a 1 rotarix® (rotavirus vaccine, live oral): gsk’s pcv1 investigation barbara howe, md vice...

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ROTARIX® (Rotavirus Vaccine, Live Oral): GSK’s PCV1 Investigation

Barbara Howe, MD

Vice President, Director

North American Vaccine Development

GlaxoSmithKline

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Why We’re Here

• Review data/information from unexpected finding of PCV1 in Rotarix

• Finding confirmed in validated lab mid-March

• GSK investigation is ongoing

• All available data support PCV1 in Rotarix is a manufacturing quality issue not a safety issue

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Regulatory History

• First licensed in Mexico July 2004

• Licensed in U.S. April 2008– 11 clinical studies

• Conducted over 8 yrs in ~ 75,000 subjects

• Included large safety study ( > 60,000 subjects) to address risk of IS

• Manufactured in compliance with CBER regulations on adventitious agent testing

• in accordance with guidance in place at time of licensure

• Extensive post-marketing pharmacovigilance ongoing – US and worldwide

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Providing Infant Protection Against Rotavirus Worldwide

• WHO prequalification – Jan 2007

• 69 million doses distributed worldwide; 2.5 million in the US

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No New Safety Concerns Found by Recent Pediatric Advisory Committee

• March 22, 2010 – routine safety review

• CBER conclusion: “No new safety concerns identified…”

• CBER recommendation: “continued monitoring of Rotarix”

• PAC unanimously endorsed CBER conclusion and recommendations

• Product reviewed contained PCV1

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Used ALV as Precedent to Guide Rotarix PCV1 Investigation

• Collaborated with experts in porcine viruses and analytical detection methods

• 1990’s ALV experience used to inform investigation algorithm

• Investigation designed to address:

– Source, nature, amount of PCV1 in manufacturing process

– Clinical implications– Potential remedial actions

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Scope of PCV1 Investigation Expanded

• IPV-containing vaccines tested for PCV1

–As with Rotarix, PCV1 detected early in manufacturing

–NOT found in purified harvest or final container

• Due to purification and inactivation of IPV

• All other GSK vaccine cell banks tested

–NO PCV1 detected

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Data Shared With Regulatory Authorities Worldwide

• EMA, WHO, FDA agree that:

– PCV1 not known to cause disease

– Rotarix has been studied extensively, presence of PCV1 poses no risk to human safety

• Many countries have chosen to continue using Rotarix

–Pending further investigation

–Because of tremendous need and benefit

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GlaxoSmithKline Presentation

Porcine Circovirus Type 1 (PCV1)

X.J. Meng, MD, PhDProfessor, Molecular VirologyCenter for Molecular Medicine and Infectious DiseasesVirginia-Maryland College of Veterinary MedicineVirginia Polytechnic Institute and State UniversityBlacksburg, Virginia

Manufacture and Testing of Rotarix Emmanuel Hanon, DVM, Ph.D.Vice PresidentEarly Prophylactic Vaccine Research & Development

Clinical investigations Gary Dubin, MDVice President, Director Global Late Clinical Development

Overview of Safety and Overall Benefit: Risk

Leonard Friedland, MDVice PresidentNorth American Clinical and Medical Affairs

ConclusionBarbara Howe, MDVice President, Director North American Vaccine Development

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External Expert

Prof. Dr. Hans NauwynckDirector Laboratory of Virology,Department of Virology, Parasitology and ImmunologyFaculty of Veterinary MedicineGhent University, Belgium

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Overview of Porcine Circovirus Type 1 (PCV1)

X.J. Meng, M.D., Ph.D.Professor of Molecular Virology

Center for Molecular Medicine and Infectious DiseasesVirginia-Maryland Regional College of Veterinary Medicine

Virginia Polytechnic Institute and State UniversityBlacksburg, Virginia

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•Discovered as a contaminant of porcine kidney PK-15 cell line (ATCC CCL-33) (Tischer et al., 1974)

•Family Circoviridae

•Small, icosahedral, non-enveloped virus particle of approximately 17 nm in size

•Single-strand, circular DNA molecule of approx. 1.7 kb genome

Characteristics of PCV1

Prof. Stewart McNultyQueen's University

Belfast, UK

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•Resistant to inactivation at pH3 and by chloroform

•Heat stable at 70°C for 15 minutes and 60°C for 30 min

•Variable sensitivity to disinfectants (Royers et al., 2001):

•no significant titer reduction for some disinfectants such as Nolvasan (chlorhexidine diacetate) and Ethanol

•2-4 log titer reduction for other disinfectants such as Sodium hydroxide and Clorox bleach

PCV1 Inactivation

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PCV1 is not PCV2

Fenaux et al., 2000

PCV1

PCV2

•Major genetic difference: differed by about 25% nucleotide sequence identity between PCV1 and PCV2

•Major phenotypic difference: PCV1 is not known to cause disease whereas PCV2 causes a disease known as “postweaning multisystemic wasting syndrome (PMWS)” in pigs

•Neither causes disease in humans

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•Productive infection in porcine kidney PK-15 cell line

•Non-productive infection in human cell lines (293, Hela, and Chang) (Hattermann et al., 2004)

•PCV1 replication and gene expression detected

•Infectious virus particles are not produced (supernatant from infected cells unable to infect naïve cells)

•Infection of human blood leukocytes (Arteaga-Troncoso et al., 2005)

•Visualization of some virus-like particles by EM

•Detection of PCV1 DNA in cells

•Infectivity was not determined

In vitro susceptibility of PCV1 to porcine and non-porcine cells

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•Widespread subclinical infection in pig population :

•60-95% seroprevalence in German pigs (Tischer et al., 1995)

•26-55% seroprevalence in Canadian pigs (Dulac and Afshar, 1989)

•PCV1-infected pigs remain clinically healthy

•PCV1 antigen detected in mesenteric lymph nodes, thymus, lung, liver, spleen and small intestines for 9 days (Allan et al., 1995)

•PCV1 viremia detected in sera for up to 35 days post-inoculation (Fenaux et al., 2004).

•No histopathological lesions in lymph nodes, thymus, intestines, tonsil, lung, and livers of PCV1-infected pigs at 21 or 49 days post-inoculation (Fenaux et al., 2004).

•PCV1 is used as the vector in the first USDA fully-licensed killed vaccine against PCV2 (Fenaux et al., 2002, 2004)

PCV1 infects but does not cause disease in pigs

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•PCV1 antibody detected in humans in Germany, likely due to cross-reaction with a related but different agent (Tischer et al., 1995).

•Loss of binding specificity in ELISA after repeated frozen/thaw and storage of human sera

•Lower OD values in human sera compared to porcine sera

•Unable to reproduce Tischer’s results in subsequent studies:

•PCV1 antibody not detected from 120 humans in Northern Ireland (Allan et al., 2000)

•PCV1 antibody not detected from 50 swine veterinarians, 6 lab workers, or 33 normal blood donors (Ellis et al., 2000)

•PCV1 DNA not detected in 1101 human serum, lymph node, blood or urine samples (168 samples from immunocompromised patients) (Hattermann et al., 2004)

No credible evidence of human infection by PCV1

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•PCV1 DNA detected in commercial pepsin but no infectivity in inoculated PK-15 cells or in inoculated pigs (Fenaux et al., 2004)

•PCV1 DNA detected in 11% (2/18) of the commercial porcine vaccines on the market (Quintana et al., 2005)

•PCV1 DNA detected in U.S. pork products (Li et al., 2010):

•69% (9/13) U.S. pork products contain PCV1 or PCV2 DNA (7 PCV2 sequences, 1 PCV1 sequence, and 1 divergent PCV sequence)

•PCV1 DNA detected in U.S. human stool samples:

•5.3% (13/247) human stool samples positive for PCV1 or PCV2 DNA (Li et al., 2010)

•Detection of PCV DNA in stool may reflect dietary consumption of PCV-containing pork products (Li et al., 2010)

PCV1 detection in commercial products and human stool

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•PCV1 infection is widespread in swine

•PCV1 does not cause any disease in pigs or other animal species including humans

•There is no concrete evidence of human infection by PCV1

•PCV1 detection in commercial products including veterinary vaccines has been reported before

•PCV1 detected in U.S. pork products

Summary and Conclusion

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Viral harvest

Purified bulk Dilution and Filling in

Final Container

RotavirusExpansion on

vero cells

Routine Rotarix Manufacturing Process

Vero cellline

Rotarix viralseed

Trypsin

+

+

+ +

+

-Rotarix vaccine

PCV1 DNA Q-PCR

(copies per ml)

Viral harvest

1010

Purified bulk

109

Final Container

107

PCV1 DNAdetection

No PCV2 DNAdetected

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Vero cell LineP124

MasterCell Bank

P133

ATCC

WorkingCell Bank

P136

GSK

Rotarix viral seed

Ancestor of Rotarix

viral seed

- +

+

-

PCV1 DNAdetection

+

PCV1 Detected in Starting Materials of Rotarix

Potential source: Porcine –Derived Trypsin used for cell propagation

1980

1983 1993

1999

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Investigation Strategy Based on ALV Precedent

Is PCV1 signal associated with presence of:

1. Viral particles?

2. Viral particles capable of infecting permissive cells?

3. Viral particles capable of productive infection in human cells?

4. Viral particles capable of causing infection in human infants?

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1. Viral particles?




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1. Viral particles?




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Infectivity Assay Used Natural Host CellsPermissive PK15 (Porcine Kidney) cell lines

PK15

PCV1 Virus

PK15

Viral Gene Expression(mRNA detected by RT-PCR)

ViralInfection

Rotarix Purified Bulk Positive (Ct value : 28.6)* (1500 doses)

*A Cycle threshold (Ct) value of 40 will indicate that the tested sample is negative.

Presence of infective viral particles demonstrated

Negative control: Medium Negative (Ct value : >40)* Positive control: PCV1 Positive (Ct value : 26.8)*(LOD 1-10 CCID50)

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Infective Viral Particle Titration Assay Vero cell line

10 x dilutionRotarixViral Harvest

1010 PCV1 DNA copies per ml

Vero cell monolayer

7 days Immunodetection anti-PCV1 protein

antibody

PCV1 titer in viral harvest : 102 CCID50 per ml → estimated 3 CCID50 of PCV1 per Rotarix dose

Low level of infective viral particles in final container can not be excluded

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Infectivity in Permissive Cells Doesn’t Mean Infectivity in Humans


1. Viral particles?




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Infectious viralparticles

Viral geneexpression

PK15

Can PCV1 Induce Productive Infectionin Human Cells?

PCV1 virus

HumanCell

?

PCV1 virus

?

Hattermann et al, Xenotransplantation 11:284 2004

18 human cell lines tested: Chang liver, FL, 293, Hep2, RH, CaCo, Hela, Ma23, Rd., Wil2, THP1, Jurkat, Molt4,

C8166, CEM, U937, H9, Human PBMCs

« Although PCV1 gene expression and DNA replication took place in human cells, the infection is non-productive »

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Can PCV1 Induce Productive Infectionin Human Cells?

Presently no evidence indicating that PCV1 associated with Rotarix can undergo productive infection in human cell lines

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Additional investigations

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PCR Results on Other Cell Banks Negative for PCV1 and PCV2 DNA

Cell bank Products Q-PCR

MRC5 Working Cell Bank HAV, Varicella, Rubella, OPV negative

Hi 5 working cell bank HPV negative

MDCK Working Cell Bank In development negative

EB66 Working Cell Bank In development negative

CHO Working Cell Bank In development negative

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Viral harvest

Purified bulk(chromatography)

Dilution and Filling in

Final Container

IPVExpansion on

vero cells

Inactivation

IPV Production Different From Rotarix Process

Vero cellline

IPV viralseed

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Rotarix Vaccine IPV-based VaccinePCV1 DNA Q-PCR (copies per ml)

PK15/Vero infectivity

PCV1 DNA Q-PCR (copies per ml)

PK15/Vero infectivity

Viral Harvest 1010 Detectable 105 ND

Purified bulk 109 Detectable (1500 doses tested)

Not detectable

Not Detectable (1500 doses tested)

Inactivated bulk NA NA Not

detectableNot Detectable (1500 doses tested)

Final container 107

Not Detectable

(10 doses tested on Vero cells)

Not detectable NA

Polio Virus Containing Vaccine Investigation

Estimated clearance of Purification step – 104 DNA copies Inactivation step – ongoing

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Rotarix Manufacturing Investigation Conclusions

• PCV1 material associated with presence of competent PCV1 viral particles

• PCV1 viral particles present in very low amount in Rotarix Final container– Estimated titer: 3 CCID50 of PCV1 per dose

• No evidence PCV1 associated with Rotarix can undergo productive infection in human cell lines

• GSK is in the process of evaluating long term manufacturing changes to remain in compliance with regulations

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Is PCV signal associated with presence of:

1. Viral particles? YES

YES

NO




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Investigation Strategy


1. Viral particles?




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Clinical Testing Approach

• Blinded retrospective laboratory evaluations on archived samples from completed Rotarix clinical trials

• Selected studies required to meet the following criteria:

– Placebo controlled – Collection of pre/post vaccination sera and stool

samples at pre-determined time points

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Selected Studies

• Samples tested from 4 completed studies

– Conducted in Africa, Asia, Europe and Latin America

– Infants aged 6 to 12 weeks at time of first dose– 3 studies in healthly infants, 1 study in HIV positive

infants

• Samples from 80 subjects included in the evaluation

– 40 Rotarix and 40 placebo recipients

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Clinical Testing Objectives

• To evaluate the presence of PCV1 DNA and pattern of detection in stool samples collected at pre-determined time points after a single dose of Rotarix or placebo

• To evaluate if infants receiving 2 or 3 doses of Rotarix or placebo develop an immune response to PCV1 as assessed by the presence of antibodies against PCV1

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Clinical Sample Selection Criteria

• Subject enrollment number

– The first 10 Rotarix and first 10 placebo recipients enrolled in each study with adequate samples

• Sample requirements

– Stool samples

• Availability of pre-vaccination and ≥ two post dose 1 samples

• At least 100 µL of residual volume

– Sera samples

• Availability of pre vaccination and post dose 2 (or 3)

• At least 125µL of residual volume

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Overview of Selected Clinical Studies (N= 80 Infants)

Study (# subjects)

Countries Population (Schedule)

Post-vaccination Sampling**

Study 1 (N=30)

Thailand Healthy infants (2 doses)

Stool: Day 7, 15 Serum: Post dose 2

Study 2 (N=20)

Finland Healthy infants (2 doses)

Stool: Day 7, 15 Serum: Post dose 2

Study 3 (N=10)

Peru Healthy infants (2 doses)

Stool: Day 3, 7, 10, 15, 30, 45 Serum: Post dose 2

Study 4 (N=20)

South Africa HIV positive infants (3 doses)

Stool: Day 7, 15, 22 Serum: Post dose 3

All stool samples collected post dose 1

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• Quantitative polymerase chain reaction (Q-PCR) to detect PCV DNA– Two replicates tested for each sample

Neg/Neg → “Negative”

Pos/Pos → “Positive”

Pos/Neg

Indeter/Neg

Indeter/Indeter

Laboratory Assays: Stool

3rd replicate tested

– Final result: “Positive”, “Negative” or “Inconclusive”

– If Q-PCR positive or inconclusive, sequencing performed to confirm PCV1 virus identity

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Laboratory Assays: Serum

• IPMA (ImmunoPeroxydase Monolayer Assay) to detect anti-PCV1 antibody response– Uses PCV1 infected PK-15 cells– Developed by Prof Hans Nauwynck (Ghent University)– Previously used to detect anti-PCV1 in pig serum – Adapted for testing of human serum samples– Pig serum used as a positive control

Courtesy of Prof Hans Nauwynck (Ghent University)

Negative serumPositive serum (Control)

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Analysis Plan

• Descriptive analyses without hypothesis testing

• Sample size selected based on the feasibility of generating data for committee review– 3 weeks available for assay set up and sample

testing• 300 stool samples for Q-PCR (+ sequencing)• 160 serum samples for IPMA testing

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- - - No evidence of viral replication

+ - +

Pre Day 3- 7 Day 15 Possible Interpretation

Considerations for Data Interpretation of PCV1 DNA in Stool

• Must consider serology results when interpreting stool testing results

•Some examples of possible detection patterns:

Dietary exposure

- + - Transient passage of PCV -1 DNA

- + ++ Consistent with viral replication

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Summary of Clinical Results (1)

Study Group Stool Q-PCR analysis

Number positive (inconclusive)

Serology

Number positiveDay 0 Day 7 Day 15 Pre-vac Post-vac

Study 1(Thailand)

Rotarix (N=15) 0 1* 0 0 0**

Placebo (N=15) 0 0 0 0 0

Study 2(Finland)

Rotarix (N=10) 0 1* (1) 0 0 0

Placebo (N=10) 0 0 0 0 0

*Confirmed as PCV1 sequence in Rotarix **1 sample non-interpretable due to high background

DNA detection pattern suggests transient GI tract passage of PCV1

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Summary of Clinical Results (2)

Study 4 (S. Africa

HIV+)

Stool Q-PCR analysis Number positive (inconclusive)

Serology Number positive

Day 0 Day 7 Day 15 Day 22 Pre-vac Post-vac

Rotarix (N=10) 0 0 0 0 0 0

Placebo (N=10) 0 0 0 0 0 0

Study 3 (Peru)

Stool Q-PCR analysis

Number positive (inconclusive)

Serology

Number positive0 3 7 10 15 30 45 Pre-vac Post-vac

Rotarix (N=5) 0 2* 0 (1) 0 0 0 0 0 0

Placebo (N=5) 0 0 0 0 1 (1) 0 (1) 0 0 0

*Confirmed as PCV1 sequence in Rotarix

DNA detection pattern suggests transient GI tract passage of PCV1

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PCV DNA Findings in Individual Rotarix Recipients (Stool Samples)

Subject #

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

461 - + - - - - -

980 - + Inconclusive* - - - -

071 - NA + NA - NA NA

005 - NA Inconclusive* NA - NA NA

036 - NA + NA - NA NA

+ = PCV1 sequence confirmed NA= not available

*Indeter/Neg → Indeter (3rd replicate testing) → Inconclusive

In each infant pattern is consistent with transient DNA passage

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Solicited Adverse Events in Rotarix Recipients with PCV1 in Stool

Subject # Diarrhea Fever Vomiting Irritability Cough/runny nose

Loss of Appetite

461 - + - + NA -

980 - + + + NA -

071 - - - - - -

005 - - - - - -

036 - - - + - -

Placebo (US PI*) 3% 33% 11% 52% 30% 25%

*Following dose 1 placebo NA= not available

• AE pattern in Rotarix recipients similar to placebo

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No evidence for PCV1 Infectionin Infants

• Detection of PCV1 only at earliest timepoints is consistent with transient passage of DNA without replication

• Sequences detected in stool identical to PCV1 sequence in Rotarix

• Absence of seroconversion in all infants (including those with PCV1 detected in stool)

• Adverse event profile in subjects with PCV1 DNA detected was similar to placebo recipients

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Is PCV signal associated with presence of:

1. Viral particles? YES

YES

NO




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Conclusions

• Testing performed on clinical samples to evaluate if children previously vaccinated with Rotarix developed evidence of PCV1 infection

• Methodology selected most relevant studies and samples and ensured blinded laboratory testing

• Currently available data do not suggest occurrence of PCV1 infection in infants who received Rotarix in clinical trials

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Overview

• Presence of PCV1 in Rotarix from the early stages of development

• GSK’s primary focus: patient safety

• PCV1: not infectious in humans, does not cause disease in humans or any other animal

• Rotarix safety database: large, extensive, continuously monitored

• No specific PCV1 lens to query database

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Outline

• Large clinical trial database supporting safety and efficacy

• Worldwide post-marketing safety and effectiveness experience

• Favorable benefit:risk of vaccine containing PCV1

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Large Global Development Program Supported US Licensure in 2008

• 11 global studies; 10 randomized, blinded, prospective, placebo-controlled

• N= 75,029: Rotarix N=40,290 Placebo N=34739

• Healthy infants; 1st dose at 5 to 17 weeks, 2nd dose 1-2 months later

• Efficacy evaluated through 2 years/rotavirus seasons after vaccination

• Safety evaluated in all studies

– specific study (N=63,225) powered for intussusception assessment

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Large Database Supported Efficacy for US Licensure in 2008

• Rotarix prevents:– Severe RV GE disease (96% Europe; 85% Latin America)

– 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 and non-G1 types

• Rotarix efficacy persists through 2 years/seasons after vaccination

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Safety Profile of Rotarix isSimilar to Placebo

• 11 clinical trials in BLA: conducted 2000 through 2007 N=75,029 (Rotarix N=40,290, placebo=34,739) consistent safety profile in each study

• Integrated Summary of Safety: 8 clinical trials N=71,209 (Rotarix N=36,755; placebo N=34,454)– Serious adverse events occurred at similar rates in Rotarix (1.7%) and

placebo (1.9%) significantly fewer SAEs associated with GE disease in Rotarix vs placebo

– Solicited adverse events occurred at similar rates in Rotarix and placebo (fever, fussiness/irritability, loss of appetite, vomiting, diarrhea, cough/runny nose)

• No increased risk of intussusception compared to placebo: controlled safety study, N=63,225, 1:1 randomization– IS within 31 days after any dose: RR=0.85 (0.30;2.42)

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Large Global Postmarketing Database Supports Ongoing Safety

• Pharmacovigilance activities– Worldwide network for spontaneous reporting– Worldwide expedited regulatory agency reporting– Enhanced PV for intussusception

• Doses Distributed: 69 million – Latin America: 45.6 million (Brazil: 33.7 million) – Europe: 3 million – US: 2.5 million – Rest of the World: 18 million

• 2981 Adverse Event reports – reporting rate 4.3 /100,000 doses distributed– including 1177 SAE reports

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Most Frequently Reported Postmarketing Events

(>0.50 per 100,000 doses)

Number of ReportsReported Frequency

per 100,000 doses

Diarrhea 786 1.14

Vomiting 640 0.92

Pyrexia 382 0.55

Intussusception 357 0.52

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Cause of DeathAge

(month)Gender Dose #

Days post vaccination

Sudden Infant Death Syndrome 4 M UNK 20

Sudden Infant Death Syndrome 2 M 1 5

Cardiopulmonary arrest 4 M UNK 3

Status epilepticus, anoxic brain injury 4 M 1 32

Severe traumatic brain injury 2 F 1 5

Probable partial mechanical airway obstruction by ectopic thymus 2 M 1 1

reports do not suggest a causal connection to Rotarix

Postmarketing Reports: US Fatalities2.5 million doses distributed in US

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US Labeled Postmarketing Experience Since Licensure in 2008

• Intussusception (including death) in temporal association*

• Kawasaki disease*

• RV GE in patients with SCID*

* Listed in US PI for the other US-licensed rotavirus vaccine

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Post-licensure Studies Continue to Evaluate Safety and Effectiveness

• Clinical trials in select populations– Safety and immunogenicity in HIV positive infants– Safety and immunogenicity in preterm infants– Transmission between twins

• Post-licensure observational studies– Safety: Mexico, Europe, US– Effectiveness: worldwide

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Rotarix is Effective in Preventing Severe Rotavirus Gastroenteritis

Country Outcome Effect Journal

Australia (New S Wales)

pos. RV isolates and ED visits due to GE

lowest numbers compared to previous 8 RV seasons

Comm Dis Intell 2009

Australia (Central)

G9 RV hospitalized GE 85% Vaccine effectiveness CID 2009

Brazil All-cause GE hospitalization 26-48% rate reduction PIDJ 2010

Brazil (Recife)

G2[P4] severe RV diarrhea 77% V effectiveness JID 2010

Brazil (San Paolo)

RV GE hospitalization 59% rate reduction ESPID 2009

El Salvador severe RV gastroenteritis 74% V effectiveness WHO WER 2009

MexicoAll-cause diarrhea-related mortality

41% rate reduction NEJM 2010

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Rotarix Benefit:Risk is Positive in Presence of PCV1

• RV leading cause of severe childhood diarrhea

• Vaccination only known effective preventative strategy

• Widespread use of rotavirus vaccines can prevent about 2 million deaths over next decade (NEJM 2010:362;4)

• Rotarix protects against RV GE, with safety profile comparable to placebo

• Safety data from clinical trails and postmarketing reflects presence of PCV1

• Benefit:risk for Rotarix remains favorable

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Where We Are Now

• PCV1 not known to cause disease in humans or animals

• GSK is committed to manufacturing PCV1-free Rotarix

• Developing new manufacturing process is complex and will take time

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GSK Investigation Results

• Manufacturing Investigation:

–Permissive Cells

• Low level of infective virus in production process

• Infective viral particles (less than LOD)in final container can not be excluded

–Human Cells

• Evidence does not indicate productive infection

• Clinical Investigation:

–No suggestion of occurrence of PCV1 infection in infants who received Rotarix

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Extensive Body of Evidence Supports Rotarix Safety Profile

• Large clinical trial database

–~ 75,000 subjects

–Multiple countries

• Extensive post-licensure safety experience

–69 million doses distributed

–Multiple countries

• All reflect safety of Rotarix containing PCV1

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Benefit of Vaccination Against Rotavirus Disease is Substantial

• US: vaccination has resulted in a 60% reduction in rotavirus disease as compared to the pre-vaccine era (MMWR 2009:58;41)

• Globally: widespread rotavirus vaccine use could prevent ~2 million deaths over next decade (NEJM 2010: 362;4)

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GSK Proposed Next Steps

• Continue investigations

• Implement manufacturing changes

–Use PCV1-free viral seeds and banks

• Continue ongoing comprehensive pharmacovigilance activities

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GSK is Prepared to Continue to Make Rotarix Available in the US

• Continuing to make Rotarix available worldwide

• Propose updating registration file and label

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GSK is Committed to Developing High Quality, Safe and Effective Vaccines

• New challenges will emerge with new detection technologies

• Decision making must be based on sound science and benefit risk algorithms

• GSK will work with FDA and worldwide authorities to meet global public health needs

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ROTARIX® (Rotavirus Vaccine, Live Oral): GSK’s PCV1 Investigation

a 1 rotarix® (rotavirus vaccine, live oral): gsk’s pcv1 investigation barbara howe, md vice...

Documents

scope of pcv1 investigation

presence of pcv1

safety issue slide

benefit slide

us slide

rotarix rotavirus vaccine

unexpected finding of

disease rotarix