=23-26)

* ELISA positive+ Dose Conc ≥106.5 CCID50

n = number of subjects with available results

A A 4747

Live Virus Shedding in VaccineesLive Virus Shedding in VaccineesDay 7 post-dose 1Day 7 post-dose 1

Study # ELISA pos / N tested

[N 1]

# cell culture pos / N tested

[N 2] *

% of Vaccinees with live RV

detected in stool

[N1 x N2]

039

(Thailand)

90/162

(55.6%)

6/13

(46.2%)

25.6 %

(95% CI 10 - 41)

048

(Finland)

49/84

(58.3%)

15/33

(45.5)

26.5 %

(95% CI 16 - 38)

* all ELISA positive samples with remaining stool cultured for live virus

A A 4848

Immunogenicity SummaryImmunogenicity Summary

• Rotarix is immunogenic

• Rotarix does not negatively impact the immune response to the antigens present in:

– Pediarix (DTaP-HepB-IPV), Prevnar (7 valent pneumococcal) and ActHIB (PRP)

• Live virus shedding: ~26% of subjects at 7 days after first dose in two clinical trials

A A 4949



Safety• Intussusception• Integrated Summary of Safety: SAEs• Events of Clinical Interest• Integrated Summary of Safety: Reactogenicity

• Reactogenicity: Europe, US & Canada

A A 5050

N=63,225infants age 6-13 weeks

randomized (1:1)

month 0

Placebo N=31,552

Rotarix N=31,673

1st D

ose

2nd D

ose

Month 1-2 Month 2-4Safety

surveillance(N=63,225)

Month 9-10


(ATPN=17,867)

Routine immunizations were co-administered according to local regulations

Study 023: Phase III Safety & Efficacy Study 023: Phase III Safety & Efficacy Study in Latin America and FinlandStudy in Latin America and Finland

Month 21-22


(ATPN=14,237)

Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354:11-22

A A 5151

Intussusception (IS) Safety ObjectiveIntussusception (IS) Safety ObjectiveStudy 023: Latin America and FinlandStudy 023: Latin America and Finland

Primary Safety Endpoint:

• Risk of IS within 31 days (day 0-30) after each vaccine dose– Definite IS according to Brighton Collaboration

• Active Surveillance for IS by independent, complementary methods– Hospital surveillance system – Info query at each study visit. Parent’s contacted who missed

a follow-up visit.

• Review of all potential IS cases– Blinded expert Clinical Event Committee– Safety monitoring by IDMC with authority to unblind

A A 5252

Intussusception Safety ObjectiveIntussusception Safety ObjectiveStudy 023: Latin America and FinlandStudy 023: Latin America and Finland

Primary Safety Objective Met if, within 31 Days of Vaccination:

• UL of the 2-sided 95% CI of the Risk Difference (Rotarix minus Placebo): below 6 per 10,000

• No stat. sig. increase in IS incidence: LL of the 2-sided 95% CI of the Risk Difference: below 0

Secondary safety endpoint:

• Occurrence of SAEs during safety surveillance period

A A 5353

Study 023 Intussusception ResultsStudy 023 Intussusception ResultsDose 1 through end of safety surveillance (median 100 days)Dose 1 through end of safety surveillance (median 100 days)

27 Investigator-Diagnosed Intussusception Cases

13 caseswithin

31 daysof a dose

12 cases>31 days of a dose

and end safety surveillance

1V:0P6V:7P 3V:9P

26 positively-adjudicated“Definite” cases

0 negatively- adjudicated

cases

1 adjudicated“Probable” case

1V:0P

1 caseafter safety surveillance completed

A A 5454

Placebo groupRotarix group

within 31 days 66 77

Relative Risk = 0.85 (0.30 ; 2.42)

Risk Difference = -0.32 (-2.91 ; 2.18)

99 1616within median 100 days

Cases of IS

Safety cohort N=31,673 Safety cohort N=31,552

Relative Risk = 0.56 (0.25 ; 1.24)

Risk Difference = -2.23 (-5.7 ; 0.94)

Study 023: No Increased Risk of Study 023: No Increased Risk of Intussusception Compared to PlaceboIntussusception Compared to Placebo

A A 5555

Study 023: No Clustering of IS Cases within Study 023: No Clustering of IS Cases within 7 or 14 Day Window Post-vaccination7 or 14 Day Window Post-vaccination

Day Range

Dose 1 Dose 2 Any Dose

Rotarix Placebo Rotarix Placebo Rotarix Placebo

N = 31,673 N = 31,552 N = 29,616 N = 29,465 N = 31,673 N = 31,552

0-7 0 0 2 0 2 0

8-14 0 0 0 2 0 2

15-21 1 1 2 1 3 2

22-30 0 1 1 2 1 3

Total (0-30) 1 2 5 5 6 7

RR= 0.5 (0.07;3.8)

RD= -0.32 (-2.03;1.2)

RR= 0.99 (0.31;3.21)

RD= -0.01 (-2.48;2.45)

RR= 0.85 (0.3;2.42)

RD= -0.32 (-2.91;2.18)

A A 5656

Study 023: No Evidence for Increased Study 023: No Evidence for Increased RiskRisk of Intussusceptionof Intussusception

• Primary Safety Hypothesis SatisfiedPre-specified statistical criteria met

• UL of the 2-sided 95% CI of the RD:< 6 per 10,000 after any dose

• LL of the 2-sided 95% CI of the RD:< 0 after any dose

• Within 31 days any dose

• RR = 0.85 (95% CI 0.3 ; 2.42)

• RD = - 0.32 per 10,000 (95% CI -2.91; 2.18)

• No evidence of clustering of IS cases within 7 or 14 days after any dose among Rotarix recipients

A A 5757

• IS cases reported to occur within 31 days after vaccination in all studies

• 10 Rotarix, 7 Placebo: RR=1.3 (95% CI 0.44 – 4.06)

• IS cases reported to occur any time after vaccination in all placebo controlled studies

• 18 Rotarix*, 22 Placebo: RR=0.72 (95% CI 0.36 – 1.41)

Intussusception: All BLA studiesIntussusception: All BLA studies

*one additional case in study 060, not included in total as not placebo controlled

A A 5858

Integrated Summary of Safety (ISS)Integrated Summary of Safety (ISS)

• Based on all RD, placebo-controlled clinical trials in the BLA

• “Core” ISS compares Rotarix licensure potency to placebo

• 8 clinical trials: US, CA, Latin America, Asia, EU

• Solicited AEs day 0-7 post each vaccination

– fever, fussiness/irritability, loss of appetite, vomiting, diarrhea, cough/runny nose

• Unsolicited AEs day 0-30 post each vaccination

• SAEs (including IS and fatalities) day 0-30 post each vaccination

• Imbalance defined as exact 95% CI for RR across studies excludes “1”

A A 5959

Core ISS: Most Frequently Reported SAEs Core ISS: Most Frequently Reported SAEs Within 31 Days of Any DoseWithin 31 Days of Any Dose

Adverse Event

(MedDRA PT)

Rotarix

N=36,755

Placebo

N=34,454 Relative Risk(95% CI)

n (%) n (%)

At least one SAE 627 (1.71%) 659 (1.91%) 0.90 (0.81 – 1.01)

Bronchiolitis 127 (0.35%) 137 (0.40%) 0.88 (0.68 – 1.13)

Pneumonia 122 (0.33%) 122 (0.35%) 0.99 (0.76 – 1.28)

Gastroenteritis 72 (0.20%) 111 (0.32%) 0.62 (0.45 – 0.84) §

§ 95% CI for RR excludes 1Relative Risk adjusted for study effect

A A 6060

Core ISS: SAEs with ImbalanceCore ISS: SAEs with Imbalance Within 31 Days of Any Dose Within 31 Days of Any Dose

Adverse Event

(MedDRA PT)

Rotarix

N=36,755

Placebo


n (%) n (%)

Gastroenteritis 72 (0.20%) 111 (0.32%) 0.62 (0.45 – 0.84) §

Diarrhea 9 (0.02%) 25 (0.07%) 0.35 (0.14 – 0.78) §

Dehydration 9 (0.02%) 21 (0.06%) 0.43 (0.17 – 0.97) §

§ 95% CI for RR excludes 1Relative Risk adjusted for study effect

A A 6161

Events of Clinical InterestEvents of Clinical Interest

Clinical Event Reason for Interest

HematocheziaReports with RotaShieldRotaTeq US Package Insert

Kawasaki disease RotaTeq US Package Insert

ConvulsionRotaTeq US Package InsertImbalance in single study (Rota-023)

Pneumonia deaths Imbalance in single study (Rota-023)

Pneumonia Imbalance in single study (Rota-036)

Bronchitis Imbalance in single study (Rota-006)

A A 6262

Events of Clinical Interest: Core ISS Events of Clinical Interest: Core ISS Within 31 Days of Any DoseWithin 31 Days of Any Dose

Adverse Event

(MedDRA PT)

Rotarix

N=36,755

Placebo


n (%) n (%)

Hematochezia SAE 0 0 -

Kawasaki disease 0 0 -

Convulsion SAE 9 (0.02%) 7 (0.02%) 1.18 (0.39 – 3.76)

Pneumonia deaths 7 (0.02%) 5 (0.01%) 1.39 (0.38 – 5.57)

Pneumonia SAE 122 (0.33%) 122 (0.35%) 0.99 (0.76 – 1.28)

Bronchitis SAE 21 (0.06%) 24 (0.07%) 0.85 (0.45 – 1. 59)

Relative Risk adjusted for study effect

A A 6363

Kawasaki DiseaseKawasaki Disease

• 27 reports in clinical trials– 22 in one large (N=10,700) ongoing phase III DB, 1:1 study in Asia

• 13 following Rotarix, 9 following placebo; RR = 1.4 (CI 0.6 - 3.4 )

• No temporal evidence of an association:– 2 reports in Rotarix and 1 report in placebo within 31 days after

vaccination (none in the 11 studies in support of licensure in the BLA)

– Median time to onset: 152 days after last dose of study vaccine (range: 3 to 578 days)

• No fatal cases

• No cases considered to be related to study vaccine

A A 6464

Safety Analysis Study 023Safety Analysis Study 023• Multiple comparisons made between groups for

exploratory purposes to evaluate potential imbalances within– 24 different MedDRA system organ classes (SOCs)– 265 different MedDRA preferred terms (PT’s)

• Asymptotic p-values used as an aid to highlight potential imbalances worth further clinical assessment– no statistical adjustment for multiple testing was made

• Findings have to be interpreted based on overall clinical assessment

A A 6565

SAE imbalances in favor of SAE imbalances in favor of Rotarix – Rotarix – study 023 within safety surveillance periodstudy 023 within safety surveillance period

• Diarrhea:Rotarix 15 (0.05%)placebo 37 (0.12%)p=0.002*

• Vomiting:Rotarix 3 (0.01%)placebo 12 (0.04%)p=0.020*

* Exploratory analysis, not corrected for multiplicity

• Gastroenteritis:Rotarix 132 (0.42%)placebo 226 (0.72%)p=0.000*

• Dehydration:Rotarix 20 (0.06%)placebo 46 (0.15%)p=0.001*

A A 6666

SAE imbalances in favor of placeboSAE imbalances in favor of placebo – – study 023 within safety surveillance periodstudy 023 within safety surveillance period

• Urticaria:Rotarix 5 (0.02%)placebo 0p=0.026*

• Convulsion:Rotarix 16 (0.05%)placebo 6 (0.02%)p=0.034*

* Exploratory analysis, not corrected for multiplicity

• Pneumonia death:Rotarix 14 (0.04%)placebo 5 (0.02%)p=0.040*

A A 6767

Convulsion SAEs Convulsion SAEs

Study Rota-023

• PT “convulsion”– Within whole surveillance period

Rotarix 16 (0.05%), placebo 6 (0.02%); p=0.034*

– Within 31 days post-vaccinationRotarix 7 (0.02%), placebo 5 (0.02%); p=0.568*

• Pooled convulsion-related PTs+

– Within whole surveillance period Rotarix 20 (0.06%), placebo 12 (0.04%); p=0.219*

– Within 31 days post-vaccinationRotarix 7 (0.02%), placebo 9 (0.03%); p=0.798*

* exploratory analysis, not corrected for multiplicity+ convulsion-related PT = convulsion, epilepsy, grand mal convulsion, status epilepticus, tonic convulsion

A A 6868

Convulsion SAEs – Overall AssessmentConvulsion SAEs – Overall Assessment

• Many subjects in Rotarix and placebo groups had pre-existing or concurrent medical conditions* that could have accounted for the convulsion

• No temporal association within 31 days after vaccination

• No imbalance with pooled convulsion-related SAEs

• No imbalance in phase III study Rota-036

• No imbalance in core ISS

• Currently available data do not suggest a causal relationship between Rotarix and convulsion

* neonatal hypoxia, family history of epilepsy, previous convulsion episodes, hypocalcemia and hyponatremia,, chronic malnutrition, seizure after metoclopramide

A A 6969

Pneumonia Deaths Pneumonia Deaths

Study Rota-023:

• Not designed to study the effect of vaccination on fatalities.

• Study not controlled for factors associated with higher post-neonatal fatality rate– prematurity, age of mother, exposure to smoking, nutritional

deficiencies

• Within whole surveillance period: pooled pneumonia-related* Rotarix 16 (0.05%), placebo 6 (0.02%); p=0.054 +

* pneumonia-related PT = pneumonia, bronchopneumonia, pneumonia CMV+ exploratory analysis, exact p-value, not corrected for multiplicity

A A 7070

Clinical Case Review Clinical Case Review

Study Rota-023: Pneumonia-related deaths in Rotarix Group

• There were no unique or distinguishing clinical characteristics, or common CXR findings

• Symptom onset of 16 cases– 7 between day 0-30; no temporal clustering

– 9 beyond day 30 (range day 31-199)

• 5 of the 16 had pre-existing conditions, risk factors and/or other alternative diagnoses** clinical diagnosis pertussis; CMV in lung tissue on autopsy, mother HIV positive;

clinical diagnosis pneumonia, exposed to HIV positive mother with bacterial meningitis; Down syndrome and congenital heart disease; Ependymoma and CSF fistula with nosocomial adenovirus pneumonia

A A 7171

Pneumonia-related* Hospitalizations Pneumonia-related* Hospitalizations Whole Surveillance Period Whole Surveillance Period – Study Rota-023– Study Rota-023

Rotarix

(N=29616-31673)

Placebo

(N=29465-31552)

Timing n Per 10000 n Per 10000

Overall follow-up period 277 87.46 273 86.52

Post-dose 1

Any time 185 58.41 177 56.10

Within 31 days 99 31.26 94 29.79

Post-dose 2

Any time 92 31.06 96 32.58

Within 31 days 49 16.55 56 19.01

* all pneumonia-containing PTs within SOC infections and infestations

A A 7272

IDMC Assessment of Safety Analysis, Nov 2004IDMC Assessment of Safety Analysis, Nov 2004

General

Rotarix vaccinees lower rates of overall hospitalization, and SAEs with diarrhea and dehydration, than placebo recipients. Hospitalization rates for respiratory diseases and for all infectious causes (excluding diarrheal disease) comparable in the two groups

Fatalities

• Finding could be due to chance; multiple analyses of safety data could have resulted in spurious finding

• No known biological explanation for this observation; natural rotavirus infection not an established cause of mortality from non-diarrheal causes

• Current trials should be continued

• Further post-licensure evaluation warranted

A A 7373

Causality assessment of pneumonia- Causality assessment of pneumonia- related deaths in Study 023related deaths in Study 023

• Consistency– finding isolated to 1 study– not confirmed by analysis of pneumonia SAEs in Study 023

• Strength of association– of marginal statistical significance– exploratory analyses, not adjusted for multiplicity

• Specificity– lower RTIs common in study population

– multiple etiologies/pathogens

• Temporal relationship– only 7/16 (44%) occurred 0-30 days after immunization – no temporal clustering within 0-30 days

• Biological plausibility – no established link between RV and lower RTIs

A A 7474

Pneumonia Deaths - Overall AssessmentPneumonia Deaths - Overall Assessment

• Currently available data do not suggest a causal relationship between Rotarix and pneumonia deaths

• Further assessment planned in PM setting

A A 7575

0

20

40

60

Fever Cough/ Diarrhea Vomiting Irritability/ Lossappetite

Core ISS: ReactogenicityCore ISS: ReactogenicitySolicited Symptoms: Any IntensitySolicited Symptoms: Any Intensity

within 8 days post-vaccination

Pe

rce

nt o

f in

fan

ts

Rotarix Placebo Dose 1 Dose 2

38o C Runny Nose Fussiness

A A 7676

0

5

10

Fever Cough/ Diarrhea Vomiting Irritability/ Lossappetite

Core ISS: ReactogenicityCore ISS: ReactogenicitySolicited Symptoms: Grade 3 IntensitySolicited Symptoms: Grade 3 Intensity

within 8 days post-vaccination

Pe

rce

nt o

f in

fan

ts

39.5o C

Rotarix Placebo Dose 1 Dose 2

Runny Nose Fussiness

Grade 3 cough/runny nose: prevented normal activityGrade 3 diarrhea: > 6 looser than normal stools per dayGrade 3 vomiting: >3 episodes per dayGrade 3 fussiness/irritability: crying unable to be comforted/prevented normal activityGrade 3 loss of appetite: not eating at all

A A 7777

/Fussiness

Reactogenicity - Study 036: EuropeReactogenicity - Study 036: Europe

0

20

40

60

80

100

Any Grade3

Any Grade3

Any Grade3

Any Grade3

Any Grade3

Any Grade3

Cough/Runnynose

Diarrhea Fever Irritability Loss ofappetite

Vomiting

Per

cen

t o

f In

fan

ts

Rotarix

Placebo

Solicited Symptoms within 8 Days of Any DoseCoadministered: DTaP-HepB-IPV/Hib (all); PCV7 (subset), MenC (subset)

A A 7878

/Fussiness

Reactogenicity - Study 005: US & CanadaReactogenicity - Study 005: US & Canada

0

20

40

60

80

100

Any Grade3

Any Grade3

Any Grade3

Any Grade3

Any Grade3

Any Grade3

Cough/Runnynose

Diarrhea Fever Irritability Loss ofappetite

Vomiting

Per

cen

t o

f In

fan

ts

Placebo

Solicited Symptoms within 15 Days of Any Dose

Coadministered: DTaP, IPV, Hib, PCV7, (HepB)

Rotarix*

*≥106 CCID50 group

A A 7979

Summary of SafetySummary of Safety

• Rotarix is well tolerated

• No increased risk of intussusception among infants vaccinated with Rotarix compared to placebo

• Fewer SAEs associated with GE disease in Rotarix group compared to placebo

• PM studies planned to monitor acute lower respiratory tract infection hospitalizations and convulsions

• No increased reactogenicity following co-administration with routine pediatric vaccines

• The overall safety profile of Rotarix is similar to placebo

A A 8080



Introduction






A A 8181

Post-Marketing Experience and Post-Marketing Experience and Pharmacovigilance Plan: OverviewPharmacovigilance Plan: Overview

• Summary of spontaneous reports up to 11 July 2007– Intussusception

• Global Pharmacovigilance Plan for Rotarix:– Intussusception– Effectiveness/impact– Other topics of interest

A A 8282

PM Experience as of July 2007PM Experience as of July 2007

• Doses Distributed: 12.3 million

– Latin America: 11.5 (8.7 million to Brazil)

– Europe: 0.4 million

– Rest of the World: 0.4 million

• 802 Adverse Event reports

– reporting rate 6.5 /100,000 doses distributed*

– Including 323 Serious Adverse Event reports

• Distribution of the reports by dose

– Dose 1 = 43% Dose 2 = 22%Unknown dose = 35%

* RotaTeq: 20.2/100,000 doses distributed by June 2007 (Dr Haber, ACIP June 07)

A A 8383

PM Experience: Most Frequently PM Experience: Most Frequently Reported EventsReported Events

Number of Reports Reported Frequency per 100 000 doses

Diarrhea 252 2.05

Vomiting 174 1.41

Intussusception 133 1.08

A A 8484

PM Experience: Fatal EventsPM Experience: Fatal Events

• One fatality in Venezuela related to ITP with symptoms within hours after vaccination

• One fatality in Mexico related to a rotavirus Infection 9 months after vaccination (not vaccinated according to pediatrician)

• One fatality in Kenya related to a Gastroenteritis caused by adenovirus, starting same day as vaccination

• 4 unconfirmed reports of fatalities related to IS in Brazil, 3 with unknown time to onset, 1 with symptoms 6 days after vaccination

A A 8585

PM Experience: IntussusceptionPM Experience: Intussusception

Male 48 (62%)

Median TTO (range) 15 days (0-244)

Median age (range) 5 months (2-13)

Fatal 0

Dose number: 1

2

Unknown

36 (45%)

25 (32%)

18 (23%)

* Confirmed refers to the manufacturer’s assessment of the diagnostic certainty according to Brighton Collaboration criteria (Bines et al, Vaccine 2004), not to the relationship to vaccination

RotaTeq: 1.9/100,000 doses distributed by June 2007 (P. Haber, ACIP June 07)

• 79 confirmed cases (out of 131 total spontaneous reports up to the DLP of July 2007)

• Reporting rate = 0.64/100,000 doses distributed*• Characteristics of the 79 confirmed cases:

A A 8686


Observed Within

30 days

Expected Within

30 days

Observed Within7 days

Expected Within7 days

global

EU

Observed versus expected analyses:Observed versus expected analyses:

A A 8787


Observed Within

30 days

Expected Within

30 days



global 58 496 40 116

EU


A A 8888


Observed Within

30 days

Expected Within

30 days



global 58 496 40 116

EU 8 19 4 5


A A 8989



Sensitivity analysis: 75% of cases reported and 75% of doses distributed Sensitivity analysis: 75% of cases reported and 75% of doses distributed

Observed within 30 days

Expected Within

30 days


Expected within 7 days

global 77 386 53 90

EU 11 14 6 * 4

* ratio is 1.7 (95% confidence intervals : 0.5 – 4.2)

A A 9090

PM experience: Events of InterestPM experience: Events of Interest

Clinical Event Number of cases reported

Reporting rate per 100,000 doses distributed

Hematochezia° 57 0.48

Kawasaki disease 0 NA

Convulsion 5 0.04

Pneumonia deaths 0 NA

Pneumonia 4 0.03

Bronchitis 5* 0.04

° excluding IS and allergic colitis, including bloody diarrhea, * 3 cases of bronchiolitis, 2 cases of bronchospasm

A A 9191

Post-licensure Post-licensure Pharmacovigilance PlansPharmacovigilance Plans

• Clinical Trials

• Post-licensure observational studies

• Enhanced pharmacovigilance

A A 9292

Post-licensure Clinical StudiesPost-licensure Clinical Studies

Dominican Republic Transmission of HRV between twins

South AfricaSafety and immunogenicity of HRV in HIV positive infants

Europe Safety and immunogenicity of HRV in preterm infants

A A 9393

Post-licensure Post-licensure Observational Studies: US cohortObservational Studies: US cohort

• Outcomes of interest: Intussusception, Kawasaki disease, hospitalizations for acute lower respiratory tract infections and convulsions.

• Powered to detect a RR of IS of 2.5 or greater with 80% probability

• Design and study setting under discussion with FDA and CDC

• All deaths will be reported to FDA and CDC

A A 9494

Post-licensure Post-licensure Observational Studies:Observational Studies: IS in Mexico IS in Mexico

• Study setting: Instituto Mexicano de la Seguridad Social

• 40 million individuals birth cohort of 575,000

• UMV in IMSS system started 2006

• Will have > 80% power to exclude a RI of IS under 1 year of age of 2.6 within 30 days following dose 1 of Rotarix (i.e. upper limit of 95% CI of RI < 2.6)

• Additional outcomes of interest: pneumonia related deaths and hospitalizations.

• Study start: December 2007, duration: 2-4 years

A A 9595

Additional Post-licensure Additional Post-licensure Observational StudiesObservational Studies

• Intussusception: Surveillance in Germany and the UK

• Vaccine effectiveness: case-control studies in Panama, Belgium and Singapore

• Vaccine strain surveillance: Europe rotavirus surveillance network

A A 9696

Enhanced PharmacovigilanceEnhanced Pharmacovigilance

• Worldwide network for spontaneous reporting

• Enhanced follow-up of all intussusception cases

• Enhanced reporting to the FDA and CDC

• Systematic observed/expected analyses

A A 9797

Rotarix Post Marketing Experience and Rotarix Post Marketing Experience and Pharmacovigilance Plans: ConclusionsPharmacovigilance Plans: Conclusions

• Currently available information from spontaneous reporting system does not suggest any increased risk for IS following Rotarix, nor any new safety signal related to other events

• A comprehensive pharmacovigilance plan has been put in place to further monitor the safety and effectiveness/impact of Rotarix

A A 9898



Introduction






A A 9999

Concluding Remarks: EfficacyConcluding Remarks: Efficacy

• Rotarix, an attenuated human rotavirus vaccine, administered as a 2-dose oral vaccine starting at 6 weeks of age induces protective immunity against RV GE:

– Severe RV GE disease (96% EUR; 85% LA)

– Any RV GE disease (87% EUR)

– RV GE hospitalizations (100% EUR: 85% LA)

– Medically attended RV GE (92% EUR)

A A 100100

Concluding Remarks: EfficacyConcluding Remarks: Efficacy

• RV GE caused by G1 and non-G1 serotypes (including G2, G3, G4 and G9)

• Severe GE disease regardless of etiology (75% EUR; 40% LA)

• Efficacy evident from post dose 1

• Persistent through at least 2 years of life

Rotarix can be concomitantly administered with US licensed pediatric vaccines

A A 101101

Concluding Remarks: SafetyConcluding Remarks: Safety

Rotarix is supported by extensive safety experience:

Clinical trials in > 75,000 (> 40,000 Rotarix; > 34,000 placebo)

• Rotarix was well tolerated; no increased reactogenicity profile following coadministration with routine pediatric vaccines

• No signal of a safety concern wrt IS according to pre-specified criteria

• Active monitoring of AEs of special interest in PM Plans

A A 102102

Concluding Remarks: SafetyConcluding Remarks: Safety

Post Marketing Safety:

Rotarix is licensed in > 100 countries (2004-present); > 12 MM doses distributed GSK is utilizing the WWavailability of Rotarix to study all outcomes of interest:

• No pattern or frequency of reporting to suggest any increased risk of IS

• No new safety signal related to any other events detected

A A 103103

Concluding Remarks: Concluding Remarks: Post Marketing PlansPost Marketing Plans

Extensive Global PM Activities including clinicaltrials, observational studies and enhancedpharmacovigilance:

• IS and other potential safety outcomes

• Vaccine effectiveness

• Vaccine transmission

• Use in immunocompromised and preterm infants

A A 104104

RotarixRotarix Risk/Benefit Risk/Benefit

• Rotavirus is a significant cause of childhood morbidity in the US– 600,000 clinic or emergency room visits/year – 55,000 to 70,000 hospitalizations/year

• Vaccination represents an important preventative strategy to control morbidity and mortality caused by RV GE

• Rotarix confers significant protection against RV GE caused by G1 and non-G1 serotypes, with an acceptable safety/reactogenicity profile comparable to placebo

• Risk-benefit ratio for Rotarix is overall favorable for the intended population

A A 105105

Vaccines and Related Biological Products Advisory Committee

February 20, 2008

GlaxoSmithKline

ROTARIX ROTARIX ®

Documents

A 1 GlaxoSmithKline’s Human Rotavirus Vaccine ROTARIX ® Vaccines and Related Biological Products Advisory Committee February 20, 2008