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A 1
ROTARIX® (Rotavirus Vaccine, Live Oral): GSK’s PCV1 Investigation
Barbara Howe, MD
Vice President, Director
North American Vaccine Development
GlaxoSmithKline
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A 2
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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A 3
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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A 4
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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A 5
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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A 6
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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A 7
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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A 8
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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A 9
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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A 10
External Expert
Prof. Dr. Hans NauwynckDirector Laboratory of Virology,Department of Virology, Parasitology and ImmunologyFaculty of Veterinary MedicineGhent University, Belgium
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A 11
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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A 12
•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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A 13
•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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A 14
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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A 15
•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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A 16
•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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A 17
•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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A 18
•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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A 19
•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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A 20
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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A 21
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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A 22
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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A 23
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?
Man
ufac
turin
gC
linic
al
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A 24
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?
Man
ufac
turin
gC
linic
al
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A 25
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?
Man
ufac
turin
gC
linic
al
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A 26
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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A 27
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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A 28
Infectivity in Permissive Cells Doesn’t Mean Infectivity in Humans
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?
Man
ufac
turin
gC
linic
al
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A 29
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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A 30
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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A 31
Additional investigations
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A 32
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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A 33
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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A 34
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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A 35
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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A 36
Rotarix Manufacturing Investigation Conclusions
Is PCV signal associated with presence of:
1. Viral particles? YES
YES
NO
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?
Man
ufac
turin
gC
linic
al
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A 37
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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A 38
Investigation Strategy
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?
Man
ufac
turin
gC
linic
al
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A 39
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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A 40
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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A 41
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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A 42
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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A 43
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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A 44
• 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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A 45
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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A 46
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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A 47
- - - 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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A 48
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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A 49
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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A 50
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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A 51
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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A 52
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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A 53
Rotarix Manufacturing Investigation Conclusions
Is PCV signal associated with presence of:
1. Viral particles? YES
YES
NO
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?
Man
ufa
ctu
rin
gC
lin
ical NO
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A 54
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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A 55
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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A 56
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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A 57
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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A 58
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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A 59
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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A 60
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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A 61
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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A 62
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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A 63
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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A 64
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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A 65
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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A 66
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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A 67
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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A 68
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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A 69
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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A 70
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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A 71
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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A 72
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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A 73
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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A 74
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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A 75
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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A 76
ROTARIX® (Rotavirus Vaccine, Live Oral): GSK’s PCV1 Investigation