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GlaxoSmithKline’s Human Rotavirus Vaccine ROTARIX ®. Vaccines and Related Biological Products Advisory Committee February 20, 2008. GlaxoSmithKline Presentation. Clare Kahn, Ph.D Vice President North America, Regulatory Affairs. Introduction. Leonard Friedland, M.D.

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Glaxosmithkline s human rotavirus vaccine rotarix l.jpg

GlaxoSmithKline’s Human Rotavirus VaccineROTARIX®

Vaccines and Related Biological Products Advisory Committee

February 20, 2008


Glaxosmithkline presentation l.jpg

GlaxoSmithKline Presentation

Clare Kahn, Ph.DVice President

North America, Regulatory Affairs

Introduction

Leonard Friedland, M.D.

Executive Director - Clinical R&DNorth America, Vaccines

Clinical Development Plan

Clinical Trial Results

Thomas Verstraeten, M.D.

Director

Head Worldwide Safety, Vaccines

Post-marketing Safety Data

Pharmacovigilance Plan

Clare Kahn, Ph.D

Conclusion


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Proposed Names

Proprietary Name

Rotavirus Vaccine, Live, Oral

Trade NameRotarix®


Human rv vaccine rotarix l.jpg

Human RV Vaccine - Rotarix

  • 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


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Proposed 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.


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610,000

1 : 205

2.4 million

1 : 50

24 million

1 : 5

114 million

1 : 1

Estimated Global Prevalence of Rotavirus Disease

Annual Burden

Risk by 5th Birthday

Deaths

Hospitalizations

Outpatient Visits

RV Episodes

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


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Annual Burden

Risk by 5th Birthday

20-60

1 : 100,000

Deaths

55,000-70,000

Hospitalizations

1 : 80

Outpatient Visits

600,000

1 : 7

2.7 million

4 : 5

RV Episodes

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

Estimated US Prevalence of Rotavirus Disease


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Distribution of Rotavirus Strains by Region between 1973 and 2003

Latin America (n=2,950)

North America (n=2,892)

Europe (n=17,475)

n= number of RV infections analyzed

Santos et al. Rev Med Virol 2005;15:29-56


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Rotavirus Virion

  • 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

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


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Human RV Vaccine - Rotarix

Human rotavirus

strain circulating in

Cincinnati in 1989

33 passages in

cell culture

G1P[8]

Initial Safety and Efficacy studies1

Limiting dilution cloning

in Vero cells and further

passage in tissue culture

Live-Attenuated

Human Rotavirus Vaccine

(RIX4414 - Rotarix®)

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

G1P[8]


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Basis for Vaccination with Human Strain

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

One Previous RV infection

Two Previous RV infections

1 Velazquez et al, N Eng J Med 1996 335 1022–1028

2 Bernstein DI, et al. JID. 1991; 164(2); 277-83

3 Velazquez et al, J Infect Dis 2000 182 1602–1609


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Rotavirus Vaccines - History

  • 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


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Global Strategy for Rotarix Vaccine 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


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CanadaUSA

Finland

France

Germany

Spain

Czech Rep

Italy

Mexico

Honduras

Nicaragua

Panama

Dominican Rep.

Thailand

Singapore

Brazil

Venezuela

Colombia

Peru

Chile

Argentina

South Africa

Phase III – Study 023

Phase III – Study 036

Other BLA Studies

Rotarix BLA Development


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Global Clinical Development

Non US clinical studies were pivotal for US licensure

as all complied with the following criteria defined by

FDA 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


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EU

Canada

Norway

Iceland

Kazakhstan

Switzerland

Bangladesh

Hong Kong

Macau

Malaysia

Myanmar

Philippines

Singapore

Sri Lanka

Taiwan

Thailand

Vietnam

Argentina

Aruba

Bolivia

Brazil

Chile

Colombia

Costa Rica

Curacao

Dom Republic

Ecuador

El Salvador

Guatemala

Honduras

Jamaica

Mexico

Nicaragua

Panama

Paraguay

Peru

Suriname

Trinidad

Venezuela

Bahrain

Israel

Jordan

Kuwait

Morocco

Oman

Pakistan

Qatar

Saudi

Turkey

UAE

Yemen

Australia

New Zealand

AngolaBeninBurkina FasoCameroon CongoDRC EgyptGabon GuineaIvory Coast Kenya Madagascar Malawi Mali Mauritania Mauritius MozambiqueNamibia Niger Nigeria

RCA SenegalSouth Africa Togo

Registration Status for Rotarix

  • WHO prequalification – Feb 2007

  • 12 million doses distributed


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GlaxoSmithKline Presentation

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

Introduction

Leonard Friedland, M.D.

Executive Director - Clinical R&DNorth America, Vaccines

Clinical Development Plan

Clinical Trial Results

Thomas Verstraeten, M.D.

DirectorHead, Worldwide Safety, Vaccines

Post-marketing Safety Data

Pharmacovigilance Plan

Clare Kahn, Ph.D.

Conclusion


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Total Exposure = 75029 subjects

Total Exposure = 75029 subjects

Rotarix<106.0 CCID50

n = 3076

Rotarix>106.0 CCID50

n = 37214

Rotarix<106.0 CCID50

n = 3076

Rotarix>106.0 CCID50

n = 37214

Placebo

n =34739

Placebo

n =34739

Phase III

Phase II

Phase II

Phase III

Efficacy, Safety (IS), Immuno

Efficacy, Safety,Immuno

Safety, Immuno

Efficacy, Safety (IS), Immuno

Immuno, Safety

Efficacy, Safety,Immuno

Safety, Immuno

Immuno, Safety

Study 005 US, Canada

n=212 n=209n=108

Study 005 US, Canada

n=212 n=209n=108

Study 004 Finland

n=270 n=135

Study 023 Latin America, Finland

n=31673n=31552

Study 039 Thailand

n=174 n=52

Study 004 Finland

n=270 n=135

Study 023 Latin America, Finland

n=31673n=31552

Study 039 Thailand

n=174 n=52

Lot consistency,Safety, Immuno

Immuno US coadvaccines, Safety

Efficacy, Safety,Immuno

Immuno OPV Coad, Safety

Immuno US coadvaccines, Safety

Efficacy, Safety,Immuno

Immuno OPV Coad, Safety

Lot consistency,Safety, Immuno

Study 060 US

n=459

Study 014S. Africa

n=297 n=150

Study 006 Latin America

n = 1139 n=570n=567

Study 014S. Africa

n=297 n=150

Study 033 Latin America

n=730n=124

Study 006 Latin America

n = 1139 n=570n=567

Study 060 US

n=459

Study 033 Latin America

n=730n=124

Immuno,Safety

Efficacy, Safety,Immuno

Efficacy, Safety,Immuno

Immuno,Safety

Efficacy, Safety,Immuno

Efficacy, Safety,Immuno

Study 036 Europe

n=2646n=1348

Study 007 Singapore

n = 1158 n=653n=653

Study 048Finland

n=100 n=50

Study 007 Singapore

n = 1158 n=653n=653

Study 036 Europe

n=2646n=1348

Study 048Finland

n=100 n=50

Summary of Clinical Studies in BLA


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Rotarix Clinical DevelopmentPivotal & 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


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Clinical Trial Data to be Presented

Efficacy

  • 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


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Clinical Trial Data to be Presented

Efficacy

  • 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


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

Dominican Republic

4056 (6.4%)

Mexico

13245 (20.9%)

Panama

4061 (6.4%)

Honduras

4195 (6.6%)

Venezuela

4250 (6.7%)

Nicaragua

4057 (6.4%)

Brazil

3218 (5.1%)

Colombia

3910 (6.2%)

Peru

12044 (19.0%)

Argentina

4671 (7.4%)

Chile

3458 (5.5%)

Finland

2060 (3.3%)

  • LA: efficacy & safety

  • Finland: safety only


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

Rotarix N=31,673

N=63,225infants age 6-13 weeks

randomized (1:1)

1st Dose

2nd Dose

Placebo N=31,552

month 0

Month 1-2

Month 2-4

Safety

surveillance

(N=63,225)

Month 9-10

1 yr Efficacy analysis

(ATP

N=17,867)

Month 21-22

2 yr Efficacy analysis

(ATP

N=14,237)

Routine immunizations were co-administered according to local regulations

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


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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


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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


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Efficacy Latin America (Study 023)

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


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Efficacy Latin America (Study 023)

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

85%

[71;93]

85%

[72;92]

85%

[70;94]

40%

[28;50]

12V:77P

11V:71P

9V:59P

183V:300P

randomization 1:1


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Efficacy Latin America (Study 023)

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

From 2 weeks post-dose 2 until 24 months of age (ATP cohort)

85%

[72;93]

85%

[70;94]

85%

[72;92]

83%

[73;90]

82%

[73;89]

81%

[71;87]

40%

[28;50]

39%

[30;47]

342V:551P

28V:154P

22V:127P

32V:161P

randomization 1:1


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

From 2 weeks post-dose 2 until 24 months of age (ATP cohort)

87%

[73;94]

82%

[65;92]

79%

[25;96]

62%

[4;87]

39%*

[-112;84]

9V:66P

10V:55P

5V:8P

3V:14P+

7V:18P

+ one episode was P[6]

randomization 1:1

*Not statistically significant


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Study 036: Phase III Study in Europe124 Sites in 6 EU Countries ~4000 Infants

Finland74%

Germany7%

CzechRepublic7.5%

France3.7%

Italy0.6%

Spain7.5%


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Study 036: Phase III Safety & Efficacy Study in Europe

Rotarix N=2,646

N=3,994infants age 6-14 wks

randomized (2:1)

1st dose

2nd dose

Placebo N=1,348

Month 0

Months 1–2

Months 7-9

Season 1 Efficacy analysis

(ATP N=3,874)

Months 19-21

Season 2 Efficacy analysis

(ATP N=3,848)

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

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


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Efficacy Europe (Study 036)

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


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Efficacy Europe (Study 036)

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


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Efficacy Europe (Study 036)

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


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Efficacy Europe (Study 036)

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

100%

[82;100]

96%

[90;99]

92%

[84;96]

87%

[80;92]

75%

[46;89]

0V:12P

10V:62P

11V:22P

5V:60P

24V:94P

randomization 2:1


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Efficacy Europe (Study 036)

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)

100%

[82;100]

96%

[90;99]

96%

[84;100]

92%

[84;96]

90%

[85;94]

87%

[80;92]

84%

[77;89]

79%

[73;84]

75%

[46;89]

72%

[53;83]

85V:204P

24V:127P

2V:25P

41V:128P

27V:48P

randomization 2:1


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Efficacy Europe (Study 036)

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

100%

[-23;100]

90%

[9;100]

1V:5P

0V:3P

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

randomization 2:1


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Type-specific Efficacy Europe

(Study 036) - Severe RV GE

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

96%

[90;99]

95%

[68;100]

94%

[53;100]

86%

[24;99]

85%

[72;93]

2V:7P*

1V:8P

1V:11P

13V:44P+

4V:57P

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

randomization 2:1


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Summary of Efficacy

  • Rotarixprevents:

    • 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)

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

  • Rotarix efficacy persists through 2 years/seasons after vaccination


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Clinical Trial Data to be Presented

Efficacy

  • 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


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Immunogenicity – 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


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Immunogenicity – “Vaccine Take”

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


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Immunogenicity – Coadministered VaccinesUS Study 060

  • Randomized 1:1, controlled, open label

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

  • N=484 (1:1)


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Immunogenicity – Coadministered VaccinesUS Study 060

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


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Viral 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


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Fecal Antigen* Shedding Study Rota-033+Columbia, Mexico, Peru

Dose 1 (n=24-26)

Dose 2 (n=23-26)

* ELISA positive+ Dose Conc ≥106.5 CCID50n = number of subjects with available results


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Live Virus Shedding in VaccineesDay 7 post-dose 1

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


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Immunogenicity 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


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Clinical Trial Data to be Presented

Efficacy

  • 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


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

Rotarix N=31,673

N=63,225infants age 6-13 weeks

randomized (1:1)

1st Dose

2nd Dose

Placebo N=31,552

month 0

Month 1-2

Month 2-4

Safety

surveillance

(N=63,225)

Month 9-10

1 yr Efficacy analysis

(ATP

N=17,867)

Month 21-22

2 yr Efficacy analysis

(ATP

N=14,237)

Routine immunizations were co-administered according to local regulations

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


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Intussusception (IS) Safety ObjectiveStudy 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


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Intussusception Safety ObjectiveStudy 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


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

27 Investigator-Diagnosed Intussusception Cases

26 positively-adjudicated“Definite” cases

0 negatively- adjudicatedcases

1 adjudicated“Probable” case

13 caseswithin

31 daysof a dose

12 cases>31 days of a doseand end

safety surveillance

1 caseafter safety surveillance completed

6V:7P

3V:9P

1V:0P

1V:0P


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6

7

Study 023: No Increased Risk of Intussusception Compared to Placebo

Rotarix group

Placebo group

Safety cohort N=31,673

Safety cohort N=31,552

Cases of IS

within 31 days

Relative Risk =0.85(0.30 ; 2.42)

Risk Difference = -0.32 (-2.91 ; 2.18)

within median 100 days

9

16

Relative Risk =0.56(0.25 ; 1.24)

Risk Difference = -2.23 (-5.7 ; 0.94)


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

RR= 0.85 (0.3;2.42)

RD= -0.32 (-2.91;2.18)

RR= 0.99 (0.31;3.21)

RD= -0.01 (-2.48;2.45)

RR= 0.5 (0.07;3.8)

RD= -0.32 (-2.03;1.2)


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Study 023: No Evidence for Increased Riskof Intussusception

  • Primary Safety Hypothesis Satisfied

    • Pre-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


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Intussusception: All BLA studies

  • 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)

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


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Integrated Summary of Safety (ISS)

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

  • “Core” ISS compares Rotarixlicensure potencyto 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”


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

§ 95% CI for RR excludes 1

Relative Risk adjusted for study effect


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

§ 95% CI for RR excludes 1

Relative Risk adjusted for study effect


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Events of Clinical Interest


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

Relative Risk adjusted for study effect


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Kawasaki 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


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Safety 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


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

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

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

  • 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


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

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

  • 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


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Convulsion SAEs

Study Rota-023

  • PT “convulsion”

    • Within whole surveillance periodRotarix16 (0.05%), placebo 6 (0.02%); p=0.034*

    • Within 31 days post-vaccinationRotarix7 (0.02%), placebo 5 (0.02%); p=0.568*

  • Pooled convulsion-related PTs+

    • Within whole surveillance period Rotarix20 (0.06%), placebo 12 (0.04%); p=0.219*

    • Within 31 days post-vaccinationRotarix7 (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


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Convulsion 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 Rotarixand convulsion

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


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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


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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


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

* all pneumonia-containing PTs within SOC infections and infestations


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IDMC 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


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Causality assessment of pneumonia- related 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


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Pneumonia Deaths - Overall Assessment

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

  • Further assessment planned in PM setting


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Core ISS: ReactogenicitySolicited Symptoms: Any Intensity

within 8 days post-vaccination

Dose 2

Rotarix

Placebo

Dose 1

Percent of infants

 38o C

Runny Nose

Fussiness


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Core ISS: ReactogenicitySolicited Symptoms: Grade 3 Intensity

within 8 days post-vaccination

Dose 2

Rotarix

Placebo

Dose 1

Percent of infants

 39.5o C

Runny Nose

Fussiness

Grade 3 cough/runny nose: prevented normal activity

Grade 3 diarrhea: > 6 looser than normal stools per day

Grade 3 vomiting: >3 episodes per day

Grade 3 fussiness/irritability: crying unable to be comforted/prevented normal activity

Grade 3 loss of appetite: not eating at all


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Reactogenicity - Study 036: Europe

Solicited Symptoms within 8 Days of Any Dose

Coadministered: DTaP-HepB-IPV/Hib (all); PCV7 (subset), MenC (subset)

/Fussiness


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Rotarix*

Reactogenicity - Study 005: US & Canada

Solicited Symptoms within 15 Days of Any Dose

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

/Fussiness

*≥106 CCID50 group


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Summary 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


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GlaxoSmithKline Presentation

Clare Kahn, Ph.DVice President

North America, Regulatory Affairs

Introduction

Leonard Friedland, M.D.

Executive Director - Clinical R&DNorth America, Vaccines

Clinical Development Plan

Clinical Trial Results

Thomas Verstraeten, M.D.

DirectorHead, Worldwide Safety, Vaccines

Post-marketing Safety Data

Pharmacovigilance Plan

Clare Kahn, Ph.D

Conclusion


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Post-Marketing Experience and Pharmacovigilance Plan: Overview

  • Summary of spontaneous reports up to 11 July 2007

    • Intussusception

  • Global Pharmacovigilance Plan for Rotarix:

    • Intussusception

    • Effectiveness/impact

    • Other topics of interest


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PM 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)


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PM Experience: Most Frequently Reported Events


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PM 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


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PM Experience: Intussusception

  • 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:

* 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)


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PM Experience: Intussusception

Observed versus expected analyses:


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PM Experience: Intussusception

Observed versus expected analyses:


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PM Experience: Intussusception

Observed versus expected analyses:


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PM Experience: Intussusception

Observed versus expected analyses:

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

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


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PM experience: Events of Interest

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


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Post-licensure Pharmacovigilance Plans

  • Clinical Trials

  • Post-licensure observational studies

  • Enhanced pharmacovigilance


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Post-licensure Clinical Studies


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Post-licensure Observational 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


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Post-licensure Observational Studies: 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


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    Additional Post-licensure Observational 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


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    Enhanced Pharmacovigilance

    • Worldwide network for spontaneous reporting

    • Enhanced follow-up of all intussusception cases

    • Enhanced reporting to the FDA and CDC

    • Systematic observed/expected analyses


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    Rotarix Post Marketing Experience and Pharmacovigilance 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


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    GlaxoSmithKline Presentation

    Clare Kahn, Ph.DVice President

    North America, Regulatory Affairs

    Introduction

    Leonard Friedland, M.D.

    Executive Director - Clinical R&DNorth America, Vaccines

    Clinical Development Plan

    Clinical Trial Results

    Thomas Verstraeten, M.D.

    DirectorHead, Worldwide Safety, Vaccines

    Post-marketing Safety Data

    Pharmacovigilance Plan

    Clare Kahn, Ph.D

    Conclusion


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    Concluding 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)


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    Concluding 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


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    Concluding Remarks: Safety

    Rotarixis 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


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    Concluding Remarks: Safety

    Post Marketing Safety:

    Rotarix is licensed in > 100 countries (2004-present);

    > 12 MM doses distributed GSK is utilizing the WW

    availability 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


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    Concluding Remarks: Post Marketing Plans

    Extensive Global PM Activities including clinical

    trials, observational studies and enhanced

    pharmacovigilance:

    • IS and other potential safety outcomes

    • Vaccine effectiveness

    • Vaccine transmission

    • Use in immunocompromised and preterm infants


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    Rotarix 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 Rotarixis overall favorable for the intended population


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    ROTARIX ®

    Vaccines and Related Biological Products Advisory Committee February 20, 2008

    GlaxoSmithKline


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