FOOD AND DRUG ADMINISTRATION

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CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

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VACCINES AND RELATED BIOLOGICAL PRODUCTS

ADVISORY COMMITTEE MEETING

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WEDNESDAY,

FEBRUARY 20, 2008

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The Committee convened at 8:30 a.m. in the Hilton Washington, DC North,
620 Perry Parkway, Gaithersburg, MD, John Modlin, MD, Acting Chair,
presiding.

PRESENT:

JOHN MODLIN, MD, ACTING CHAIR

CHRISTINE WALSH, RN, EXECUTIVE SECRETARY

SETH HETHERINGTON, MD, INDUSTRY REPRESENTATIVE

VICKY DEBOLD, PHD, RN, CONSUMER REPRESENTATIVE

LISA JACKSON, MD, MPH, MEMBER

JACK STAPLETON, MD, MEMBER

JOSE ROMERO, MD, MEMBER

PABLO SANCHEZ, MD, MEMBER

ERMIAS BELAY, MD, TEMPORARY VOTING MEMBER

ROBERT DAVIS, MD, MPH, TEMPORARY VOTING MEMBER

FRANK DESTEFANO, MD, MPH, TEMPORARY VOTING

MEMBER

BRUCE GELLIN, MD, MPH, TEMPORARY VOTING MEMBER

PAMELA MCINNES, DDS, MSC, TEMPORARY VOTING

MEMBER

STEVEN SELF, PHD, TEMPORARY VOTING MEMBER

MELINDA WHARTON, MD, MPH, TEMPORARY VOTING

MEMBER

PRESENT: (CONT.)

STEVEN ROSENTHAL, MD, FDA

DOUGLAS PRATT, MD, FDA

NORMAN BAYLOR, PHD, FDA

This transcript has not been edited or corrected, but appears as
received from the commercial transcribing service. Accordingly, the Food
and Drug Administration makes no representation as to its accuracy.

A G E N D A

CALL TO ORDER AND OPENING REMARKS 4

ADMINISTRATIVE MATTERS 4

TOPIC 1: [SAFETY AND EFFICACY OF rotavirus]{.underline}

[VACCINE MANUFACTURED BY GSK BIOLOGICALS]{.underline}

FDA BRIEF INTRODUCTION/PRESENTATION

OF QUESTIONS 14

SPONSOR PRESENTATION 17

BREAK 102

FDA PRESENTATION 102

LUNCH 144

OPEN PUBLIC HEARING 145

FDA PRESENTATION OF QUESTIONS 146

COMMITTEE DISCUSSION OF FDA QUESTIONS/

COMMITTEE RECOMMENDATIONS 147

ADJOURN

P-R-O-C-E-E-D-I-N-G-S

(8:33:15 a.m.)

DR. MODLIN:  Good morning, everyone. My name is John Modlin, and I am
serving as the Acting Chair for this meeting of the VRBPAC Committee. I
would like to start out by welcoming the new members to the Committee,
Dr. Pablo Sanchez, Dr. Jose Romero, and Dr. Vicky Debold. And I think
I\'ll now turn things over to Christine.

EXEC. SECRETARY WALSH:  Good morning, everyone. I\'m Christine Walsh,
the Executive Secretary for today\'s meeting of the Vaccines and Related
Biological Products Advisory Committee. I would like to welcome all of
you to this meeting of the Advisory Committee.

Today and tomorrow\'s sessions will consist of presentations that are
open to the public, as described in the Federal Register Notice of
February 1^st^, 2008.

I would also like to request that any media inquiries be directed to Ms.
Karen Riley from the FDA, Office of Public Affairs.

I would like to request that everyone please check your cell phones, and
pagers, and Blackberries to make sure they are off, or in the silent
mode. I would now like to read into public record the conflict of
interest statement for today\'s meeting.

The Food and Drug Administration, FDA, is convening the February
20-21st, 2008 meeting of the Vaccines and Related Biological Products
Advisory Committee under the authority of the Federal Advisory Committee
Act, FACA, of 1972. With the exception of the Industry Representative,
all participants of the Committee are Special Government Employees,
SGEs, or Regular Federal Employees from other agencies, and are subject
to the Federal Conflict of Interest laws and regulations.

The following information on the status of this Advisory Committee\'s
compliance with federal ethics and conflict of interest laws, including,
but not limited to 18 USC 208 and 712 of the Federal Food, Drug and
Cosmetic Act are being provided to participants at this meeting, and to
the public.

FDA has determined that all members of this Advisory Committee are in
compliance with federal ethics and conflict of interest laws. Under 18
USC 208, Congress has authorized FDA to grant waivers to Special
Government Employees, and Regular Government Employees who have
financial conflicts when it is determined that the Agency\'s need for a
particular individual\'s service outweighs his or her potential
financial conflict of interest.

Under 712 of the Food, Drug, and Cosmetic Act, Congress has authorized
FDA to grant waivers to Special Government Employees, and Regular
Government Employees with potential financial conflicts when necessary
to afford the Committee their essential expertise.

Related to the discussion of this meeting, members and consultants of
this Committee have been screened for potential financial conflict of
interest of their own, as well as those imputed to them, including those
of their spouses or minor children, and for the purpose of 18 USC 208,
their employers. These interests may include investments, consulting,
expert witness testimony, contracts and grants, CRADAs, teaching,
speaking, writing, patents and royalties, and also primary employment.

The Committee will discuss and make recommendations on the safety and
efficacy of a rotavirus Vaccine manufactured by GlaxoSmithKline. This is
a particular matter involving specific parties, Topic 1.

For Topic 2, the Committee will discuss and make recommendations on the
selection of strains to be included in the influenza virus for the
2008-2009 influenza season. This is a particular matter of general
applicability.

For Topic 3, the Committee will discuss clinical development of
influenza vaccines for pre-pandemic uses. This is a particular matter of
general applicability.

Based on the agenda and all financial interests reported by members and
consultants, conflict of interest waivers have been issued in accordance
with 18 USC 208(b)(3), and 712 of the Food, Drug, and Cosmetic Act.

Related to Dr. John Modlin, Dr. Modlin\'s waivers include a consulting
arrangement with two firms that could be affected by the Committee\'s
discussions, Topics 1, 2, and 3. The waivers allow Dr. Modlin to
participate fully and vote on the Committee discussion.

Related to Dr. Robert Couch, Dr. Couch\'s waivers include a contract
with a firm that could be affected by the Committee\'s discussions,
Topics 2 and 3. The waivers will allow Dr. Couch to participate fully
and vote on the Committee discussions.

FDA\'s reason for issuing the waivers are described in the waiver
documents, which are posted on the FDA\'s website at
www.fda.gov/ohrms/dockets/default.htm. Copies of the written waivers may
be obtained by submitting a written request to the Agency\'s Freedom of
Information Office, Room 6-30 of the Parklawn Building, Rockville,
Maryland.

With regard to FDA\'s guest speaker, the Agency has determined that the
information provided is essential. The following information is being
made public to allow the audience to objectively evaluate any
presentation and/or comments.

For Topic 2, Dr. Tony Colgate is the Influenza Technical Affairs Manager
at Novartis Vaccines in the United Kingdom. He is a member of several
European groups which focus on influenza vaccines and pandemic issues.

Dr. Seth Hetherington is serving as the Industry Representative, acting
on behalf of all related industry, and is employed by Icogen,
Incorporated. In addition, Dr. Hetherington\'s spouse is employed by
GlaxoSmithKline. Industry representatives are not Special Government
Employees, and do not vote.

This conflict of interest statement will be available for review at the
registration table. We would like to remember members, consultants, and
participants that if the discussions involve any other products or firms
not already on the agenda, for which the FDA participant has a personal
or imputed financial interest, the participants need to exclude
themselves from such involvement, and their exclusion will be noted for
the record.

FDA encourages all other participants to advise the Committee of any
financial relationships that you may have with the Sponsor, its product,
and if known, its direct competitors.

I also have one additional announcement, and that is that Dr. Bruce
Gellin will be present for this morning\'s presentations, and will be
participating in the morning\'s discussions. However, he does have an
unavoidable obligation this afternoon, and will not be able to return to
the meeting after lunch.

That ends the conflict of interest statement. Dr. Modlin, I turn the
meeting back over to you.

DR. MODLIN:  Thanks, Christine.

I\'d like to next ask the members of the Committee to introduce
themselves, and where they\'re from. And I think we\'ll begin with Dr.
Jackson.

DR. JACKSON:  I\'m Lisa Jackson from the Group Health Center for Health
Studies in Seattle.

DR. SANCHEZ:  Pablo Sanchez from University of Texas Southwestern
Medical Center in Dallas. I\'m a Neonatologist in Pediatric ID.

DR. SELF:  Steve Self from Hutchinson Cancer Research Center, University
of Washington.

DR. MCINNES:  Pamela McInnes, National Institutes of Health.

DR. ROMERO:  Jose Romero, University of Nebraska, Omaha, Pediatric
Infectious Diseases.

DR. HETHERINGTON:  Seth Hetherington from Icogen Research, Triangle
Park, North Carolina.

DR. DEBOLD:  And Vicky Debold from the National Vaccine Information
Center here in Vienna, Virginia.

DR. BELAY:  Ermias Belay from the Centers for Disease Control and
Prevention in Atlanta, Georgia.

DR. GELLIN:  I\'m Bruce Gellin with the National Vaccine Program Office,
Department of Health and Human Services.

DR. DAVIS:  Bob Davis, Kaiser Permanente Georgia.

DR. STAPLETON:  Jack Stapleton, University of Iowa, Iowa City, Iowa.

DR. DeSTEFANO:  Frank DeStefano, RTI International in Atlanta.

DR. WHARTON:  Melinda Wharton, Centers for Disease Control and
Prevention, Atlanta.

DR. BAYLOR:  Norman Baylor, Food and Drug Administration, Office of
Vaccines.

DR. PRATT:  Douglas Pratt, Division of Vaccine Applications, Office of
Vaccines, FDA.

DR. ROSENTHAL:  Steve Rosenthal, Division of Vaccines, FDA.

DR. MODLIN:  Thank you. As Christine mentioned, our purpose here today
is to provide advice to the Agency, to the Vaccines Division on the
safety and efficacy of the GSK Human rotavirus Vaccine. Dr. Rosenthal, I
understand you\'ll be leading off with the introductory remarks.

DR. ROSENTHAL:  Thank you, Dr. Modlin. Good morning. I want to thank
everyone, Members of the Advisory Committee for coming today to help the
Agency in its evaluation of Rotarix, a new rotavirus vaccine.

After my brief introduction, GlaxoSmithKline will talk in regard to
their evaluation of the product. And after a break, I will present
CBER\'s evaluation of the license application.

I want to acknowledge my colleague, Paul Kitsutani, who did the primary
work for this presentation. He recently became a father, and that is the
reason he\'s not here with us today.

Rotarix is a live attenuated oral human monovalent rotavirus vaccine
derived from human 89-12 strain, which belongs to the G1P(8) type. It is
prepared as a lyophilized formulation with an end-of-life shelf potency
of greater or equal to 10 to the 6.0 median cell culture infective dose,
or CCID 50 for each dose after reconstitution with liquid diluent. The
vaccine contains no preservatives.

The proposed indication for Rotarix vaccination is the prevention of
rotavirus gastroenteritis, or GE, caused by G1 and non-G1 types,
including G2, G3, G4, and G9 types. It is to be orally administered as a
two-dose series to infants 6-24 weeks of age, with the first dose
beginning at six weeks of age, the second dose given by 24 weeks of age,
and an interval of at least four weeks between doses.

Rotarix has been under a U.S. Core since July 2000; however, many
non-Core studies have been conducted thereafter outside the U.S.,
including the pivotal efficacy and safety study submitted to the BLA.

Pre-BLA meetings involving the applicant and FDA were held from
July-September 2006, and based on an FDA applicant agreement during this
period, 10 of the completed Phase 2 and Phase 3 studies were to be
submitted to the BLA. An additional Phase 3 study conducted in the U.S.
Trial Rota-60, which evaluated non-inferiority of immune responses to
routine vaccinations when co-administered with Rotarix was to be
submitted to the BLA after study completion. The Rotarix BLA was
subsequently submitted to FDA on June 1^st^, 2007.

So the first question we\'ll be asking the Advisory Committee: Are the
available data presented adequate to support the efficacy of Rotarix in
preventing rotavirus gastroenteritis caused by serotypes G1, G2, G3, G4,
and G9, when the first dose of vaccine is administered beginning six
weeks of age, followed by a second dose separated by at least four
weeks? If not, what additional information should be provided?

Question 2: Are the available data presented adequate to support the
safety of Rotarix when used in a two-dose series beginning with the
first dose at six weeks of age, followed by a second dose separated by
at least four weeks? If not, what additional information should be
provided?

And, lastly: Are there additional issues that should be addressed in
post-marketing studies beyond the applicant\'s proposed U.S.
post-licensure safety study?

Thank you for your attention.

DR. MODLIN:  Thanks, Dr. Rosenthal. I understand that GSK\'s
presentation will be led by Dr. Leonard Friedland. I\'m wrong. Sorry,
Dr. Clair Kahn. I beg your pardon, Dr. Kahn.

DR. KAHN:  Good morning, Mr. Chairman, Members of the VRBPAC, FDA and
guests. I\'m Dr. Clair Kahn, as you see, Vice President of Regulatory
Affairs for Vaccines North America for GlaxoSmithKline, and it\'s my
pleasure to introduce our candidate rotavirus vaccine.

Dr. Leonard Friedland will present the Clinical Development Plan and
results for efficacy and safety, and Dr. Thomas Verstraeten will discuss
the current post-marketing safety experience, and the proposed pharmaco
vigilance plan for the post-licensure period. And then I will return for
some concluding remarks.

As noted, the generic name for the vaccine is rotavirus Vaccine Live
Oral, and the brand name, which we will use throughout these
presentations is Rotarix.

Rotarix, as mentioned by Dr. Rosenthal, is a lyophilized vaccine. It\'s
reconstituted with a liquid diluent containing calcium carbonate buffer,
and each one ML contains a dose of at least 10 to the 6L culture
infective dose 50 of live attenuated human rotavirus strain.

It is administered in two oral doses beginning at six weeks of age, with
an interval of at least four weeks between first and second dose. The
two-dose series should be completed by 24 weeks of age.

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 two-dose series to infants 6-24 weeks of age.
rotavirus is the most common cause of severe gastroenteritis in infants
and young children worldwide. By the age of five, as you see here,
almost 100 percent of children will have an episode of RVGE, rotavirus
gastroenteritis, 15-20 percent of whom will require treatment in a
clinic, one in 50 will require hospitalizations, as many as one in 205
will die from this disease. In absolute numbers on the left-hand side,
this translates into 114 million episodes of gastroenteritis, 24 million
clinic visits, 2.4 million hospitalizations, and over 600,000 deaths in
children under the age of five each year.

Not only is there a similar incidence of disease in developing
countries, and in developed world, severe RV infections are equally
common in the developing world, and in the developed world. They usually
occur between three months and 35 months of age.

Looking at the impact of the disease in the United States,
industrialized living does little to reduce infection rates. Almost all
children, four out of five children, will be affected by RV by their
fifth birthday. This amounts to 2.7 million episodes of gastroenteritis
in a year, and while better supportive care lessens the risk of
hospitalization and death, this 2006 report of Glass, et al. cites
600,000 clinic or emergency room visits, up to 70,000 hospitalizations,
and 0 to 60 deaths which occur annually in the United States.

rotavirus is the most common cause of nosocomial acquired diarrhea in
children, and an important cause of acute gastroenteritis in children
attending daycare. Hospitalizations for rotavirus can account for as
many as 2.5 percent of all pediatric hospitalizations, and of these 17
percent are younger than six months of age.

As I noted, the similar incidence of rotavirus disease between
developing and developed countries suggests that both treatment and
preventive measures have only a limited impact on the disease burden;
and, therefore, vaccination against RV represents an important
preventive strategy in controlling the morbidity and mortality of what
is a very common pediatric disease.

Studies in the U.S. have shown that G1 here shown in the green, G1, G2,
G3 and G4, these types represent the majority of the strains each year.
The G1 type, as you see, has been the predominant circulating strain in
the U.S. for over 30 years, with an average prevalence of over 70
percent. Now depending on the year, the prevalence of other common types
in the U.S. can vary, and it has ranged from 6 to 15 percent for G2,
from 1 to 11 percent for G3, and zero to 3 percent for G4. In the 1990s,
the G9 type here in blue appeared, emerging as the fifth most common
type.

The distribution of the predominant rotavirus types in North America is
concordant with other regions, including here Europe and Latin America,
the countries where Rotarix pivotal efficacy and safety trials were
conducted.

The rotavirus virion is an icosahedral non-envelope particle 17
nanometers in diameter. The genome of 11 segments of double-stranded RNA
is encased by three protein capsids, and in a capsid VVP2 is shown in
green, a middle VP6 shown in purple, which is common to all RV strains
that cause human disease. Then there\'s an outer capsid with two outer
capsid proteins, VP7, shown in yellow, which is called the G-protein,
and the red structures are VP4, and they are referred to as the
P-protein. These G and P proteins induce neutralizing antibodies which
are thought to be important in protective immunity. And it\'s, thus,
these proteins that were key targets for vaccine development.

Human rotaviruses are classified into 10G and 11P genotypes. However,
five GP combinations constitute 90 percent of human rotavirus strains
worldwide, and these are G1-P8, G2-P4, G3-P8, G4-P8, and G9-P8, and
it\'s important to note that genotypes P4 and P8 share cross-reactive
epitopes.

So rotavirus vaccine is derived from a G1-P8 human rotavirus strain
which was isolated from a child in Cincinnati, Ohio. It\'s my pleasure
to acknowledge Dr. David Bernstein, one of the originators of this
vaccine, as he is sitting here in the audience today.

The candidate vaccine was acquired by Virus Research Institute, now
Avant Therapeutics, Inc., who further cultivated the vaccine before
conducting successful proof of concept studies with the virus at
Passage-33, and GSK next acquired this vaccine and subjected it to
further cell passages and cloning of the strain resulting in the vaccine
known as RIX4414, a live attenuated human rotavirus vaccine.

RIX4144, and the original unpassaged isolate genome differ by 12 nuclear
type mutations, which include for 10 amino acid substitutions. RIX4414
is genetically stable from seed to final vaccine.

The basis for vaccination with a human strain comes from studies of
natural RV disease. Studies conducted by Velasquez and others show that
rotavirus infection induces immunity against subsequent re-infection
episodes of gastroenteritis. Here we show one previous infection,
various severities, and two infections confer virtually 100 percent
protection against clinically moderate to severe disease regardless of
the serotype.

GSK chose to develop a human rotavirus vaccine in order to mimic human
infection, and to provide broad cross-reactive protective immunity using
a two-dose vaccine. There\'s a high degree of homology between human
rotavirus vaccine proteins and human rotavirus strains.

Clinical research and development of rotavirus vaccines began in the
1970s with strains isolated from bovine and rhesus hosts. However, the
efficacy of these animal-derived vaccines was variable, so animal-human
reassortant vaccines were developed. The first of such vaccines was
RotaShield, licensed in the U.S. in 1998. RotaShield was a rhesus-human
reassortant vaccine given in three doses. This vaccine, however, was
withdrawn in 1999 due to safety concerns related to an increased risk of
intussusception following the immediate vaccination period.

The second, RotaTeq, is a three-dose bovine-human reassortant vaccine
that was licensed in 2006. And Rotarix is a live attenuated vaccine, as
mentioned, derived from a human RV strain administered on a two-dose
schedule. The experience with RotaShield set a new standard on the size
of pre-licensure trials required to demonstrate the acceptable safety of
subsequent vaccines.

Several key considerations were taken into account to determine the
global strategy for Rotarix development. As previously mentioned, very
large studies of at least 60,000 subjects would be necessary to
adequately assess the risk of vaccine-induced intussusception following
the market withdrawal of RotaShield. And at that time of uncertainty
about where such a vaccine might be developed, because there was nothing
then to go to the Third World, the WHO called for manufacturers to
extend development programs to countries with the highest medical need
where the benefit-risk would be very clear. The majority of deaths
resulting from rotavirus gastroenteritis occur in Southeast Asia,
Africa, and Latin America.

Other considerations included the availability of good data on the
epidemiology of RV disease, and the epidemiology of intussusception, and
a health career infrastructure that could handle the conduct of very
large trials.

With this in mind, Phase III clinical development was initiated last
year in Latin America, shown here in green, and then we moved to the
more industrialized North for a second pivotal trial, which was
conducted in Europe, shown here. Additional clinical development was
conducted in the U.S., Canada, and many other regions here shown in
blue, including the pivotal co-administration study, Study 60, in the
United States.

A very nice tabulation of the study characteristics and the demographics
with respect to gender and ethnicity in the over 75,000 subjects in the
file is presented in the FDA\'s briefing document in Table One. The US
IND was opened in August 2000, and as development progressed overseas,
GSK met with CBER to discuss the use of the two pivotal trials to
support U.S. licensure. Following year, a pre-BLA meeting was held to
agree BLA content, and in July 2006 the U.S. BLA was filed. Sorry, I beg
your pardon, June 2007 the BLA was filed.

It\'s very important to note that the two pivotal clinical trials
conducted in Latina and Europe complied with the criteria defined by the
FDA for acceptance of foreign clinical data. The epidemiology of
circulating serotypes in Latina and Europe is similar to the United
States. The epidemiology of intussusception is similar across the
Americas.

The assessment of the pivotal endpoints was objective, such that any
potential regional differences in clinical practice could be minimized,
and these include the identification of intussusception, the case
definition for RVGE, and the use of an internationally accepted scoring
system for the severity of gastroenteritis. And, furthermore, as
mentioned, all studies were well conducted by experienced investigators,
and appropriate ethical standards and good clinical practice.

Rotarix is currently licensed in over 100 countries worldwide, shown
here. These include Canada, Mexico, Australia, European Union, with the
first launch in Mexico in January 2005. And Rotarix is recommended in
several national immunization programs across the world.

Rotarix is the first rotavirus vaccine to be awarded WHO
pre-qualification, February of 2007. This allows the United Nations
agencies, such as PAHO and UNICEF, to purchase and use Rotarix for
massive vaccination programs. To date, more than 12 million doses of
Rotarix have been distributed. Actually, I could say that since the BLA
was filed, it\'s close to 20 million, and have these doses distributed
worldwide outside the United States since 2005.

So now I\'ll turn the podium over to Dr. Leonard Friedland. He\'s the
Executive Director of Clinical Research and Development for Vaccines
North America.

DR. FRIEDLAND:  Thank you, Dr. Kahn. Members of the VRBPAC, FDA, and
guests, I am pleased to be here today to present an overview of the
clinical development program for the candidate vaccine, and the clinical
trial results in support of the biologics licensing application.

As mentioned by Dr. Kahn, GSK undertook a global development program
designed to support license requirements for initial registration in
developing countries, areas of the world where rotavirus vaccine is more
urgently needed. And, subsequently, to support licensure requirements in
developed countries, including the United States.

Shown on this slide is an overview of the 11 clinical studies submitted
in support of licensure of Rotarix in the United States. In these
clinical trials, more than 40,000 infants received Rotarix, and more
than 34,000 received placebo, over 37,000 infants received a formulation
of at least 10 to the 6^th^ median CCID, which is currently marketed
outside of the United States, and is the formulation intended for U.S.
licensure.

There were six Phase II studies. Objectives in these studies included
dose ranging evaluations, and assessments of vaccine efficacy, safety,
and immunogenicity. Over 35,000 infants received the licensure
formulation in five Phase III studies. Objectives in these studies
included vaccine efficacy, safety, including intussusception,
manufacturing lot consistency, and immunogenicity of Rotarix in the
context of co-administered vaccines.

Ten of the studies were prospective, randomized, blinded, and
placebo-controlled. In all 11 studies, infants enrolled were healthy and
received their first study vaccine dose between five and seventeen weeks
of age. In the Phase III studies, the first dose was administered
between six and fourteen weeks of age, and the second dose administered
one to two months after the first dose.

Vaccine efficacy was evaluated through two years, or two rotavirus
seasons after vaccination. Two Phase III studies, Studies Rota-O23, and
Rota-O36, are pivotal to the proposed efficacy indications. Safety was
evaluated in all studies, and one particular study, Rota-O23, was
specifically designed and powered to assess intussusception as the
primary endpoint.

Immunogenicity was evaluated, and co-administration of routine infant
vaccines according to local recommendations were allowed in nine of the
eleven studies. One study, Rota-060, conducted in the United States,
included all of the vaccine antigens currently administered to U.S.
infants.

The clinical data that I will review with you today are the following;
efficacy data from the two Phase III studies, Study O-23 conducted in
Latin America, and Study O-36 conducted in Europe. I will present
immunogenicity data in terms of IGA seroconversion and vaccine take,
co-administration data with U.S. licensed vaccines, and data on fecal
antigen and live virus shedding.

I will conclude the clinical trial presentation with a review of safety
data on intussusception, serious adverse event data from an integrated
summary of safety, events of clinical interest, reactogenicity data from
the integrated summary of safety, and conclude with a review of
representative reactogenicity data from studies conducted in Europe, and
the United States, and Canada.

Prior experience with live oral vaccines, such as oral polio virus and
the first licensed rotavirus vaccine, RotaShield, demonstrated variable
vaccine efficacy and immunogenicity in developed and developing world
countries, generally lower in developing world countries. Participating
factors may include diverse populations, socio-economic class
differences, interaction with co-administered vaccines, and host
factors, such as maternal antibodies, breast feeding, interfering
enteric pathogens, and malnutrition. Therefore, GSK conducted vaccine
efficacy trials in countries of both the developed and the developing
world.

Two Phase III studies, Rota-023 conducted in Latin American, and
Rota-036 conducted in Europe, as mentioned, are pivotal to the proposed
efficacy indications. I will now review these two Phase III efficacy
studies.

The first efficacy study results come from Study Rota-023, a Phase III
efficacy and safety study conducted in 11 countries in Latin America,
and in Finland. Over 63,000 infants were enrolled and vaccinated in this
trial. Please note that vaccine efficacy was only studied in this study
in the 11 Latin American countries.

This is a schematic of the O23 Study. I\'ll walk you through this a bit.
Infants six to thirteen weeks of age were randomized one-to-one to
receive Rotarix or placebo, and a second dose was given one to two
months later. There were no feeding restrictions in this trial. Routine
immunizations, except oral polio virus vaccine, were co-administered
according to local recommendations. All infants were followed for 30 to
90 days after receiving their second dose of study vaccine. This cohort
was followed for a median of 100 days after dose one.

In the presentation, I will refer to this follow-up period as the safety
surveillance period. The safety surveillance period is illustrated on
this slide by the green bar. A subset shown by the white bar on the
slide, only from the 11 Latin American countries, were followed through
one-year of age for vaccine efficacy analysis. And infants from 10 of
the 11 Latin American countries, as shown by the red bar, were followed
through a second year for vaccine efficacy analysis.

The primary objective of this study was to determine if two doses of
Rotarix can prevent severe rotavirus gastroenteritis caused by
circulating rotavirus strains starting from two weeks after dose two
until one year of age. Secondary objectives included efficacy against G1
and non-G1 types, efficacy using the Vesikari efficacy scale, and
efficacy through two years of age.

The case definition for severe RVGE was diarrhea, three or more loose
stools in a 24-hour period with or without vomiting that required
hospitalization and/or rehydration therapy in a medical facility. This
case definition will subsequently be referred to as the clinical case
definition.

rotavirus antigen in stool was detected by ELISA. rotavirus type was
determined by reverse transcriptase PCR, followed by reverse
hybridization assay or option sequencing, as needed. This methodology
allowed for discrimination between G1 vaccine virus and wild-type G1
rotavirus. Efficacy endpoints included protection against severe
rotavirus gastroenteritis as assessed by the clinical case definition,
and by the Vesikari scale. The Vesikari scale is an internationally
accepted and widely used 20 point scoring system in which severity of
gastroenteritis episodes is assigned according to the intensity and
duration of diarrhea and vomiting, fever, dehydration, and type of
treatment. This scale has also been used in efficacy trials with the
previous licensed RotaShield vaccine. Severe gastroenteritis on the
Vesikari scale is defined as a score greater than or equal to 11.

Endpoints also included efficacy against RV hospitalizations, and
all-cause severe gastroenteritis, rotavirus type-specific efficacy, and
efficacy in the second year after vaccination. Vaccine efficacy in this,
and in the other Phase III efficacy study which I will soon speak about,
was evaluated through two years after vaccination as the majority of
rotavirus in children occurs under the age of two.

I\'d like to take a moment to orient you to this slide presentation,
which you\'ll see again. Efficacy outcomes are shown on X axis. The
numbers at the bottom of the efficacy bars represent numbers of cases
reported in the Rotarix group. Well, I can\'t figure out to how it,
shown by V. And rates in the placebo group are shown at the bottom of
the bars by P. Vaccine efficacy rates with 95 percent confidence
intervals are shown at the top. Vaccine efficacy rates with 95 percent
confidence intervals are shown at the top of each efficacy bar.

As shown on this slide, Rotarix was highly efficacious. Through the
first year of life, vaccine efficacy was 85 percent against severe RVGE
using both the clinical case definition and the Vesikari scoring system.
Efficacy was 85 percent against rotavirus gastroenteritis
hospitalizations, and 40 percent against all-cause severe
gastroenteritis regardless of etiology.

This slide shows efficacy rates through two years after vaccination.
Efficacy was sustained at similar high rates through two years of age
against all of the outcomes studied.

Type-specific efficacy against severe RVGE through two years of age is
shown on this slide. Statistically significant efficacy was demonstrated
for common circulating RV-types G1, G3, G4, and G9.

The second Phase III efficacy study was Study Rota-O36, conducted in six
countries throughout Europe. The majority of the infants enrolled in
this study were from Finland. This is a schematic of the O36 study, and
I\'ll walk you through it briefly.

Nearly 4,000 infants six to fourteen weeks of age were randomized
two-to-one to receive Rotarix or placebo, and a second dose was given
one to two months later. There were no feeding restrictions in this
study. All of the infants received concomitant vaccination with DTaP,
HepB, IPVHIB combination vaccine, and a subset received concomitant
vaccination with pneumococcal conjugate or meningococcal-C conjugate
vaccine. All infants were followed through the first rotavirus season
after vaccination, and again through the second rotavirus season after
vaccination.

Whereas, in Study O-23 the primary objective was efficacy against severe
RVGE, objectives in Study-O36 included efficacy against any severity and
severe RVGE during the first rotavirus season after vaccination.
Secondary objectives were similar to those in Study O-23 with the
addition in Study O-36 of an efficacy assessment against medically
attended RVGE. Medically attended RVGE was defined as gastroenteritis
that required a contact or a visit with a medical provider, evaluation
in an emergency department, or hospitalization.

The case definition for rotavirus gastroenteritis was diarrhea, three or
more loose stools in a 24-hour period with or without vomiting. Severity
was assigned using the previously discussed Vesikari severity scale.
rotavirus detection and typing methodology was the same as in Study
O-23.

Efficacy endpoints in this study were similar to those in Study-O23 with
the addition in Study O-36 of efficacy assessment of any severity of
RVGE, of medically attended RVGE, and efficacy from dose one up until
dose two.

In this second Phase III study, Rotarix was also highly efficacious.
Through the first rotavirus season after vaccination, efficacy was 87
percent against any severity, and 96 percent against severe RVGE.
Rotarix was 100 percent effective in preventing RVGE hospitalizations,
and 92 percent effective in preventing RVGE which required medical
attention.

Vaccination also has the potential to reduce the overall burden of
gastroenteritis disease during early childhood because RV infections are
the most important cause of severe gastroenteritis in young children.
Reductions in hospitalizations, as shown on this slide, for all-cause
gastroenteritis regardless of etiology was 75 percent.

Efficacy in this study was sustained through two rotavirus seasons after
vaccination against all outcomes. In this study, 82 percent of the
infants received their first dose of study vaccine prior to the
rotavirus season, 10 percent of the infants had completed the full
two-dose series before the start of rotavirus season. As a result, a
small number of rotavirus cases occurred prior to the time the infants
received their second dose of vaccine. Thus, vaccine efficacy from dose
one up until dose two could be analyzed, and was shown to be 90 percent
against any severity, and 100 percent against severe RVGE with wide
confidence intervals given the small number of cases.

In contrast to Study O-23, in Study O-36 through two rotavirus seasons
there were sufficient number of cases of all serotypes to assess
efficacy for all common circulating strains. Statistically significant
vaccine efficacy was demonstrated for all circulating rotavirus types,
including Type G2.

In summary, Rotarix is highly effective in preventing RV
gastroenteritis. Rotarix prevents severe RVGE, any severity RVGE, RV
hospitalizations and medically attended visits due to rotavirus, and
efficacy was observed as early as after the first dose. As expected, a
small difference in vaccine efficacy was observed in the developing
world countries in Latin America compared to the developed world
countries and Europe.

Serotype-specific data indicate that Rotarix prevents gastroenteritis
caused by all common circulating types. Rotarix efficacy persists
through at least two years or two rotavirus seasons after vaccination.

I\'d like to now switch focus to immunogenicity data. Immunogenicity of
Rotarix was assessed by IGA seroconversion and vaccine take.
Immunogenicity results from a co-administration study with U.S. licensed
infant vaccines will be presented, as will data on fecal antigen and
live virus shedding.

A relationship between antibody responses to rotavirus vaccination and
protection against RVGE has not been established. However, serum anti-RV
IGA antibodies are a commonly used indicator of the immune response to
rotavirus. Seroconversion was used as a measure of Immunogenicity in the
clinical trials, and was defined as a post-vaccination anti-rotavirus
IGA antibody concentration greater than or equal to 20 units per ml in
subjects who were negative for rotavirus prior to their first dose.

In the pivotal Phase III safety and efficacy studies after the two-dose
regimen, 87 percent of the infants in Study O-36, and 77 percent of the
infants in Study O-23 seroconverted. This difference in immunogenicity
between Europe and Latin America is consistent with previous
observations using other live oral vaccines. Efficacy, especially
against severe RVGE paralleled, but was always higher compared to
antibody response indicating that the antibody response tends to
underestimate the level of protective immunity elicited by the vaccine.

It has been observed that in some cases after vaccination or natural
infection there is no detectible serum IGA antibody response, although
rotavirus antigen in stools is detected for several days or weeks
indicating that virus replication has taken place. Therefore, in
addition to seroconversion, in selected studies and subsets of subjects
vaccine take was assessed as a combined endpoint of serum IGA antibody
seroconversion and/or stool rotavirus antigen positivity in infants
negative for rotavirus prior to their first dose. AS shown on this
slide, across the clinical trials, vaccine take rates ranged from 73
percent to 98 percent.

Rotarix was investigated in U.S. infants in a Phase III study when
co-administered with the U.S. licensed routine infant vaccinations,
Pediarix, Prevnar, and ActHIB. The study design is shown on this slide.
Infants in the co-administration group received Rotarix concomitantly
with Pediarix, Prevnar, and ActHIB, and infants in the separately
administered group received Rotarix one month apart from the routine
vaccines.

The objective of this study was to demonstrate that co-administration
with Rotarix does not impair the immune response to any of the antigens
contained in each of the vaccinations currently included in the ACIP
Infant Immunization Schedule.

The pre-specified criteria for demonstrating non-inferiority of antibody
responses at one month after dose three of Pediarix, Prevnar and ActHIB
were met for all 17 co-administered antigens, namely, the lower limits
of the 95 percent confidence interval for the treatment difference in
seroprotection rates or GMC ratios for the respective antigens as listed
on this slide exceeded the pre-specified non-inferiority criteria. The
results from this study demonstrate that Rotarix does not negatively
impact the immune responses to any of these routine vaccine antigens.

Fecal rotavirus antigens excretion is a feature of natural wild-type
rotavirus infection. Up to 30 percent of children with rotavirus
gastroenteritis continued to excrete antigen for more than 21 days after
the onset of symptoms, and antigen shedding has been detected for as
long as 57 days after disease onset in immunocompetent infants.

As Rotarix is a live attenuated human rotavirus vaccine, after oral
administration excretion of rotavirus antigen is expected in the absence
of GE symptoms, and is an indication of vaccine activity.

Viral shedding following Rotarix administration was evaluated by two
methods. The first was the presence in stool of rotavirus antigen
demonstrated by ELISA. The ELISA test detects the presence of the highly
conserved antigen VP-6 from infectious particles, as well as from
non-infectious viral debris. However, it is important to note that
detection of antigen does not necessarily imply the presence of
infectious rotavirus. Therefore, the presence of live rotavirus
particles in stool detected by cell culture was also evaluated.

Fecal rotavirus antigen shedding, as assessed by ELISA, was studied in a
subset of subjects in seven of the eleven studies. Shown on this slide
is representative data in Study Rota-O33, in which antigen shedding
measured by ELISA was assessed at multiple time points after each dose.
After the first dose, as shown in blue, the rate of antigen shedding
measured by ELISA peaked at 50 percent on day seven, was 20 percent at
day 15, and antigen shedding was not detected at day 30. Shedding, as
might be expected after the second dose was lower, and is shown by the
yellow bar, peaked at 17 percent on day three, and was not detected at
day 10.

As mentioned previously, detection of antigen does not necessarily imply
the presence of infectious rotavirus. In the two studies shown on this
slide, all stool samples collected at day seven after the first vaccine
dose that were ELISA-positive for rotavirus antigen and with sufficient
quantity of stool remaining were tested for the presence of live
rotavirus in cell culture by indirect fluorescence. The percentage of
vaccinees with live rotavirus detected in stool was extrapolated by
multiplying the proportion of stools that were rotavirus antigen
positive by the proportion of rotavirus antigen positive stools
containing live rotavirus. Thus, it was estimated that approximately 26
percent of the infants were shedding live rotavirus at day seven after
dose one in these two studies. In summary, the data presented show that
Rotarix is immunogenic. Rotarix can be administered with the routine
recommended infant vaccines in the United States without impacting the
immune response to antigens present in DTaP, HepB, IPV/Hib, pneumococcal
conjugate, and HIB vaccines. Live virus shedding was reported in
approximately 26 percent of subjects on day seven after dose one.

The overall clinical trial database, which will be reviewed shortly,
shows that Rotarix is not associated with an increase in GE symptoms in
vaccine as compared to placebo recipients. Nearly all children will be
infected with natural rotavirus by an early age. The limited potential
of transmission of attenuated human rotavirus strain should be weighted
against the high likelihood of acquiring and transmitting natural
rotavirus.

The last section of the safety data presentation is vaccine safety. I
will present data from Study O-23, which was the pivotal study which
evaluated intussusception. An integrated summary of safety serious
adverse event data, information on events of clinical interest,
integrated summary of safety reactogenicity data, and reactogenicity
data from studies conducted in Europe, and the United States, and Canada
will be reviewed.

This is a schematic of Study O-23, which I showed earlier. As a
reminder, all 63,000 infants were followed through the safety
surveillance period noted on the slide by the green bar. The safety
surveillance period was a median of 100 days after dose one.

The primary endpoint for safety was a case of intussusception diagnosed
within 31 days of receiving the first or second dose of vaccine.
Intussusception cases were detected by independent complimentary
methods. All hospitals and study areas were informed about the study,
and relevant hospital departments were advised to contact study
personnel regarding each case of intussusception evaluated. Parents of
participating infants were informed about symptoms consistent with
intussusception, and instructed to seek medical advice at the nearest
hospital if symptoms suggestive of intussusception appeared, and to
inform the investigator.

At each study visit or contact the investigators queried each subject\'s
parent on whether the infant had been evaluated in a hospital or
emergency department for a complaint that led to abdominal surgery, or
had an abdominal radiology procedure. Every affirmative answer was
followed with a complete case investigation by the study personnel. All
potential intussusception cases were reviewed by an Independent Clinical
Events Committee composed of a pediatric gastroenterologist, surgeon,
and radiologist who remained blinded to treatment allocation and
characterized cases of intussusception as definite, probable, or
possible using the Brighton Collaboration Intussusception Criteria.

As an additional layer of safety monitoring, an Independent Data
Monitoring Committee was established to monitor the safety of the
Rotarix development program. The IDMC had the authority to unblind the
data.

Before reviewing the study\'s primary safety objective, it\'s important
to mention that the criteria for meeting the study\'s primary objective
were revised during the course of the study when the trial remained
fully blinded. The reason is the following; when the study was initially
designed, we used available information on age-specific background rates
of intussusception. At the time, the most reliable information was
available from the United States. During the course of the trial,
updated information on estimates of age-specific background rates of
intussusception in Latin America were obtained through a concurrent
prospective epidemiology study conducted in the same Latin American
countries. The study showed that although the overall rates of
intussusception in Latin America were comparable to those in the United
States, the peak incidence started one month earlier Latin American
coincident with the time of the second dose of vaccine administration in
Study O-23.

This finding supported by a higher than expected overall incidence of
intussusception cases in the clinical trial led to the conclusion that
the original assumption was no longer appropriate. Accordingly, before
any analyses were performed, the criteria for meeting the primary
objective were revised. This change was discussed with the study\'s
IDMC, and endorsed prior to implementation when the trial remained fully
blinded.

After the adjustment to the primary endpoint, the primary safety
objective was set as listed on this slide. The primary objective would
be met if the upper limit of the two-sided 95 percent confidence
interval of the risk difference for intussusception within 31 days after
vaccination was below 6 per 10,000, and there was no statistical
significant increase in the incidence of intussusception within 31 days
after vaccination defined as the lower limit of the two-sided 95 percent
confidence interval for the risk difference was below zero.

Considering an incident rate of 3 to 5 definite cases of intussusception
for 10,000 infants within 31 days in the placebo group, a sample size of
60,000 had more than 86 percent power to meet the primary objective if
the risk difference was truly zero. A secondary safety objective was the
occurrence of all serious adverse events during the study. Now on to the
intussusception results.

From dose one through the end of the safety surveillance period, among
the over 63,000 infants enrolled and vaccinated, there were 27
investigator-diagnosed intussusception cases. The Independent Clinical
Events Committee adjudicated one case as probable, and 26 cases as
definite. Among the 26 definite cases, 13 were diagnosed within 31 days
of a dose of study vaccine, 6 cases in the Rotarix group, and 7 cases in
the placebo group, 12 cases were diagnosed between 31 days of a dose of
study vaccine, and the end of the safety surveillance period. The next
two slides present additional information on the intussusception cases
which are reported.

This slide shows the adjudicated definite intussusception cases. Within
31 days of any dose, there were six cases in the Rotarix, and seven in
the placebo group. The relative risk was 0.85, and the risk difference
was -.32 per 10,000. Within the safety surveillance period, which was a
median of 100 days after dose one, there were nine cases in the Rotarix,
and sixteen in the placebo group. The relative risk was 0.56, and the
risk difference was -2.23 per 10,000. The safety results from this study
demonstrate that Rotarix is not associated with an increased risk of
intussusception. In addition, the characteristics of the intussusception
cases were reviewed, and they were similar in subjects who received
Rotarix or placebo.

Illustrated on this slide are the 13 definite intussusception cases
within 31 days of any dose by day range in relation to dose. As you can
see, the cases occurred sporadically. There was no clustering of
intussusception cases within seven or fourteen days after any vaccine
dose. Specifically, there were no intussusception reported within 14
days of dose one in any group, which was the period of greatest risk of
intussusception associated with RotaShield.

In pivotal safety Study O-23, the primary safety hypothesis with regard
to intussusception was satisfied. Within 31 days of any vaccine dose,
the upper limit of the two-sided 95 percent confidence interval of the
risk difference was below 6 per 10,000, and the lower limit of the 95
percent confidence interval of the risk difference was below zero,
demonstrating no statistical increase in intussusception incidents.

In Study O-23 within 31 days of any dose, the relative risk was .085
with an upper limit of 2.4, and the risk difference was -.32 with an
upper limit of 2.18. There was no clustering of intussusception cases
within seven or fourteen days of any dose.

Cases of intussusception were also captured in all of the eleven
clinical trials, which included different formulations of Rotarix. In
all clinical trials, within 31 days after vaccination, there were 10
cases of intussusception in Rotarix, and seven in placebo subjects, with
a relative risk of 1.3. Among intussusception cases which occurred
regardless of time to onset after vaccination, in all placebo-controlled
trials there were 18 cases in Rotarix, and 22 in placebo, with a
relative risk of 0.72. In summary, the clinical trial database on
intussusception provides a high level of confidence that Rotarix is not
associated with intussusception.

An integrated summary of safety of all randomized placebo-controlled
trials submitted in the licensing application was performed. The Core
Integrated Summary of Safety, which I\'ll call the Core ISS, includes
eight randomized placebo-controlled trials, and compares placebo to
Rotarix at potency greater than or equal to 10 to the 6^th^ median CCID
50, the potency licensed for use outside of the United States, and
proposed for use in the United States. The ISS includes data on
solicited adverse events, unsolicited adverse events, and serious
adverse events.

The relative risk accounting for study effect with the exact 95 percent
confidence interval of Rotarix versus placebo was estimated for each
safety endpoint. Statistical imbalances for each safety endpoint were
defined as the 95 percent confidence interval for the relative risk
excludes one. Due to the multiple comparisons between the groups without
adjustment for multiplicity, imbalances between groups should be
interpreted with caution, as it is possible that these findings may have
occurred by random chance.

In the Core ISS, including over 36,000 infants receiving Rotarix, and
over 34,000 infants receiving placebo, at least one serious adverse
event was reported by similar numbers of subjects in both groups. The
most common serious adverse events occurring within the 31-day
post-vaccination period after any dose reported with a frequency of
greater than 0.1 percent in either group were bronchiolitis, pneumonia,
and gastroenteritis. Bronchiolitis and pneumonia were reported at
similar rates in both groups. As would be expected, given the protective
effect of Rotarix against gastroenteritis, gastroenteritis was reported
more frequently in the placebo group.

Compared to placebo subjects, Rotarix subjects reported significantly
less diarrhea, gastroenteritis, and dehydration in keeping with the
protective effect of Rotarix against gastroenteritis. All other serious
adverse events reported within the 31-day post-vaccination period,
including deaths, intussusception, nervous system disorders, and as
previously mentioned, bronchiolitis and pneumonia, were reported by
similar proportions of subjects in both the Rotarix and the placebo
groups.

Although the ISS did not show any significant imbalances in favor of the
placebo group, the company has identified six events worthy of further
exploratory analysis and follow-up. These events were identified either
because they were highlighted in the context of another rotavirus
vaccine, or because they were found to be occurring at higher rates
following Rotarix compared to placebo in single studies.

The first event, bloody stools, was reported as part of the spectrum of
gastrointestinal illness related to RotaShield. Hematochezia is also a
clinical sign of intussusception, and information on Hematochezia is
included in the Rota Teq U.S. package insert. The second and third
events, Kawasaki disease and convulsions, have been discussed in the
context of Rota Teq. Convulsions and the remaining events, pneumonia
deaths, pneumonia and bronchitis are events of clinical interest because
an imbalance was found during exploratory analyses of single Rotarix
studies. It should be noted that for each of these events, the imbalance
was only noted in a single study, and not in any other study, or in the
Core Integrated Summary of Safety.

The pivotal safety results for this licensing application come from the
pooled Integrated Summary of Safety. In the Core ISS, there were no
hematochezia serious adverse events, or cases of Kawasaki disease within
31 days of vaccination. For the four events of clinical interest where
an imbalance was noted in a single study, in the Core ISS within 31 days
of vaccination there were no imbalances for convulsions serious adverse
events, pneumonia deaths, pneumonia serious adverse events, or
bronchitis serious adverse events. Because of their clinical importance,
I will discuss the following events of clinical interest in more detail;
Kawasaki disease, convulsion, and pneumonia deaths.

In the completed and ongoing clinical trials, including more than 90,000
subjects, a total of 27 cases of Kawasaki disease have been reported
following Rotarix or placebo. Five of these reports occurred in trials
that were either not placebo-controlled, or not one-to-one randomized,
and their importance is difficult to interpret. The remaining 22 cases
occurred in Southeast Asia, where the background rate of Kawasaki
disease is known to be higher than in other parts of the world.

This past June, GSK unblinded these 22 cases. The distribution of these
cases is 13 in the Rotarix, and 9 in the placebo group. The associated
relative risk is 1.4, and the 95 percent confidence interval includes
one. Among all 27 reports, time to onset after vaccination does not
suggest any clustering in either group. Only three cases occurred within
31 days after vaccination, two cases in the Rotarix, and one in the
placebo group.

The currently available data do not indicate an increased risk of
Kawasaki disease associated with Rotarix. GSK will further investigate
Kawasaki disease in the post-marketing setting.

Before reviewing data on convulsions and pneumonia deaths, it is
important to mention that in Study O-23, the primary safety objective
was the occurrence of the serious adverse event intussusception.
Multiple comparisons of other serious adverse events were made between
the Rotarix and placebo group for exploratory purposes to evaluate
potential imbalances. The reported serious adverse events in Study O-23
were coded to 24 different system organ classes, and 265 different
preferred terms according to the MedDRA Classification system.
Asymptotic P values were used as an aid to highlight potential
imbalances worth further clinical evaluation. Thereafter, the assessment
of such imbalances should be based on thorough qualitative clinical
evaluation.

GSK has evaluated any potential signal. We reviewed cases coded to
similar preferred terms. We\'ve reviewed data from other clinical
trials, consulted with the study\'s IDMC, reviewed the clinical
characteristics of each case looking for consistent patterns, and
checked for symptom onset in close proximity to vaccination.

In the exploratory analysis of serious adverse events, imbalances in
favor of Rotarix were noted for diarrhea, vomiting, gastroenteritis, and
dehydration. These observed differences most likely reflect efficacy of
Rotarix in preventing gastroenteritis-related symptoms.

In the exploratory analysis of SAEs, imbalances in favor of placebo were
noted for urticaria, convulsion, and pneumonia deaths. A brief mention
first about the urticaria serious adverse events. Four of the five
infants who developed urticaria developed the urticaria between 15 and
82 days after dose one. All four infants went on to receive a second
dose of Rotarix without a recurrence of urticaria or other symptoms. The
fifth infant had onset day four after dose two. No cases of anaphylaxis
or drug hypersensitivity were reported in any of the Rotarix subjects.
These observations, in our opinion, are inconsistent with an increased
risk of immediate hypersensitivity to Rotarix.

Now on to discussion of the convulsions serious adverse events. Within
the whole safety surveillance period in Study O-23, 16 cases of
convulsion were reported in Rotarix, and 6 in placebo subjects.
Considering convulsions within 31 days after vaccination, the time
window that might be considered the most relevant for biologic
plausibility, there were seven convulsions reported in the Rotarix, and
five in the placebo group.

The investigators in this study reported new onset seizures under five
different diagnoses. These were convulsion, epilepsy, grand mal
convulsion, status epilepticus, and tonic convulsion. To better capture
all seizures, reports for all serious adverse events related to these
five convulsive disorders were grouped together for an exploratory
analysis, which showed that during the whole surveillance period there
were 20 convulsion-related cases in the Rotarix, and 12 in the placebo
group. Within 31 days after vaccination, there were seven
convulsion-related cases in the Rotarix, and nine in the placebo group.

This finding in Study O-23 was further investigated. A review of the
individual case histories revealed that many subjects in both the
Rotarix and the placebo groups had pre-existing or concurrent medical
conditions as risk factors. A temporal association related to
vaccination was not established. Imbalances were not observed when
pooled terms related to convulsions were analyzed. In addition,
imbalances in convulsion-related SAEs were not observed in the other
large Phase III study Rota-O36, or in the Core Integrated Summary of
Safety.

The currently available data do not suggest a causal relationship
between Rotarix and convulsions. Further assessment is planned in the
post-marketing setting, and these post-marketing plans will be discussed
later in the presentation.

A discussion on the pneumonia deaths now. Study O-23 was not designed to
study the effect of vaccination on fatalities, and the study was not
controlled for factors associated with higher post-neonatal fatality,
such as prematurity, age of mother, smoking exposure, and nutritional
deficiencies. In this study, when looking at the entire safety
surveillance follow-up time, there were 56 deaths in the Rotarix, and 43
deaths in the placebo group, a difference that is not statistically
significant.

A blinded Independent Safety Review Committee appointed by the study\'s
IDMC reviewed each death, and assigned a primary cause of death. Among
multiple exploratory analyses performed, the only potential imbalances
noted was for death coded to the preferred term pneumonia. Several
supplementary analyses were performed to assess the relevance of this
finding.

First, as pneumonia could be reported under various terms, an additional
exploratory analysis was performed combining preferred terms that were
related to pneumonia. During the whole surveillance period, there were
16 pneumonia-related deaths in the Rotarix, and six in the placebo
group.

Second, we looked at whether this imbalance was replicable in other
studies. There are no studies that have been completed to-date in which
a comparable number of deaths have occurred.

As a next step, we reviewed the individual cases to look for patterns
that may suggest a relationship to vaccine. A review of the cases shows
that there were no unique or distinguishing clinical characteristics,
consistent patterns, or common chest x-ray findings. Seven of the
sixteen cases had symptom onset between day zero and 30 after
vaccination. Within 30 days after vaccination, the time window that
might be considered the most relevant for biologic plausibility, two of
the cases occurred within one week of vaccination, two in the second
week after vaccination, two in the third week after vaccination, and one
in the fourth week after vaccination. This absence of clustering does
not suggest a causal association.

Nine of the sixteen infants had symptom onset beyond 30 days after
vaccination occurring between 31 and 199 days after vaccination. Five of
the sixteen infants had pre-existing conditions, risk factors, or
alternative diagnoses that could have contributed to the pneumonia.

One would expect that a vaccine-associated signal in pneumonia deaths
would be part of a clinical spectrum of vaccine-associated
pneumonia-related disease, including non-fatal severe pneumonia
resulting in hospitalization. Therefore, an additional analysis was
performed to evaluate pneumonia-related hospitalizations. In the
previous slide, I was speaking of pneumonia deaths. On this slide now
we\'re going to look at pneumonia hospitalizations in Study O-23.

As mentioned, this slide shows the additional exploratory analyses on
all hospitalizations coded to the various pneumonia-related preferred
terms. Let me remind you that in Study O-23, the parents and guardians
of the infants in the study were contacted by study personnel at least
every four days, and emergency department and hospital admission logs
were systematically reviewed. There were approximately 275
hospitalizations for pneumonia in both groups, numbers that would have
been large enough to detect an imbalance if vaccination was associated
with serious adverse respiratory outcomes.

These data show that the observed imbalance in pneumonia-related deaths
among Rotarix recipients was not supported by observation of other
pneumonia-related serious adverse events.

An Independent Data Monitoring Committee has monitored the safety
aspects of the Rotarix development program since 2002. In their report
on Study O-23, the IDMC said the following: \"Overall, compared to
placebo recipients, Rotarix vaccinees had lower rates of
hospitalizations and GE-related SAEs. Hospitalization rates for
respiratory diseases and for all infectious causes, excluding diarrheal
disease, were comparable in the two groups.\"

Concerning the observed fatalities, the IDMC stated that \"these could
be due to chance. The multiple analyses of safety data could have
resulted in a spurious finding of statistical significance.\" The IDMC
noted that \"there is no known biological explanation for this
observation. Natural rotavirus disease is not an established cause of
mortality from non-diarrheal causes.\"

Because of the unclear significance of this finding, and the potential
benefit of the vaccine, the IDMC recommended that the current trials
should be continued. The IDMC concluded that \"further evaluation is
warranted.\" The IDMC continues to monitor the safety of the Rotarix
development program.

There are two studies currently ongoing in Africa which have enrolled
nearly 5,000 infants in which, as could be expected, a considerable
number of deaths have occurred. In fact, in these two ongoing studies,
135 deaths have occurred, 60 of these deaths were pneumonia-related.

GSK remains blinded to treatment allocation in these two ongoing studies
in Africa. GSK has asked the IDMC that oversees these studies to inform
us of imbalances in deaths, and specifically pneumonia-related deaths it
may observe. The IDMC met recently, and in their last statement said
that \"there are no safety concerns in these two ongoing studies in
Africa, nor in other ongoing studies.\"

Several sets of criteria to assess causality exist, of which the
Bradford Hill may be the best known. In this slide, I summarize our
findings as they relate to the criteria that apply to vaccine safety.
The first criterion is consistency. The association between pneumonia
deaths and Rotarix was seen only in Study O-23, and not in other
studies, including ongoing Phase III studies in Africa, where a large
number of deaths, including pneumonia deaths, as mentioned, have
occurred. In addition, there was no consistency within Study O-23 in
that no imbalances were observed in non-fatal pneumonia
hospitalizations.

The next criterion is strength of association. In this particular case,
the strength is weak. The P-value in our, as well as in the FDA
analyses, is close to, or only slightly below .05. In addition, these
P-values do not take into account the multiplicity of the exploratory
analyses from which this finding stemmed.

The third criterion looks at specificity. The adverse event of interest,
pneumonia deaths, although relatively rare did not occur exclusively in
the vaccine group. Lower respiratory tract infection, in general, occurs
quite frequently in the study population. There are multiple alternative
etiologies for lower respiratory tract infections, including fatal
pneumonia.

The next criterion is relationship in time to vaccination. Less than
half of the events in the Rotarix group occurred within the zero to
30-day interval after vaccination, the time window in which one would
expect a vaccine-associated reaction. Among the seven cases that
occurred within that time frame, again, there was no clustering in time
as they were spread equally over the first month after vaccination.
Among the additional nine cases, the day of symptom onset ranged from 31
to 199 days after vaccination without temporal clustering.

The final criterion is biological plausibility. Although there are
several reports of respiratory symptoms among infants with rotavirus
infection, the existence of a rotavirus syndrome leading to lower
respiratory tract infections has not been established.

Based on these observations, our overall assessment is that the
currently available data do not suggest a causal relationship between
Rotarix and pneumonia deaths. However, GSK follows the conclusion of the
IDMC and further assessment is planned. These post-marketing plans will
be discussed by my colleague, Dr. Verstraeten, in a few moments.

The last part of the clinical trial data presentation is a review of
reactogenicity data. In the Integrated Summary of Safety, in the 8-day
period after each of the two vaccinations, similar percentage of infants
in the Rotarix group and the placebo group reported any intensity of
fever, cough and runny nose, diarrhea, vomiting, irritability,
fussiness, and loss of appetite.

Overall, reporting rates of Grade 3 were severe intensity solicited
symptoms in all groups was low, mostly below 5 percent. In the 8-day
period after each of the two vaccinations, similar percentages of
infants in the Rotarix and the placebo groups reported Grade 3 symptoms
for all outcomes. When considering individual studies included in the
ISS, the incidences of solicited adverse events were comparable between
vaccine and placebo groups in each study, irrespective of potency of
vaccine tested. As examples, solicited adverse events in studies
conducted in Europe, and the United States, and Canada will now be
presented.

In the Phase III Study O-36 conducted in Europe, reactogenicity data was
evaluated in a subset of approximately 1,400 subjects. Routine pediatric
vaccines used in Europe, combination DTAP, HepB, IPV/HIB, pneumococcal
conjugate, and meningococcal-C conjugate vaccines were co-administered.
The incidences of solicited adverse events of any intensity, and under
the Grade 3 intensity, were similar, and not statistically different in
the Rotarix and placebo groups.

Study O-05 was a Phase II dose ranging study conducted in the United
States and Canada. Over 500 infants were enrolled in this study, and
received either one of two Rotarix formulations which differed in virus
titer or placebo, concomitantly with routine recommended infant vaccines
used in the U.S. and Canada; specifically, DTaP, IPV/HIB, pneumococcal
conjugate, and HepB. In this study, the incidence of solicited adverse
events of any intensity and of Grade 3 intensity were comparable among
the Rotarix licensure potency group, and the placebo groups.

In summary, the safety data presented show that Rotarix is
well-tolerated. There is no increased risk of intussusception among
infants vaccinated with Rotarix compared to placebo. In single studies,
statistical differences in convulsions, pneumonia deaths, pneumonia
SAEs, and unsolicited bronchitis were observed. In all of the other
clinical trials, and in the Core Integrated Summary of Safety,
imbalances were not noted for convulsions or acute lower respiratory
tract infections.

GSK plans to monitor convulsions and acute lower respiratory tract
infections in the post-marketing setting, which will be discussed next
in the presentation.

Other serious adverse events, including deaths, intussusception,
bronchiolitis, pneumonia, and nervous system disorders were reported by
similar proportions of subjects in the Rotarix and placebo groups. There
is no increased reactogenicity following co-administration with routine
pediatric vaccines. The overall safety profile of Rotarix is similar to
placebo.

Now I\'d like to turn the podium over to my colleague, Dr. Thomas
Verstraeten, who\'s Director and head of Worldwide Safety for Vaccines
at GSK.

DR. VERSTRAETEN:  Thank you, Dr. Friedland, and good morning, everyone.

Before I joined GSK, I spent two years at the CDC\'s Vaccine Safety
branch, during which time I participated in the assessment of the
association between RotaShield and intussusception. I will present to
you today the post-licensure safety profile of a rotavirus vaccine
manufactured in my own country.

First, I will present a brief summary of the adverse events that have
been reported to us in the first two-and-a-half years since launch, with
some detailed attention to the reports of intussusception. Following
this, I will present to you an overview of the plans GSK has to monitor
the safety of Rotarix in the post-marketing setting worldwide, including
our plans to monitor intussusception, the effectiveness of Rotarix, and
some other events of interest.

In the first two-and-a-half years since the launch of Rotarix in Mexico,
the company has distributed over 12 million doses of the vaccine. The
majority of these, 11-1/2 million doses, have been distributed in Latin
America, of which most in Brazil. An additional .4 million doses have
been distributed in Europe, and the remaining doses in other parts of
the world.

In the same period, the company has received a total of 802 reports of
events that occurred following the administration of Rotarix. This
represents a reporting rate of 6.5 per 100,000 doses distributed. Note
that this rate is not unusual for a new vaccine.

Among the 802 reports, 323 referred to events considered to be serious.
The distribution by dose is also shown on this slide, suggesting a
slightly higher reporting rate for the first dose of the vaccine.

This table lists the three events most frequently reported as occurring
after Rotarix administration. It is not surprising to note the two
gastrointestinal events, diarrhea and vomiting, as the most frequently
reported ones, following this orally administered vaccine. To see
intussusception on the list of most frequently reported events is also
not surprising, given the large awareness that exists on the event
following the RotaShield experience. I will come back to the
intussusception reports in more detail later.

A total of seven fatal events have been reported in temporal association
with Rotarix. One fatality occurred following a severe thrombocytopenia
that was detected within hours of administration of Rotarix, and is,
therefore, not likely to be actually related to the vaccine.

Another fatality occurred as a complication of a rotavirus infection in
a child nine months old. The company received conflicting information
from the treating pediatrician and a relative on whether the child was
actually vaccinated against rotavirus or not.

A third fatality occurred in Kenya as a complication of gastroenteritis
caused by adenovirus.

Finally, the company has received four reports of fatalities following
intussusception in Brazil. None of these reports reached us from the
treating physician directly, but either through the Brazilian Ministry
of Health, a consumer, or a sales representative. For two of these, the
company, nor the Ministry of Health could confirm that the cases
actually occurred. The information on the other two cases is very
limited, and does not allow us to make a sound assessment of their
potential relationship to Rotarix.

The time to onset was reported in only one of these four Brazilian
cases. In this case, symptoms of intussusception would have started
within six days after vaccination.

Let\'s now look in more detail at the reports of intussusception and
temporal relationship to Rotarix. Out of the 131 reports of
intussusception made spontaneously to the company between January 2005,
and July 2007, 79 could be considered as confirmed when applying the
Brighton criteria. Further analysis will focus on these 79 cases.

The corresponding reporting rate is .64 cases per 100,000 doses
distributed. The time to onset between vaccination and onset of symptoms
varied from zero to 244 days, with a median of 15 days. The age at which
the intussusception occurred varied from two to thirteen months, with a
median of five months. There were no fatalities among these confirmed
cases. As observed for all adverse events, there were slightly more
reports following the first dose compared to the second dose of Rotarix.

To assess whether the number of reports received reflects the natural
background rate of intussusception in the countries where the reports
originated from, or potentially reflects an increased risk following
Rotarix, we conducted an observed expected analysis. In this analysis,
the number of confirmed cases occurring within 30 days of Rotarix is
compared to the number of cases expected to occur by coincidence taking
into account the known background rate in the regions of interest, the
expected age distribution of intussusception, and the age at which
Rotarix is expected to be administered.

Given that the reporting rates in Latin America where the majority of
the vaccine has been distributed, thus far, may be lower than in Europe,
we have applied this analysis both on a global level, and on a
Europe-only level.

From this table we can see that the global number of cases we observed
through passive reporting to be 58 within 30 days of Rotarix. That\'s
the number on this cell, and 40 within seven days of Rotarix. The number
of cases expected to occur according to our most recent estimations is
496, and 116 for the same respective 30 and seven-day intervals.

This comparison suggests that the number of cases that have been
reported to the company on a worldwide basis does not exceed the number
expected to occur by coincidence after vaccination.

When limiting the analysis now to Europe, we can see that the number of
cases we observed through passive reporting to be eight within 30 days
after Rotarix administration, and four within the seven-day interval
after Rotarix. The number of cases expected to occur for the same
respective intervals is 19 and five. We did see that also in Europe the
number of cases reported is below the number of cases expected.

Note also that the difference between the numbers observed and those
expected is smaller in the Europe-only analysis, suggesting that
reporting is probably more complete at the European level, and less
complete at the Latin American level.

Now, we have also conducted a sensitivity analysis in which we assumed
that the number of doses administered is only 75 percent of dose
distributed, and the number of cases reported is only 75 percent of dose
that actually occurred. These are the same assumptions that were
proposed as the most realistic assumptions in a recent ACIP review of
intussusception cases after RotaTeq administration in the United States.

In this sensitivity analysis, we note that the number of cases reported
is still below those expected, except for the Europe-only analysis of
the seven-day interval, where the number of cases reported is
extrapolated to be six, compared to four cases expected. Corresponding
reporting ratio is 1.7 with 95 percent intervals largely overlapping
one, suggesting that this difference is not significant.

Besides intussusception, we also pay special attention to any reports of
the events of interest that have been previously highlighted in a
clinical safety discussion, and are listed again on this table. As can
be noted, few, or even no reports have been made for these events, and
the estimated reporting rates are, therefore, very low, suggesting no
new safety concerns from this data.

I would now like to present the additional plans GSK has put in place to
monitor the safety and effectiveness of Rotarix in the post-licensure
setting. These plans include various Phase IV clinical trials, several
observational studies, as well as some enhancements to the classic
pharmacovigilance activities. I will go through these individually. It
should be noted that several of these activities have already started
following licensure in Europe or elsewhere.

In addition to the many clinical trials presented to you by Dr.
Friedland, GSK is currently conducting a clinical trial to assess the
frequency of transmission of the human rotavirus vaccine between twins.
For each twin, one brother or sister has been randomized to receive the
vaccine, and the other the placebo.

GSK is also conducting a study in South Africa to assess the safety and
immunogenicity of Rotarix in infants who are HIV positive. This is the
same study that was reviewed by the IDMC, as mentioned by Dr. Friedland,
and which, in combination with an efficacy study, showed no imbalance
for the pneumonia deaths. Finally, a study is ongoing in Europe to
assess the safety and immunogenicity of Rotarix in infants born
prematurely.

In addition to these clinical trials, GSK has put, or is putting in
place, a number of observational studies to further monitor the safety
and effectiveness of Rotarix in the real-life setting. GSK intends to
conduct an observational study in the United States to monitor the
safety of Rotarix in relationship to intussusception, Kawasaki disease,
hospitalizations for acute lower respiratory tract infections, and
convulsions. This study will be powered to detect an increased risk of
intussusception due to the vaccine of 2.5 or greater, with 80 percent
probability. All deaths that occur in this study will also be reported
in an expedited fashion to the FDA and the CDC.

The design of this study, as well as the site where the study will take
place are currently under discussion with the FDA and the CDC. GSK will
assess the feasibility of conducting the study outside the existing
vaccine safety datalink network. Sites will be considered that have
access to a sufficiently large population, are capable of linking health
records with reliable capture of vaccination, and, of course, all
outcomes of interest. These sites should have access to medical records
for review, and preferably have a track record in performing vaccine
safety research.

You will recall that Dr. Friedland showed you that the upper limit of
the relative risk of intussusception observed in our large Phase III
trial was 2.4; whereas, we and others believe that this is very
reassuring, we wanted to evaluate whether we could reassess this
relative risk in the real-life setting, and achieve an upper limit of
the confidence interval that is even lower. We soon realized that this
would only be feasible in a large country that uses our vaccine on a
large scale.

In Mexico, a large study has just started that intends to follow more
than one million children vaccinated with Rotarix to evaluate their risk
for intussusception in the first month after vaccination. This study is
run within one of the country\'s largest healthcare systems called the
Instituto Mexico de la Seguridad Social, or IMSS. This system covers
approximately 40 million individuals in birth cohorts of 575,000
children. When combining several birth cohorts we will have over 80
percent power to exclude a relative risk of 2.7 for intussusception
following within 30 days of the first dose of Rotarix, and over 80
percent power to exclude a relative risk of 1.6 of intussusception
occurring within 30 days of the second dose of Rotarix.

Besides intussusception, this study also has pneumonia deaths as an
additional outcome. All deaths that may be related to a lower
respiratory tract infection are actively captured in this study. For
each of these, standardized information is being obtained, and then
submitted to an adjudication committee for review.

Finally, GSK is currently assessing the feasibility of studying
hospitalizations for lower respiratory tract infections as an additional
outcome in this study. In addition to these two observational studies,
GSK has initiated, or is involved in a number of other observational
studies which are listed here by outcome of interest.

Surveillance for intussusception conducted at the request of GSK, and in
collaboration with Merck and Sanofi Pasteur has just been concluded in
Germany, and is now taking place in the United Kingdom. The objective of
this surveillance is primarily to obtain reliable background rates on
intussusception in Europe.

Three studies to assess the effectiveness of Rotarix in preventing
severe rotavirus gastroenteritis in the real-life setting are about to
start in Panama, in Belgium, and in Singapore.

Finally, GSK has partnered with the European Rotavirus Surveillance
Network, and again with Merck and Sanofi Pasteur to monitor the
circulating rotavirus strains in Europe, with the objective of
identifying any shifts as a consequence of vaccination.

Last, but not least, we are, and we will be very closely following all
adverse events reports that are made to us spontaneously. GSK has a
worldwide network of safety personnel to receive such reports. All cases
of intussusception are actively followed to obtain as much information
as possible. We intend to forward all these, and additional reports, in
a more expedited fashion than is strictly required to the FDA.

We will also continue to perform the types of cumulative analysis, such
as the observed expected analysis, and engage in regular discussions
with the FDA and the CDC on the results of these analyses.

In conclusion, I have illustrated to you how the currently available
information from spontaneous reporting systems does not suggest any
increased risk for intussusception following Rotarix, nor do these data
suggest any new safety signal related to other events of interest. In
addition, you\'ve heard how GSK has put in place a comprehensive
pharmacovigilance plan to further monitor the safety and the
effectiveness of Rotarix. Thank you.

DR. KAHN:  I have some very brief concluding remarks. To summarize,
Rotarix, GSK\'s attenuated human rotavirus vaccine induces protective
immunity against RVGE, as demonstrated in two pivotal trials conducted
in Europe and Latin America. In both studies, robust efficacy against
RVGE was consistently demonstrated against severe disease, any disease,
hospitalizations, and medically attended RV disease.

There was broad efficacy against disease caused by all the common
circulating human serotypes. And efficacy was demonstrated against
severe gastroenteritis, regardless of the etiology, indicating that RV
is the leading cause of gastroenteritis worldwide. Efficacy was evident
early post-dose one, and was persistent through at least two years.

Importantly, Rotarix may be concomitantly administered with U.S.
licensed pediatric vaccines without interference. Rotarix is supported
by extensive safety database from clinical trials, and post-marketing
experience, which provide a high level of confidence in the safety of
the vaccine.

Rotarix was well-tolerated in clinical trials with no increased
reactogenicity following co-administration with routine pediatric
vaccines. The safety profile was clinically acceptable with no safety
signal related to intussusception according to the pre-specified
criteria. There will be active monitoring of adverse events of special
interest in the post-marketing plans. Post-marketing experience is
already substantial with relicensure already in over 100 countries, and
over 12 million doses distributed, so GSK is able to use the worldwide
availability to study outcomes of interest. And, to date, there\'s been
no pattern or frequency of reporting to suggest an increased risk of
intussusception, and no new safety signal determined.

Extensive global and U.S. post-marketing activities are ongoing or
planned, and they include prospective clinical trials, observational
studies, and enhanced pharmacovigilance. These approaches will address
not only intussusception and other potential outcomes, but also vaccine
effectiveness, vaccine transmission, and use in immunocompromised and
pre-term infants.

Rotavirus is a significant cause of childhood morbidity in the United
States. The data on disease burden worldwide demonstrates the importance
of vaccination as the only effective preventive strategy. Rotarix
confers broad and robust protection against RVGE during the first two
years of life, and offers an acceptable safety and reactogenicity
profile; thus, the risk-benefit ratio for Rotarix is favorable for the
intended population. And that concludes GSK\'s presentation. Thanks.

DR. MODLIN:  Thank you, Dr. Kahn. I\'d like to thank both you and your
colleagues for presenting an awful lot of information, and staying on
time. I think we\'ve earned a break. We will have an opportunity for
questions from members of the Committee and from the floor, ample
opportunity, a little bit later on. But, for now, why don\'t we go ahead
and take our break, and we\'ll see everybody back promptly at a quarter
of 11.

(Whereupon, the proceedings went off the record at 10:19:24 a.m., and
went back on the record at 10:46:05 a.m.)

DR. MODLIN:  The next portion of the meeting will be the FDA
presentation. And, Dr. Rosenthal, it looks like you\'re the man for the
entire presentation.

DR. ROSENTHAL:  Okay. Thank you, Dr. Modlin. Welcome back, everyone.

I will now discuss findings of FDA\'s clinical review of Rotarix. For
this talk, I will first present the clinical overview of the Rotarix
BLA, and overviews of efficacy of the two pivotal Phase III studies,
safety in terms of serious adverse events, and co-administration of
Rotarix with routine childhood vaccines. I will conclude the talk with
an overview of the applicant\'s post-marketing commitments, and after
lunch present again FDA\'s questions to the Committee.

Complete results of 11 clinical studies were submitted to the BLA. These
included the two pivotal Phase III efficacy studies, Rota O-23 and Rota
O-36, two supportive Phase II efficacy studies, Rota O-04 and Rota O-06,
one Phase III concomitant childhood vaccination study, Rota O-60, and
one Phase III lot-to-lot consistency study, Rota O-33. Safety and
anti-RV IGA immunogenicity were evaluated in all studies, with Study
Rota O-23 also considered a pivotal safety study for intussusception.
All studies were designed and conducted in a randomized double blind and
placebo-controlled manner.

Please refer to your handout for a better view of this slide. This slide
provides a tabular summary of the 11 BLA studies. Most of the studies
were conducted in Latin America, Europe, and Asia. Two of the studies,
Rota O-05 and Rota O-60, were conducted in the U.S. Rota O-23 and Rota
O-36, the two pivotal studies, enrolled and vaccinated the largest
numbers of subjects.

In nine of the studies, including all Phase III studies, Rotarix
vaccination at the proposed licensure potency of greater than and equal
to 10 to the 6^th^ CCID 50 was evaluated. The mean age at first dose was
similar across studies, 8.3 to 8.7 weeks, with the exception of Rota
O-07, Rota O-14, and Rota O-36, in which the mean ages were three to
five weeks older.

Vaccine doses were separated by one month, two months, or either one or
two months. Significant imbalances in male-to-female ratios were not
observed. Ethnicity in each study reflected the expected ethnic
composition of the participating countries.

Finally, co-administration of routine infant vaccines was allowed in
nine of the studies. Of note, only one study, Rota O-14, allowed
concomitant administration of OPV with Rotarix.

From the BLA studies, over 40,000 Rotarix, and over 34,000 placebo
recipients received at least one study dose with over 78,000 Rotarix,
and 67,000 placebo doses given. Over 37,000 infants received Rotarix at
the potency formulation in storage conditions intended for commercial
use, namely, greater than or equal to 10 to the 6.0 CCID 50 per dose
lyophilized buffered and stored at 2 to 8 degrees Celsius.

Across all studies, between 90.4 to 99 percent of Rotarix and between
90.3 and 100 percent of placebo recipients received two doses.

I would now like to discuss the efficacy of Rotarix based on the pivotal
studies. Vaccine efficacy was measured in two pivotal Phase III studies,
Rota O-23, conducted in Latin America, and Rota O-36, conducted in
Europe. Year one, according to protocol or ATP efficacy cohort was used
for the primary efficacy analysis in each study. Criteria for inclusion
in the ATP cohort included vaccination with two doses of Rotarix, or
placebo, no rotavirus other than the vaccine strain in GE stool samples
between dose one and two weeks post dose two, and entry into the year
one efficacy follow-up period.

This slide summarizes the total number of subjects included in the year
one ATP efficacy cohort for each study. A total of 17,867 and 3,874
subjects were included in Rota O-23, and Rota O-36, respectively.
Demographic data from the year one ATP cohort of each study are
summarized in this slide.

Rota O-23 was conducted in 11 Latin American countries, while Rota O-36
was conducted in six European countries. The mean and median ages at
dose one and dose two were lower in Rota O-23, compared to Rota O-36.
The mean and median duration of follow-up was eight months in Rota O-23,
compared to six months in Rota O-36. Male-to-female ratios were similar
in both studies. Most of the study subjects in Rota O-23 were Hispanic,
compared to white Caucasian in Rota O-36.

For inclusion into either study, subjects needed to be free of obvious
health problems, and their parents or guardians needed to be able to
comply with study procedures. The age range at dose one was similar
between studies. In Rota O-036, an additional criterion required that
the birth weight of subjects be greater than 2,000 grams.

Exclusion criteria common to both studies included a history of chronic
gastrointestinal disease, or another serious medical condition, an
immunocompromised condition, including HIV infection, and being treated
for greater than 14 days with immuno-suppressive therapy.

In addition, there were no feeding restrictions in either study.
Co-administration of infant vaccines was allowed in Rota-23, except OPV,
which was administered two weeks apart from study vaccination. The
choice of vaccines was determined according to national recommendations
in each country, and included whole cell DTP, DTaP, Hepatitis B, IPV,
OPV, and MMR vaccines. Co-administration of infant vaccines was also
allowed in Rota O-36. Infanrix HexaA, DTaP, Hib, HepB, IPV combination
vaccine was given in the Czech Republic, Finland, Germany, Italy, and
Spain. Infanrix Hexa, and Infanrix polio Hib, DTaP, Hib, IPV combination
vaccine was given in France. In addition, MeningaTeq, Meninge C
conjugate vaccine was given in Spain, while Prevnar and pneumococcal
seven-valent conjugate vaccine was administered in France and Germany.

In Rota O-23, the primary efficacy objective was to determine if two
doses of Rotarix could prevent severe wild-type rotavirus
gastroenteritis during the year one efficacy period, defined as the
period from two weeks post-dose two, until one year of age. Secondary
efficacy objectives were to determine year one efficacy of Rotarix
against severe G1 wild-type rotavirus gastroenteritis, severe non-G1
wild-type GE, both pooled and by individual type, and severe rotavirus
GE using the Vesikari scale case definition, which I\'ll explain
shortly.

In Rota O-36, the primary efficacy objective was to determine the
efficacy of two doses of Rotarix given with childhood vaccines against
any wild-type rotavirus GE during the year one efficacy period defined
as the period from two weeks post-dose two until the end of the first
rotavirus season. Secondary efficacy objectives were to determine year
one efficacy of Rotarix against severe wild-type rotavirus GE, and any
severe G1 wild-type rotavirus GE, any and severe non-G1 wild-type
rotavirus GE, hospitalization for rotavirus GE, and any medical
attention for rotavirus GE.

Following case definitions for diarrhea, vomiting, and GE were applied
to both studies. Diarrhea was defined as greater than or equal to three
looser than normal stools within a day. Vomiting was defined as greater
or equal to one episode of forceful emptying of partially digested
stomach contents greater than or equal to one hour after feeding within
a day. GE was defined as diarrhea with or without vomiting. A definition
of medical attention used in Rota O-36 was any medical provider contact,
advice, or visit, or any emergency room contact or visit, or
hospitalization.

Rotavirus GE was defined as an episode of GE in which rotavirus, other
than the vaccine strain, was identified in a stool sample collected no
later than seven days after GE symptom onset. In Rota O-23, the main
definition of severe rotavirus GE was an episode of rotavirus GE
requiring hospitalization, and/or rehydration therapy equivalent to WHO
Plan B or C in a medical facility. In Rota O-36, the main definition of
severe rotavirus GE was defined as an episode of rotavirus GE with a
Vesikari score of greater than or equal to 11 points. This Vesikari
scale case definition was also used for one secondary endpoint in Rota
O-23, mentioned previously.

The Vesikari scale is based on seven parameters, duration of diarrhea,
maximum number of diarrheal stools for 24 hours, duration of vomiting,
maximum episodes of vomiting for 24 hours, maximum temperature, degree
of dehydration, and treatment. Points are assigned based on the severity
in each parameter. A maximum of 20 points can be scored per GE episode.

In both studies, rotavirus GE cases were ascertained through active
surveillance. In Rota O-23, hospitals and other medical facilities in
the study areas were contacted at least twice a week. Subjects were also
contacted or visited at least every four days to identify severe cases
not picked up by routine medical facility surveillance. In Rota O-36,
subjects were contacted weekly by telephone from week one post-dose one
until the end of the first rotavirus season, which was the end of May
2005.

Diary cards were distributed to parents to collect temperature, stool,
NMSS data. Parents were instructed to collect, label, store, and submit
stool samples for each GE episode. All collected stools were tested for
rotavirus antigen by ELISA at the applicant\'s laboratory in Belgium.
Rotavirus antigen positive stools were further analyzed for G and P type
by RTPCR followed by reverse hybridization assay, or optional sequencing
at the Delft Diagnostic Laboratory in the Netherlands.

Vaccine efficacy was calculated using the formulation shown in this
slide; that is, one minus the relative risk, or one minus the ratio of
the attack rate in the Rotarix group over the attack rate in the placebo
group. The attack rate in each group was calculated by dividing the
number of subjects reporting at least one episode of the rotavirus GE
endpoint of interest, divided by the total number of subjects in that
group.

This slide summarizes year one vaccine efficacy results against any
rotavirus GE, and against severe rotavirus GE for the ATP cohort in Rota
O-36. Efficacy against any rotavirus GE was 87.1 percent with a 94
percent confidence interval of 79.6 to 92.1 percent. Against severe
rotavirus GE, efficacy was 95.8 percent with a 95 confidence interval of
89.6 to 98.7 percent.

Vaccine efficacy results against any rotavirus GE by G type are
summarized in this slide. Rotarix demonstrated statistically significant
efficacy against G1, G3, G4, and G9 types. Of note, these types were
associated with the P8 type. Although efficacy against G2 was 62
percent, the 95 percent confidence interval was very wide and included
zero.

Among the G2 cases, the P type of one case, a placebo subject, could not
be characterized, while the rest were associated with the P4 type. While
all non-G1 types were pooled, efficacy was 79.3 percent with a 95
percent confidence interval of 64.6 to 88.4 percent.

Efficacy results against severe rotavirus GE by G type are summarized in
this slide. Similar to results from the previous slide, Rotarix
demonstrated statistically significant efficacy against severe G1, G3,
G4, G9 gastroenteritis and non-G1 gastroenteritis when pooled. However,
the efficacy estimate against severe G2 gastroenteritis did not reach
statistical significance, as can be seen by the wide 95 percent
confidence interval. All efficacy estimates against severe GE were
higher than against any GE that was shown in the previous slide. Rotarix
also demonstrated an efficacy of 100 percent against hospitalization for
rotavirus GE, and 91.8 percent against any medical attention for
rotavirus GE is shown here.

Year one efficacy results against severe rotavirus GE for the ATP cohort
in Rota O-23 are presented here. Efficacy against severe rotavirus GE
using the main case definition was 84.7 percent, with a 95 percent
confidence interval of 71.7 to 92.4 percent. When the case definition
based on the Vesikari scale was used, efficacy was nearly identical at
84.8 percent with similar 95 percent confidence interval.

Vaccine efficacy results against severe rotavirus GE by G type are
summarized on this slide. Rotarix demonstrated statistically significant
efficacy against G1, G3, and G9 types. The efficacy estimate against
severe G2 gastroenteritis was 41 percent with a wide 95 percent
confidence interval that included zero. Efficacy against severe G4 GE
was not calculated due to the limited number of cases. When all non-G1
types were pooled, efficacy was 75.4 percent with a 95 percent
confidence interval of 50, then 89 percent. All G1, G3, G4, and G9 types
were associated with the P8 type, while all G2 types were associated
with the P4 types.

In calculating efficacy, FDA considers it more appropriate to use the
time to first episode analysis than using attack rates in each group.
This is because the time to event approach accounts for differential
follow-up of subjects, while the latter approach does not. FDA is,
therefore, inclined to place more importance on efficacy results based
on the Cox Proportional Hazards Model.

Using this model, the applicant calculated efficacy estimates of 84.8
percent against severe rotavirus GE in Rota O-23, and 87.4 percent
against any rotavirus GE in Rota O-36. These estimates, along with their
95 confidence intervals, were similar to corresponding estimates using
attack rates that were previously mentioned.

Next, I will present safety findings of Rotarix, first by discussing the
intussusception study in Rota O-23. The primary safety objective in Rota
O-23 was to determine the safety of Rotarix with respect to
intussusception, abbreviated as IS, within 31 days, that is day zero to
30 after each dose. The primary safety endpoint was the occurrence of
definite IS within 31 days after each dose. The Brighton Collaboration
IS Working Group case definition for definite IS was used.

This slide summarizes the Brighton IS Working Group case definition. A
case of IS was classified as definite if demonstration of intestinal
invagination surgically and/or radiologically could be achieved.
Definite IS could also be defined by demonstration of intra abdominal
mass by ultrasound with specific characteristic features, such as target
or donut sign that could be reduced by hydrostatic enema, or by
demonstration of intestinal invagination on autopsy.

To capture all IS events, IS cases were reported irrespective of whether
they met the Brighton case definition for definite IS. A Clinical Events
Review Committee, or CEC performed blinded objective reviews of all IS
cases occurring from dose one to visit three. Visit three was
approximately one to two months post-dose two, or two to four months
post-dose one. The CEC was made up of physicians acting as consultants
who were not study investigators, or medical care providers to the study
subjects.

Rota O-23 was specifically designed and powered to assess the risk of IS
following Rotarix vaccination, with over 31,000 subjects in both the
Rotarix and placebo groups receiving at least one study dose. The
original criterion for meeting the primary safety objective was an upper
limit of the 90 percent confidence interval of the IS risk difference,
Rotarix minus placebo, less than two cases for 10,000 subjects. This
criterion was based on the consensus estimate of the RotaShield
attributable risk of one case for 10,000 vaccinees.

RotaShield was the first U.S. licensed rotavirus vaccine that was
subsequently withdrawn from the market due to the development of an
unexpected association with IS.

Nine months after study initiation, the blinded overall IS incident rate
31 days post-vaccination was calculated as two to four cases per 10,000.
This rate exceeded the anticipated rate of 0.3 per 10,000 in the placebo
group, and, therefore, the upper limit of the 90 percent confidence
interval exceeded two per 10,000.

In addition, a background IS incident rate of 5 per 10,000 was
calculated from a separate concurrent prospective multi-center
epidemiologic study in the same countries involving children less than
two years of age who were not vaccinated with Rotarix.

The higher than expected IS incidence rate led to criteria for meeting
the primary safety objective being revised to the following. One, the
upper limit of the 95 percent confidence interval of the risk difference
for definite IS to be less than 6 per 10,000. This was based on an IS
incident of 3 to 5 per 10,000 in the placebo group, and 30,000 subjects
in each group. And, two, the lower limit to be less than zero. The study
had greater than 86 percent power to meet the primary objective if the
risk difference was truly zero.

This table summarizes the analysis of definite IS diagnosed within 31
days post vaccination. After any dose, six cases occurred in the Rotarix
group, compared to seven in the placebo group. The risk difference was
negative 0.32 per 10,000, with the upper and lower limits of the 95
percent confidence interval being 2.18, and negative 2.91 respectively.
The relative risk was 0.85, with a 95 percent confidence interval that
included one.

The risk differences after dose one or dose two also favored the Rotarix
group, as demonstrated by the negative values, with the upper limits
being less than 6 per 10,000, and the lower limits being less than zero.
Based on this data, the primary safety objective was met.

The applicant noted that when the original criterion for meeting the
primary safety objective was used, the objective was still met as the
upper limit of the 90 percent confidence interval was 1.71 per 10,000,
less than the required two per 10,000. In addition, 25 definite IS cases
were diagnosed from dose one until visit three, nine in the Rotarix
group, and 16 in the placebo group. The risk difference was negative
2.23 per 10,000, with a 95 percent confidence interval that included
zero. The relative risk was 0.56, with a 95 percent confidence interval
that included one.

Data just presented for definite IS within 31 days post vaccination was
based on the date of IS diagnosis. However, one definite IS case in the
Rotarix group had onset on day 29, but was diagnosed on day 31. From
FDA\'s analysis of IS risk within 31 days after any dose using onset,
rather than diagnostic date, there were seven cases in each group. The
risk difference was very small with the upper and lower limits of the 95
percent confidence interval still meeting the primary safety objective.
The relative risk was close to 1.0.

Numbers of definite IS cases by onset interval after each dose are
tabulated in this table. These figures do not indicate an apparent
pattern of IS occurrence during day zero to 30, or beyond day 30 after
either dose one, or dose two.

Numbers of definite IS cases during days three to seven, and days three
to fourteen after each dose are tabulated in this table. These intervals
were chosen because the risk of IS appeared to be increased among
RotaShield vaccine recipients during days three to fourteen post-dose
one, and days three to seven post-dose two. Of note, no cases occurred
during either interval after dose one. Numbers of cases in each group
after dose two were also small; therefore, one cannot rule out that they
occurred during these intervals by chance alone.

As mentioned previously, criteria to meet this primary safety objective
in Rota O-23 was revised during the conduct of the study. Such changes
while the trial is ongoing could potentially compromise the integrity of
the study. Because the study wasn\'t performed under US IND, the FDA
wasn\'t discussing this with the applicant at the time that this
happened. The Agency asked for more detailed information on whether or
not proper procedure was followed, and the applicant responded, and FDA
was satisfied with that response. So I\'ll now present safety data on
serious adverse events.

For safety analysis, integrated safety summary, or ISS analysis, were
conducted. These analyses were based on total vaccinated cohort data
from 10 studies, the exception being Rota O-60, and involved pooling of
subjects into Core ISS and Supplementary ISS groups. The Core ISS group
was composed of pooled subjects who received Rotarix at a potency of
greater than or equal to 10 to the 6 CCID 50 per dose, or placebo, while
the Supplementary ISS group was made up of pooled subjects who received
Rotarix at a potency of less than 10 to the 6 CCID 50 per dose or
placebo.

In the Core ISS analysis group, over 36,755 Rotarix, and 34,454 placebo
subjects were pooled from eight studies. In the Supplementary ISS
analysis group, 3,076 Rotarix, and 1,613 placebo subjects were combined
from five studies. For studies included in both ISS analysis groups, the
same numbers of placebo subjects were used.

ISS analysis endpoints included both fatal and non-fatal SAEs that
occurred from day zero to 30 post vaccination, and during the entire
length of the studies. SAEs were coded using the Medical Dictionary for
Regulatory Activities, or MedDRA. For each MedDRA preferred term, or PT,
the relative risk defined as the rate in the Rotarix group divided by
the rate in the placebo group along with a 95 percent confidence
interval were calculated. Relative risk estimates were adjusted for
study effect, and a multiplicity adjustment was not performed.

SAE analysis for pivotal studies Rota O-23 and Rota O-36 will be
presented. In both studies, SAEs were recorded throughout the study
periods, approximately two years each in duration, and risk differences,
Rotarix minus placebo, and 95 percent confidence intervals were
calculated for each MedDRA PT. For Rota O-23, over 31,000 Rotarix and
placebo subjects were included in the safety analysis, while for Rota
O-36, 2,646 Rotarix, and 1,348 placebo subjects were included.

A total of 128 post-vaccination deaths were reported from 10 studies
included in the ISS analysis. In addition, there were no deaths in Rota
O-60. In the Core ISS group, 68 deaths were reported, with 62 of them
occurring in Rota O-23. Five deaths were reported in the Supplementary
ISS group, and 55 deaths were reported in the placebo group. Similar to
the Core ISS group, most of the deaths in the placebo group occurred in
Rota O-23.

In the Core ISS group, 53 deaths were reported from day zero to 30
post-dose, 33 were in the Rotarix group, and 20 were in the placebo
group. The relative risk was 1.64 with a 95 percent confidence interval
of 0.92 to 3.02. Notable imbalances were not observed for each MedDRA
PT. The PT pneumonia was the most common death code, with seven deaths
in the Rotarix group, compared to five in the placebo group. The
relative risk was not statistically significant.

In the Core ISS group, 118 deaths were reported throughout the study
periods, 68 and 50 in the Rotarix and placebo groups respectively.
Again, PT pneumonia was the most common death code with 19 in the
Rotarix, and 10 in the placebo groups. Relative risk estimates were not
statistically significant.

In the Supplementary ISS group, seven deaths were reported from days
zero to 30 post dose, three in the Rotarix group, and four in the
placebo group. The relative risk was 0.38. Eleven deaths were reported
throughout the study periods, five in the Rotarix group, and six in the
placebo group. The relative risk was 0.42.

During Rota O-23, 111 post-vaccination deaths were reported, 62 or .2
percent were in the Rotarix group, and 49 or .16 percent were in the
placebo group. Ninety-nine of the 111 deaths were reported from dose one
to visit three, 56 in the Rotarix group, compared to 43 in the placebo
group. The risk difference was 4.05 per 10,000, with a 95 percent
confidence interval including zero.

When looking at the deaths within 31 days post-dose, 22 Rotarix versus
11 placebo deaths occurred post-dose one, with a risk difference o 3.46
per 10,000. Post-dose two, there were two Rotarix, compared to five
placebo deaths for a risk difference of negative 1.02 per 10,000, 95
percent confidence intervals, for both risk difference estimates
included zero.

Among the 99 deaths reported from dose one to visit three, PT pneumonia
was reported significantly more in the Rotarix group than the placebo
group, 14 versus 5, risk difference of 2.84 per 10,000, P value of 0.04.
Seven of these pneumonia deaths had symptom onset within 31 days post
dose, five in the Rotarix group, versus two in the placebo group.
Because the etiologic pathogen was not recovered in all
pneumonia-related deaths, the applicant conducted an ad hoc analysis by
combining PTs, pneumonia, bronchopneumonia, and CMV pneumonia.

After combining, the number of deaths remained higher in the Rotarix,
with a risk difference of 3.15 per 10,000. However, the P value was
0.054. Within 31 days post-dose, there were seven Rotarix, compared to
three placebo deaths. There appeared to be no clear temporal association
of pneumonia-related deaths by week of onset.

For the ad hoc pneumonia deaths analysis mentioned in the previous
slide, the exact P value of the risk difference calculated by FDA
differed from that calculated by the applicant. To reiterate, 16
combined pneumonia-related deaths occurred in the Rotarix group,
compared to six in the placebo group from dose one to visit three, with
a risk difference of 3.15 per 10,000, and the applicant\'s P value of
0.054. However, FDA calculated P values of 0.0345 and 0.0354 using two
different statistical methodologies.

In the Core ISS group, a total of 1,286 subjects reported at least one
SAE, fatal or non-fatal, from day zero to 30 post-dose, 1.71 percent of
subjects in the Rotarix group, compared to 1.91 percent in the placebo
group for a relative risk of 0.90. Rates of PTs, diarrhea,
gastroenteritis, and dehydration were significantly less in the Rotarix
group, while rates of PTs, pneumonia and convulsions, were the same or
very similar between groups. Throughout the study periods, 4,519
subjects reported at least one SAE, with significantly less subjects in
the Rotarix group, compared to the placebo group, as reflected by the
relative risk of 0.89, and 95 percent confidence interval of 0.84 to
0.94. Results of MedDRA PT analysis were similar to those observed from
day zero to 30.

When looking at intussusception in the Core ISS group, among cases of IS
with onsets from days zero to 30 post-dose, nine occurred in the Rotarix
group, compared to seven in the placebo group. The relative risk was
1.23, but not statistically significant. These figures included definite
IS cases in the Rota O-23 IS study previously discussed. Of note, no
cases had onsets from day zero to 14 post-dose one. Of the IS cases with
onset throughout the study periods, 16 were reported in the Rotarix
group, compared to 22 in the placebo group, for a relative risk of 0.69.

In the Supplementary ISS group, only one IS case occurred from day zero
to 30 post-dose. That in the Rotarix subjects, six days post-dose one.
Throughout the study periods, IS was reported in two Rotarix subjects
versus one placebo subject.

In Rota O-23, significantly less Rotarix than placebo recipients
reported at least one SAE from dose to visit three, 2.93 percent versus
3.32 percent, with a risk difference of negative 38.8 per 10,000, and a
P value of 0.005. PTs diarrhea, vomiting, gastroenteritis, and
dehydration were also reported significantly less in the Rotarix group.
No notable imbalances between groups for pooled pneumonia-related PTs
were observed from dose one to visit three, or for hospitalizations for
pneumonia-related PTs during this period. In Rota O-23, the PT
convulsions was reported significantly more in the Rotarix group than
the placebo group, 16 versus 6, risk difference of 3.15 per 10,000, P
value of 0.034.

The applicant performed an ad hoc analysis by combining PTs convulsions,
epilepsy, grand mal seizures, tonic convulsions, and status epilepticus.
After pooling, the number of SAEs remained higher in the Rotarix group,
with a risk difference of 2.51 per 10,000, but a P value that was no
longer statistically significant.

Within 31 days post-dose, there were seven Rotarix compared to nine
placebo convulsion-related SAEs, with no notable imbalances either
post-dose one, or post-dose two.

In Rota O-36, less Rotarix than placebo recipients, 11 percent versus 13
percent reported at least one SAE from dose one to visit seven, visit
seven being the end of the second rotavirus season. During this
interval, PTs gastroenteritis and gastroenteritis rotavirus were
reported significantly less in the Rotarix group. From dose one to visit
seven, PT pneumonia was reported significantly more in the Rotarix
group, .9 percent versus .3 percent, with a risk difference of 61 per
10,000, and a P value of 0.029. However, over half of the cases occurred
after visit five, the end of the first rotavirus season. From day zero
to thirty post-dose, only one case in a Rotarix subject was reported.

To determine whether an imbalance in non-febrile convulsion-related PTs
was present, FDA performed an analysis by combining subjects in each
group who were coded for the PTs convulsions, epilepsy, infantile
spasms, myoclonus, and partial seizures. When combined, the frequency of
convulsion-related PTs from day zero to 30 post-vaccination was similar
between groups.

Similarly, to determine whether an imbalance in pneumonia-related PTs
was present, FDA performed an analysis by combining subjects in each
group who were coded for the PTs pneumonia, bronchopneumonia, low bar
pneumonia, and pneumonia viral. When pooled, the frequency of
pneumonia-related PTs from dose one to visit seven was higher in the
Rotarix group, 1.2 percent versus 0.5 percent. However, from day zero to
thirty post-dose, only two Rotarix subjects reported a pneumonia-related
PT compared to zero placebo subjects.

Now I would like to briefly discuss Kawasaki disease. At the ACIP
meeting on June 28^th^, 2007, FDA presented data on the occurrence of
Kawasaki disease, or KD, within 30 days after RotaTeq vaccination during
Phase III clinical trials. Five out of 36,150 RotaTeq subjects developed
KD, compared to one out of 35,536 placebo subjects. The unadjusted
relative risk was 4.9, with a 95 percent confidence interval of 0.6 to
239.1. The causal relationship between RotaTeq and KD was not
established, although post-licensure studies are ongoing.

Upon request by FDA, the applicant submitted an analysis report of KD
following Rotarix on July 20^th^, 2007. This report included all cases
of KD from completed and ongoing clinical trials. An information
amendment in response to FDA comments was submitted on February 1^st^,
2008. A total of 27 unblinded cases of KD were reported in Rotarix
clinical trials. In Rota O-23, KD was reported in a two-year old
Hispanic female Rotarix subject from Mexico, with onset 19 months
post-dose two of Rotarix, seventeen months post wholesale DTP, HepB, Hib
and OPV vaccinations, and seven months post-Hepatitis A vaccination.

This case lacked clinical information to assess whether criteria for
either KD or incomplete KD were met. In Rota O-06, KD was reported in a
13-month male Rotarix subject of mixed ancestry from Brazil with onset
seven months post-dose two of Rotarix, and five months post routine
vaccinations with wholesale DTP, Hepatitis B, and Hib. In Rota O-61, not
one of the eleven studies submitted in the original BLA, KD was reported
in a three-month white male Rotarix subject from Finland with onset 12
days after dose two of Rotarix dose two, DTAP, IPV, HepB and Hib.

The remaining 24 cases were reported from four Asian studies, Rota O-07
and Rota O-28 in Singapore, Rota O-29 in Hong Kong, and Rota O-30 in
Taiwan. Fifteen or .21 percent Rotarix subjects developed KD, compared
to nine, or 0.15 percent of placebo recipients. The male-to-female ratio
was 15-19, and all subjects were of Asian ethnicity. The median onset
interval after Rotarix or placebo was 5.5 months, with a range of three
days to 19 months. The median onset after routine vaccinations was 3.5
months, with a range of three days to 18 months. From day zero to 30
post-dose with Rotarix or placebo, one case each was reported in both
groups. In addition, one case, a Rotarix subject who developed KD 55
days post-dose two lacked clinical information to assess whether
criteria for either KD or incomplete KD were met.

I\'ll now present immunogenicity results from Rota O-60, a study that
evaluated the co-administration of Rotarix with other childhood
vaccines.

As previously mentioned, co-administration of other routine childhood
vaccines with Rotarix was allowed in nine of the eleven BLA studies.
However, only Rota O-60 was specifically designed to evaluate
non-inferiority of immune responses to routine U.S. childhood vaccine
antigens, when these vaccines were co-administered with Rotarix.

All subjects were given three doses each of PEDIARIX, the DTAP, Hep B,
IPV combination vaccine, Prevnar, the pneumococcal seven-valent
conjugate vaccine, and ActHIB, Haemophilus B conjugate vaccine on a
zero, two, and four month schedule. Subjects were randomized to one of
two groups, the co-ad group where Rotarix was administered with the
first two sets of routine vaccine doses, and the sep-ad group where
Rotarix was given one month after dose two, and one month after dose two
of routine vaccines.

One hundred and eighty co-ad and 137 sep-ad subjects were included in
the ATP immunogenicity cohort. Antibody responses to Diphtheria,
Tetanus, Pertussis, Hepatitis B surface, Poliovirus, Hib and
pneumococcal antigens were measured at one month post-dose three of
routine vaccinations. Geometric mean concentrations, or GMCs, or
geometric mean titers, or GMTs were measured for all antigens.
Definitions of seroprotection for anti-PRP, anti-HBS, anti-polio,
anti-diphtheria, and anti-tetanus responses are shown in this table.

Demonstration of non-inferiority of the immune response to routine
vaccine antigens in the co-ad group required meeting the following
criteria. The lower limit of the 95 percent confidence interval for the
difference in seroprotection rate with difference being defined as the
rate in the co-ad group minus the rate in the sep-ad group needed to be
greater than or equal to negative 10 percent to the anti-PRP, anti-HBS,
anti-polio, anti-diphtheria, and anti-tetanus responses.

In addition, the lower limits of the 95 percent confidence interval for
the GMC ratio defined as the GMC in the co-ad group divided by the GMC
in the sep-ad group needed to be greater than or equal to 0.67 for the
anti-pertussis response to each of the three antigens, greater than or
equal to 0.5 for the anti-pneumococcal response to the seven serotypes.

Non-inferiority of seroprotection rates in the co-ad group compared to
the sep-ad group was demonstrated for anti-PRP, anti-HBs, anti-polio,
anti-diphtheria, anti-tetanus responses based on the lower limits of the
95 percent confidence intervals on the difference in the seroprotection
rates all being greater than or equal to negative 10 percent.
Non-inferiority of GMCs in the co-ad group compared to the sep-ad group
was also demonstrated for the anti-pertussis responses to the three
antigens, and anti-pneumococcal responses to the seven serotypes based
on the lower limits of the 95 percent confidence intervals for the GMC
ratios, all being greater than or equal to 0.67.

FDA also looked at non-inferiority of the anti-polio response when the
lower limit of the 95 percent confidence interval for the difference was
increased from greater than or equal to 10 percent, to greater than or
equal to negative 5 percent. Despite this increase, non-inferiority
criterion for each polio virus type was still met.

So, in summary, Rotarix was effective in preventing any rotavirus
gastroenteritis and severe rotavirus gastroenteritis during the first
year of life. Protection was also demonstrated against wild-type G1, G3,
G4, and G9 types individually, and non-G1 types when pooled together.

Rotarix did not increase the post-vaccination risk of intussusception.
However, increased rates of pneumonia-related deaths, and
convulsion-related SAEs were observed in the Rotarix group from dose one
to visit three in Study Rota O-23.

Finally, co-administration of Rotarix with other routine vaccines in the
U.S. did not interfere with immune responses to each of these vaccine
antigens.

As part of the pre-BLA agreement, the applicant will conduct a U.S.
post-licensure observational study, safety study in which a cohort of
infants will be vaccinated in a routine pediatric healthcare setting.
Safety data will be collected prospectively, and the total number of
vaccinated infants will be calculated in order to provide 80 percent
power to detect a relative risk of intussusception greater than or equal
to 2.5 at a 5 percent significance level.

Other measured outcomes in the study will include deaths from all
causes, hospitalizations due to acute lower respiratory tract
infections, including pneumonia, convulsions, and Kawasaki disease.

I\'d like to acknowledge all the members of the FDA review team listed
in this slide, as well as other CBER members who assisted with
preparations for this Advisory Committee meeting. Thank you very much.

DR. MODLIN:  Thank you, Dr. Rosenthal. We do have a few minutes. I
thought maybe I might first give Bruce Gellin an opportunity to ask any
questions or make any comments, since you\'re not going to be here this
afternoon. And I know it\'s premature, but we do have some time, Bruce.
I didn\'t know if there\'s anything that you wanted to \-- 

DR. GELLIN:  Thank you for the opportunity, John. I think that we\'re
going to have a discussion about some more of the details of the
post-marketing studies, and I\'ll be interested in some of those. But
that\'s the place I\'d like to focus. Thanks.

DR. MODLIN:  All right. If not, I think what we\'ll do, given the time,
again, let\'s take the opportunity to take an early lunch break. We will
start back up at 1 p.m. sharp, and I think we will, again, have ample
opportunity for questions, and for discussion. So thank you, everyone.

(Whereupon, the proceedings went off the record at 11:37:03 p.m., and
went back on the record at 1:01:29 p.m.)

DR. MODLIN:  At this point on the agenda, we have allotted time for the
open public hearing. I\'m going to turn things over to Christine.

EXEC. SECRETARY WALSH:  Thank you, Dr. Modlin. As part of the FDA
Advisory Committee meeting procedure, we are required to hold an open
public hearing for those members of the public who are not on the
agenda, and would like to make a statement concerning matters pending
before the Committee. I have received two written comments. One comment
has been received from B. Sachau, and the other is from Dr. Leonard P.
Ruiz. Copies of their statements have been given to the Committee
members, will be made part of the meeting record, and are available for
review in the viewing notebook at the registration desk.

Is there anyone in the audience who would like to make a statement
during this open public hearing before the Committee?

DR. MODLIN:  Thank you. Dr. Rosenthal, do you want to go ahead and
present the questions before the Advisory Committee?

DR. ROSENTHAL:  Thank you. I\'d just like to restate the questions that
were presented earlier in the day. Question One: Are the available data
presented adequate to support the efficacy of Rotarix in preventing
rotavirus gastroenteritis caused by serotypes G1, G2, G3, G4, and G9
when the first dose of vaccine is administered beginning six weeks of
age, followed by a second dose separated by at least four weeks? If not,
what additional information should be provided?

Question Two: Are the available data presented adequate to support the
safety of Rotarix when used in a two-dose series beginning with the
first dose at six weeks of age, followed by a second dose separated by
at least four weeks? If not, what additional information should be
provided?

And Question Three: Are there additional issues that should be addressed
in post-marketing studies beyond the applicant\'s proposed U.S.
post-licensure safety study? Thank you very much.

DR. MODLIN:  Why don\'t we leave those up? Before we start, I\'m going
to ask if there are any questions about the questions. We sometimes do
have them, believe it or not, from the Committee.

Seeing none, what I would like to do would be to give the members of the
Committee and others opportunities to address questions to both the
Sponsor and to the Division, before we actually begin to focus
specifically on each of those questions. Now is the time to do so. I
assume a number of people will have questions. We can take them in any
particular order, but maybe starting with Dr. Jackson, if you have them.

DR. JACKSON:  I had some questions that were then addressed by the FDA
presentation. What I have left is pretty minor, so I think I\'ll pass.

DR. MODLIN:  Pablo, Dr. Self. Dr. McInnes.

DR. McINNES:  I have a question about data to support the timing. So the
issue on the table is that the first dose beginning at six weeks of age,
two doses to be completed by 24 weeks of age with four weeks between
dose one and dose two. So if you back down from 24 weeks, you could
actually get your first dose at 20 weeks of age, get your second dose
and be completed at 24. And I have a question about what data are
available, both efficacy and safety data, to support this first dose
being given as late as 20 weeks, and yet still meet the time parameters.
And in O-23, I know the mean age at dose one was 8.4 weeks, and in O-36
it was 11.5, but I didn\'t see data that would address dose one really
being given as late as 20 weeks.

DR. MODLIN:  That\'s a great question, and I think others have it in the
same \-- Dr. Friedland?

DR. FRIEDLAND:  Yes. Thank you for that question. We would not propose
to give the first dose as late as 20 weeks. We would propose to give the
first dose, as studied in the clinical trials. In Study O-23, the first
dose was per protocol given between six and 13 weeks of age, and in that
study 10 percent of the infants enrolled in the total vaccinated cohort,
so both safety data, including efficacy there, were given the dose at 12
weeks of age, and 3 percent of those enrolled were given a dose at 13
weeks of age.

In Study O-36, the per protocol criteria for dosing of dose one is
between six and 14 weeks of age, and in that study, 13 percent of those
enrolled received their first dose \-- I\'m sorry, 21 percent of those
enrolled received their first dose at age week 13, 7 percent received
their first dose at age week 14, and .3 percent were out of protocol and
received their first dose in the 15^th^ week of age, so we would not
propose to give a dose as late as you were back-calculating.

DR. McINNES:  So could you then maybe define more specifically what your
window would be for those ones, because the way it\'s phrased right now,
one doesn\'t get an indication of that.

DR. MODLIN:  Perhaps this is the best time to maybe look specifically at
the language that\'s intended to be in the label. And, Dr. Rosenthal, do
you want to address that? It would seem this is an appropriate time to
do.

DR. ROSENTHAL:  If \-- we haven\'t started our negotiations yet with
labeling language with the applicant. I mean, I guess you could present
your draft of the label that you\'ve presented to us already. Where it
stated that the first dose should begin at six weeks of age following a
second dose four weeks apart. That\'s sort of where we are now.

DR. MODLIN:  But it sounds like Dr. McInnes\' question, if I understand
it, is the concern about both safety and efficacy for the upper limit
for the first dose. And the data that we\'ve just heard, the information
that we\'ve just heard from Dr. Friedland is that the numbers of
individuals in these trials that have received their doses beyond 13
weeks is exceedingly small, probably not large enough to support either
safety or efficacy in that age group. Is that fair?

DR. FRIEDLAND:  As mentioned, the data after 13 or 14 weeks of age based
on two studies is very limited. And as mentioned by Dr. Rosenthal, we
have yet to begin negotiations over the label, and will settle on an
appropriate age range for the first \-- recommendations for the first
dose.

DR. MODLIN:  Thanks, Pam, for bringing that up. Did you have any other
questions, Pamela, before \-- Dr. Self?

DR. SELF:  Related to this, have you looked at trends in either safety
or efficacy outcomes by age of administration? This was a related
question and some of the other materials. And if you\'ve done those
analyses, could you describe them?

DR. FRIEDLAND:  We haven\'t done any specific analyses based on age of
administration; although, we have looked at the children who had
intussusception at the age in which they were vaccinated. And I can
provide you those data, as I pull them up here.

So, specifically, in the 13 definite intussusception cases that occurred
within 30 days of vaccination, in the total vaccinated cohort at-large,
the mean age of the first dose given in that study was 8.2 weeks, and
the mean age in the children who had intussusception who received
Rotarix was similarly 8 weeks. The range were that three of the six
infants were dosed at first dose at ages 6, 7, and 7 weeks, and three
were dosed at 11, 11, and 12 weeks. In the placebo group, there was a
similar mean age. As mentioned, in the placebo subjects, of the seven,
the time of age when they received their first dose, and those who had
intussusception was 6 weeks, 6 weeks, 7 weeks, 7 weeks, 9 weeks, 10
weeks, and 12 weeks, so we don\'t see an increased risk of
intussusception in infants who are vaccinated at an older age.

DR. MODLIN:  Thank you.

DR. VERSTRAETEN:  Dr. Modlin?

DR. MODLIN:  Yes.

DR. VERSTRAETEN:  Can I add something?

DR. MODLIN:  Yes, certainly.

DR. VERSTRAETEN:  Few more data on that. Because the issue of the
association between the risk of intussusception and age has come up
related to another vaccine, we\'ve done some analysis to look into that.
So I\'d like to show you a graph we did. Basically, what we did is we
looked at the relative risks as they relate to the age at the first dose
of vaccination.

Now, within the clinical trials, we stopped vaccinating. There were few
children that were vaccinated beyond 90 days of age. Can you project the
slide, please? So this is a smoothed curve of the relative risk of
intussusception in the vaccinated group compared to the placebo group,
as it relates to age at the first dose. And, as you can see, the red
line is actually the relative risk, and the pink lines are the 95
confidence intervals around it, so this certainly doesn\'t suggest that
there\'s any increase in risk with age.

In addition, and since the label in Europe allows vaccination of the
first dose up to 20 weeks, we\'ve also looked at our spontaneous reports
to see if there\'s any indication that there\'s an increased risk with
age. Can I have the next slide, please?

Now this becomes a little bit complex, because we were thinking how are
we going to evaluate spontaneous reports where we don\'t have
denominators? And what we wanted to see is what\'s the age distribution
of the cases that\'s being reported to us. Now there\'s three different
parameters that can influence that age distribution. The first one, of
course, is the age distribution of intussusception and the background,
the natural age distribution. The second one is the age at vaccination,
and the third one is the probability of a report being made to us in
function of age.

Now, the second and the third parameter we\'ve combined. Basically,
we\'ve had it represented by the distribution of the age of other
reports that are being made to us, non-intussusception reports related
to Rotarix. For the first parameter, we took data from a recently
completed study in Switzerland. Can I have the next slide?

So this is the age at which reports are being made to us spontaneously
following Rotarix, excluding intussusception reports. The next slide,
please. This represents the age distribution of intussusception in
Europe. Next slide. So this is what, when we combine the two previous
curves, this would be the age at which we expect cases of
intussusception to be reported to us, assuming there is no association
at all between the age and the risk of intussusception. So what we
figured is if there is a true association with higher risk, that curve
should be shifted to the right when we look at the reports we received
in reality. So can I have the next slide?

So the green curve now shows you the actual age distribution of reports
of intussusception made to us, which very nicely fits the actually
expected age distribution. Now this is for all doses. Can I have the
next slide? This is the distribution of the two different doses that we
have for Rotarix. And then the next slide, this is what we see for the
first dose. Again, the green curve, which is the real age distribution,
fits very well on the red curve, which is the expected age distribution.
So at least the spontaneous reports do not insinuate that there\'s any
association between the age at vaccination and the risk of
intussusception.

DR. MODLIN:  Very helpful. Thanks, Dr. Verstraeten.

DR. FRIEDLAND:  Dr. Modlin, may I add one more thing?

DR. MODLIN:  Certainly.

DR. FRIEDLAND:  Ken mentioned that there\'s a study that was presented
by the FDA this morning when we talked about the Kawasaki cases, a study
ongoing that\'s recently finished in Asia. And in that study, there are
a number of infants who are vaccinated ages 17, 18, and 19 weeks of age.
And if the Agency is interested, we can submit those data for your
review.

DR. MODLIN:  Thank you. We\'ll continue on. Dr. Romero, do you have
questions?

DR. ROMERO:  I do, and tentatively, since this is my first meeting. So
the safety data has focused on the issue of convulsions or seizures. Is
there any data that you looked at with regard to encephalopathy not
associated with convulsions; that is, rotavirus, natural rotavirus
infection is associated with encephalopathic conditions, not associated
with seizures. Any comment on that?

DR. MODLIN:  So you\'re asking something that\'s a little bit more
general than just presence of seizures, but something that might include
seizures, may or may not include seizures, but may be something even
more general than that.

DR. ROMERO:  Correct.

DR. MODLIN:  Okay.

DR. FRIEDLAND:  Yes. When we look at the Core Integrated Summary of
Safety, I took a look to see if there were reports of encephalopathy,
encephalitis, et cetera, and there are very limited numbers of reports,
one, two cases, sometimes in Rotarix, sometimes in placebo, no signal
there for those types of adverse events.

DR. ROMERO:  And in your post-marketing, will you specifically look for
these events, other than just seizure?

DR. VERSTRAETEN:  We\'re just checking, but we do look at all
neurological serious adverse events, of course. As far as I recall, we
have not seen any such events, but I will check with my colleague who\'s
dealing with the vaccine, specifically. And as soon as we have the
information, we\'ll give you that answer.

DR. MODLIN:  All right. I know that Roger Glass and colleagues have
recently published a review of rotavirus-related CNS events, including
actually demonstration of the presence of rotavirus antigen in CSF in
patients that apparently had disease following natural rotavirus
infection, so that question has come up in our clinic around RotaTeq, so
that\'s a terrific question to ask. Do you have further \-\-\-- Jose?

DR. ROMERO:  Yes, just one other question. I don\'t know if it\'s
germane to this, John, so guide me. But one of the questions I was going
to ask is, have you at all looked at viremia associated with your
vaccine, or is that not germane or relevant to this?

DR. MODLIN:  Viremia as measured by anigenemia, or PCR, or whatever?

DR. ROMERO:  Well, I would be interested to hear whether they did
either/or.

DR. FRIEDLAND:  There are limited data on antigenemia and viremia with
natural rotavirus infection, and also with vaccine. We have limited data
with our vaccine. There was a Phase II study called Study O-03, which
was not part of the BLA. It was a study with early formulations of
Rotarix, and in this study, Dr. Vesikari from Finland, and colleagues,
presented data on RNAemia from the study at the Second European
rotavirus meeting this past summer. And I can tell you briefly the
results from the study.

Approximately 6 percent of infants who were given Rotarix had evidence
of RNA in their serum. At the same time, 20 children with rotavirus who
were admitted to the hospital in Finland were also evaluated in Dr.
Vesikari\'s lab. And testing there showed that 11 of the 20 samples
tested were RNAemia positive from wild-type rotavirus testing. So
RNAemia does occur after vaccination at significantly lower rates than
in wild-type natural infection.

DR. MODLIN:  Any further questions?

DR. ROMERO:  Thank you, John.

DR. MODLIN:  Seth?

DR. HETHERINGTON:  Getting back to the question of immunogenicity and
the intervals of vaccination, is there any information available as to
the magnitude of the duration of antibody response based on the
intervals between the two doses? In other words, does interval between
the doses impact either magnitude or durability of the immune response?

DR. MODLIN:  Did you get the question, Dr. Friedland?

DR. FRIEDLAND:  I don\'t believe we have such data to answer that
question. Most of the clinical trials, the first and second dose was
given either one to two months after the first dose. What we do have
data on is an effect of time to testing antibody levels after
vaccination. And we know that antibody levels are sensitive to time with
IGA levels, and that the further from the last dose that the sample is
tested, in general, the lower the antibody level.

DR. MODLIN:  Dr. Debold?

DR. DEBOLD:  Okay. This is my first meeting, so bear with me. I have a
lot of questions, some of them are just general, because I\'m new to the
subject. But I was curious as to why the OPV was avoided in some of the
clinical trials. And, also, why administration of Hepatitis B vaccine
was a criteria for non-eligibility for the one \-- Hepatitis B vaccine
at birth or within four weeks of getting the rotavirus vaccine was a
criteria for not being included in the one U.S. co-administration study,
Rota O-60, I believe?

DR. FRIEDLAND:  Yes, I\'m happy to address those in the order that you
asked regarding OPV. OPV is an Oral Poliovirus Vaccine. There would be a
question if two oral vaccines given at the same time might have some
interference. We did do one study in the BLA, Study O-14 conducted in
South Africa where OP was given at the same time as Rotarix, and in that
study poliovirus seroconversion levels were adequate. There was no
evidence of interference, and the antibody response to Rotarix, itself,
was adequate.

Subsequent to that, we have completed a study that is not part of the
BLA. It\'s finished after the BLA was submitted in Latin America where
Rotarix was given with OPV on an EPI schedule, versus a placebo plus OPV
on an EPI schedule. That was a safety and efficacy study, and in that
study it was demonstrated that Rotarix is efficacious, as previously
seen in Latin America, and there was no interference on the OPV, or the
Rotarix responses.

The second question you asked had to do with Hepatitis B. In the United
States, Hepatitis B vaccine is recommended to be given at birth, and
then subsequent doses, two subsequent doses, so we wanted to make sure
in the Rota O-60 study, if a child was vaccinated with Hepatitis B, that
it was given at birth, and that we knew about that so we wouldn\'t give
them additional doses of Hepatitis B in the study. So they were
completely vaccinated appropriately with Hepatitis B in that study.

DR. VERSTRAETEN:  Just one additional comment, because your question was
also why did we avoid co-administration with OPV at the beginning? As
you may or may not recall, when the whole RotaShield and intussusception
concern was raised, there was also a certain concern at a certain point
in time that OPV could be linked to intussusception, and we wanted to
make sure that our data would only refer to our vaccine, and not to
another vaccine that would have been co-administered at the same time.
However, as Dr. Friedland said, in a later stage we then did studies
where we co-administered the two.

DR. DEBOLD:  Should I go ahead?

DR. MODLIN:  Please, do.

DR. DEBOLD:  I have a question, too, about the horizontal transmission
issue. In the materials that were provided to us, there were seven
documented cases of vaccine strain rotavirus in placebos. I\'m just
wondering if the manufacturer could talk a little bit about what effect
that might have on some of the results that were observed? And I also,
while I\'m at it, would like to know \-- because it sounds like what was
provided was that the placebos that tested positive for the vaccine
strain were asymptomatic. How frequently does asymptomatic infection
with wild-strain or wild-strain rotavirus vaccine occur? And to what
extent could that have affected the results that you observed?

DR. FRIEDLAND:  Yes, if I could have this slide up, please. In the
clinical trials, stool samples were obtained at pre-determined time
points, and among the 421 stool samples that were collected on placebo
subjects, seven were positive for rotavirus vaccine strain. Shown on the
slide, too, the samples came from Study O-05 in the United States, a
Phase II study, one sample from a study in Latin America, three samples
from a study in Singapore, and the last sample from a study in Taiwan.
Two of the seven placebo subjects shed vaccine virus at two time points,
as mentioned, as you\'ve just said. We reported that none of these
symptoms reported fever or gastrointestinal symptoms at or around the
time of vaccination. Four of the seven subjects seroconverted, had an
antibody response, and two of the subjects both from Study 5, had a twin
in the same study at the same time.

Your question regarding how often does rotavirus infection occur without
gastrointestinal symptoms; it certainly has been reported, but the
classic presentation for rotavirus is vomiting, diarrhea, and fever.
We\'d like to say that if shedding is occurring, it\'s not occurring
with associated gastrointestinal symptoms.

It\'s important to point out that nearly all children in the United
States will be exposed to natural rotavirus at an early age, certainly
under the age of five, and probably by the time they\'re two years of
age. This is an attenuated human rotavirus strain, and one needs to
weigh the high likelihood of acquiring natural rotavirus to the
potential likelihood of transmission from an attenuated human rotavirus
strain.

DR. MODLIN:  But your question, also, was how it might affect the
results of the study, presumably, the efficacy results. And to the
degree to which your placebo patients are being immunized with vaccine
strains, presumably, they also are being protected, and that would
actually have the effect of reducing the observed efficacy when you
think about it.

DR. FRIEDLAND:  Yes. Thank you, Dr. Modlin.

DR. MODLIN:  If that were an important effect. Do you have other
questions, Dr. Debold? Okay. Would you like to pass, and we can come
around again?

DR. DEBOLD:  I\'ll pass.

DR. MODLIN:  Dr. Belay.

DR. BELAY:  I also had a question about the convulsion or the seizure in
the patients. I was curious about the investigator\'s conclusion as to
what might be causing the convulsions in some of those patients. Did
they, for example, look at each one of the cases and see or come up with
another potential explanation for them? I was just curious about that.

DR. FRIEDLAND:  Yes. The question is regarding the seizures and the
investigators, and how did they reach that diagnosis, what type of
evaluations were done? All of the cases were reviewed, and of the cases
of convulsions, of the 20 cases that occurred during the whole
surveillance period in the Rotarix group, and the 12 that occurred in
the placebo group, almost exclusively these diagnoses were made
clinically. Very few of the patients had an EEG, and in all cases when
an EEG was done, it was normal. Very few had further evaluations,
including imaging or other testing. And almost exclusively, these cases
were clinically diagnosed.

DR. BELAY:  Any evidence that the seizure actually continued and they
became epileptic, for example?

DR. FRIEDLAND:  I can look at my notes, and I can tell you that in rare
cases, patients were reported to have seizures at a second time during
the study.

DR. MODLIN:  Any further questions? Dr. Davis.

DR. FRIEDLAND:  I can just answer that.

DR. MODLIN:  I\'m sorry.

DR. FRIEDLAND:  Two of the 20 subjects had a repeat seizure. I should
also mention that many of the subjects had pre-existing or concurrent
medical conditions that could have accounted for the seizures, such as
hypocalcemia, or hyponatremia, severe neonatal hypoxia, et cetera.

DR. DAVIS:  Thank you. I have three questions, one actually from a
safety standpoint, one from an efficacy or effectiveness from a parent
viewpoint, and one from a statistical viewpoint. So the first question
is, both Bruce Gellin and I were talking about sort of the one thing
that is a little bit concerning, which is the pneumonia-related deaths,
or the pneumonia deaths. And we both wanted to know if it was possible,
or maybe if you had a slide that shows in a bit more granularity the
time line of the pneumonia-related deaths. You sort of have them divided
into, I think before 30, and after 30 days, and we both were interested
in just seeing a more sort of in-depth view of that.

And related to that is, are there pneumonia-related deaths in any other
rotavirus vaccine studies, including this vaccine, or the other two
previous vaccines that have been developed, and about to market? Has
this ever been seen before?

DR. FRIEDLAND:  Okay. Thank you. I\'ll first start with your question
about \-- 

DR. DAVIS: So that\'s the first question, and then I\'ll get to the
other two in a second.

DR. FRIEDLAND:  Right. The first part of the first question.

DR. DAVIS:  Yes.

DR. FRIEDLAND:  If I could have this slide up, please. This is the time
of onset of the pneumonia deaths. There were, as mentioned, when we look
at the pneumonia-related, 16 deaths in the Rotarix group, and 6 in the
placebo group. The light blue color are the children who received
Rotarix, and the dark red color are those who received placebo. And as
you can see, there is no clustering after vaccination close to either
dose one or dose two.

If I could have \-- in addition, you were asking about other pneumonia
deaths. If I could have Slide Y. H-19 I think is what I\'d like. So the
deaths that we mentioned this morning were deaths that occurred in Study
O-23. Yes, thank you. There were additional studies included in the BLA,
which I\'ll show on this slide, if I can have this slide up, please. So
if we look at the additional studies within the licensing application
that were submitted, there were four additional pneumonia-related deaths
in the other studies submitted to the BLA in the Rotarix group, and
there were five pneumonia-related deaths reported in placebo subjects in
the other studies submitted to the BLA.

One of these four subjects had pneumonia-related death onset within 30
days of a vaccine dose. Three of the placebo subjects had
pneumonia-related death within 30 days of receiving the placebo.

I should mention that there are additional studies that have been
completed since the licensing application was submitted. One of them was
a study known as 24, which I mentioned was a study where Rotarix was
given OPV on an EPI schedule, and then the other study we talked about
briefly earlier related to Kawasaki disease, a large study conducted in
Asia, Study 28, 29, 30. The FDA has not received these data to review,
but they were aware that we might be interested in presenting these data
anticipating such a question. They have given us permission to show you
these data, but they have not had time to fully review it on their own.

Within those two studies, 24 in Latin America, and 28, 29, 30 in Asia,
over 9,700 children received Rotarix, and over 7,500 received placebo.
And there were three pneumonia-related deaths in the Rotarix group, .03
percent, one in the placebo group, none of these deaths occurred within
30 days of vaccination.

I did mention earlier that there are two ongoing studies in Africa,
where one is a safety and efficacy study, and one is a study of
HIV-infected infants. And as might be expected, deaths are occurring
with increased frequency compared to other studies in that study,
including pneumonia-related deaths. If I could have the next slide,
please.

Again, the FDA is allowing us to show you these data, but they\'ve not
received these data for review. But they are aware that we wanted to
show you these data. I should mention that both of these studies are
ongoing. They\'ve completed enrollment, but they are ongoing.

GSK remains blinded to treatment allocation. The IDMC has been reviewing
these data, and they are unblinded to treatment allocation. In these two
studies involving over 5,000 infants, 135 deaths have been reported, 60
of the deaths are said to be pneumonia-related. The IDMC, as I
mentioned, met recently and said to GSK that they have no safety
concerns based on these studies. So that\'s the additional information
we have related to additional pneumonia deaths.

I\'d like to introduce Thomas Breuer from GSK.

DR. BREUER:  Good afternoon. I\'m the head of Clinical and Achievement
Legal Office of GSK Biologicals. The second part of your question was
whether that has been observed with other rotavirus vaccines, RotaShield
and RotaTeq. I just want to point out that death in a post-neonatal
period due to infectious diseases happen quite often in areas where we
have performed a study; namely, Latin America, and in some Asian
studies, and then again in Africa. However, the other programs were
predominantly studied in the U.S. and in Europe, where you have almost
no infectious disease-related death in the post-neonatal period, so you
would not expect to see such signals in these programs. So I think it\'s
important to point that out, that these three programs, two were
predominantly run in Western World kind of area, and the other one were
run in Latin America, Africa, and Asia.

DR. DAVIS:  Great. Thank you. So the second is, as I mentioned, from a
parental viewpoint, which is you showed the protective effect of the
rotavirus vaccine against gastroenteritis. When the vaccine-associated
gastroenteritis was excluded, and when gastroenteritis in the first two
weeks after vaccination was excluded, and as a parent getting
vaccinated, you don\'t really care about those exclusions. You want to
know what\'s the effectiveness of the vaccine against everything from
this moment on. And I\'m sure you\'ve anticipated this question, and I
was wondering if you wouldn\'t mind sharing data towards that. What the
protective effect of all gastroenteritis is from the moment of
vaccination?

DR. FRIEDLAND:  Yes, I can show you. If I can have Slide E-8. So this
would be a total vaccinated cohort efficacy analysis.

DR. DAVIS:  Right.

DR. FRIEDLAND:  If I could have this slide up. So this is efficacy in
the study in Europe, Study O-36, but the same data are available if
you\'d like for O-23. Looking at efficacy from beginning, from the time
the infants received their first dose of vaccine, and if you were to
look back into your binder, you would see that the efficacy results in
the total vaccinated cohort are that the first season to the second
season are very, very similar to the results seen in the according to
protocol analysis. We have the same type of data for Study O-23.

DR. DAVIS:  Okay. Good. Thank you. I assumed such, I just wanted to
\-- okay. So then the third question is, in the safety analysis, there
was a statement made. And I apologize, Tom, this was adjusted for study
effect. And I have no idea what that means, or how it was done, or why
it was done. And I\'m wondering if you could just clarify what you mean
by \"adjusted for study effect.\" I think I have a clue, but I\'ve never
seen it done before.

DR. VERSTRAETEN:  Okay. Thanks for that question, Bob. You know, when
you pool this data, you always have to be very careful, because you
might have difference between the studies. Now in this particular case,
most of our studies are one-to-one randomized, so it may not make such a
lot of difference. If you start mixing studies with different
randomization ratios, this becomes really crucial. So the adjustment for
study effect is basically taking the difference that may exist between
the different studies into account. It\'s like you would calculate a
relative risk across different studies, and then average those out.
That\'s what it means.

DR. MODLIN:  No questions, Dr. DeStefano?

DR. DeSTEFANO:  I have three questions. The first one is for Dr.
Friedland. I think you mentioned, or maybe I missed it, that in the
pneumonia-related deaths, that you took out deaths that had some
underlying cause, or attributable cause for the pneumonia, that you
reduced the number. I wonder if you have similar data for the placebo
pneumonia-related deaths that didn\'t have any other attributable cause?

DR. FRIEDLAND:  Yes, I do, and I\'m going to find those. There were
\-- of the six pneumonia-related deaths in the placebo group, two of the
infants had some pre-existing conditions. One was a questionable infant.
This was a child who 46 days after receiving dose one of placebo
developed cough, fever, dysmia, infultates, cardiomegaly, and died three
days later. The chest x-ray was read as having upper lobe infiltrates
and cardiomegaly. And the clinical diagnosis from the clinicians was a
suspected patent ductus arteriosus.

The last case, or the second of the placebo subjects was an 83-day old
who had a history of a communicating hydrocephalus. And this patient had
emesis after receiving sedation for a CT scan, and subsequently
developed pneumonia.

DR. DeSTEFANO:  Thank you. I have a couple of questions for Dr.
Verstraeten. First of all, it looked like in your post-marketing
surveillance, as I understand it, had about 12 million doses distributed
worldwide, and almost 9 million were from Brazil. I wonder if you could
describe the post-marketing or pharmaco vigilances in Brazil, and if you
have any data on sort of completeness of reporting?

DR. VERSTRAETEN:  Yes and no. So, I mean, I\'m certainly not an expert
on the whole pharmaco vigilance system in Brazil. But what I can tell
you is that what we have seen is that overall, the reports that we
receive from Brazil have come in the lower frequency than what we
receive in the rest of the world. However, when we look specifically at
serious adverse events, they approach must closer what we see from the
rest of the world. And then the best news is, when we look at
intussusception, the rates that they report are not very much lower to
what we see in the rest of the world.

Now to go back a couple of years, when I was working with you at the
CDC, you will remember the whole Yellow Fever investigations that were
going on. And at a certain moment, Dr. Chen and I went down to Brazil to
help them set up some surveillance. And I have to say, we also took
advantage to look at their Brazilian VRS, and I was pretty positively
impressed, I have to say, with what they collect as data, so they do
have a system in place. However, the reporting rates are lower than what
we see in the rest of the world. I have to acknowledge that.

DR. DeSTEFANO:  And one other question for you. I guess in this study
that you have planned in Mexico with the one million birth cohort, it
seemed like you have questions about whether you\'re going to include
Kawasaki disease and pneumonia deaths, and I was just wondering what
kind of \-- what would the reasoning be, or what it would take to
include those, because it seems like this is a tremendous opportunity to
really get good data.

DR. VERSTRAETEN:  Can you repeat? I\'m not sure I understood.

DR. DeSTEFANO:  I think in Mexico you said that, whether you include
Kawasaki disease, and perhaps pneumococcal deaths. You\'re not sure
whether you\'re going to include that as part of your outcomes that
you\'re evaluating.

DR. VERSTRAETEN:  Okay. So pneumonia deaths, that\'s one of the outcomes
of the study, actually, intussusception and pneumonia deaths, those are
the two main outcomes of the study. The question was posed to us whether
we should look at Kawasaki disease in the study.

There\'s a number of concerns we have there. First of all, Kawasaki
disease is not very \-- is not so common in Latin America, and Mexico,
we\'re closer to U.S. It might not be that rare, but we\'d be mostly
concerned about the ascertainment rates of Kawasaki disease.

DR. DeSTEFANO:  You mean, they may not diagnose it there?

DR. VERSTRAETEN:  They may not diagnose it, and then the other question
is will we actually capture it, even if we look for it? So the way
we\'ve set up the study is, we go through \-- I\'m looking at Camille
\-- I think it\'s 224 hospitals throughout Mexico. We go and actively
look for cases of intussusception and for cases of deaths that may be
related to low respiratory tract infection. To add Kawasaki onto that
would be a huge undertaking, and I\'m not sure we actually could get
much out of it, so we\'re more comfortable looking at that in the U.S.
setting where I think we\'ll have better data.

DR. DeSTEFANO:  So this is very sort of manual-type system. It\'s not
all computerized data systems that \-- 

DR. VERSTRAETEN:  Well, it\'s a mix of the two. So it\'s active
surveillance, where we go and look, and find the data. In addition, they
do have a database, and it\'s a huge database. It\'s 40 million people
that are in the database, so we use the database as a backup. Basically,
we\'ll search for these cases, and after that, we\'ll search through the
database to see if there\'s anything we may have missed. So we\'ll then
match the two, and anything we find in the database that we didn\'t find
in the surveillance, we\'ll go back to the hospitals and see if those
are true cases or not.

DR. DeSTEFANO:  All right. Thank you.

DR. FRIEDLAND:  I\'d like to just add with regards to Kawasaki,
post-marketing studies that are planned in Latin America or North
America are in areas of the world where the incident rate of Kawasaki is
lower than in Southeast Asia, and we just happened to have been doing
the study in Southeast Asia, Study 28, 29, 30, which I mentioned had
over 10,000 infants. So we have fairly robust data on Kawasaki, even
though we hadn\'t planned to do the study for that reason that we have
presented, and so I think we have a good handle, thus far, on Kawaski
incidence in clinical trials of children who received Rotarix.

DR. DAVIS:  John, could I just ask \--

DR. MODLIN:  Of course. Please, do.

DR. DAVIS:  The study in Mexico. What\'s not clear to me, it sounds like
you\'re doing fairly intensive active surveillance, but what you
haven\'t described is what you\'re going to use as the comparison group.

DR. VERSTRAETEN:  Thank you for that question, again. So the method used
is a self-controlled case serious analysis, so it\'s basically what
Trudy has also done in the RotaShield study, where she did the case
control and the self-controlled, so we won\'t really be needing
controls, since we have a predefined exposure or risk period after
vaccination. We\'ll use that one.

DR. MODLIN:  John?

DR. ROMERO:  May I offer a comment about the Kawasaki issue in Mexico?

DR. MODLIN:  Yes, sure.

DR. ROMERO:  As somebody who was born and raised, and trained in Mexico,
and did his internship in Mexico \-- 

DR. MODLIN:  Jose, could you bring the microphone a little closer to
you?

DR. ROMERO:  I\'m sorry. And is familiar with the Mexican health system;
although, I did not train in the IMSS, the IMSS system. I\'m not certain
that this type of a diagnosis would be a diagnosis that would be readily
evaluatable under that system. And it\'s not to be demeaning or
pejorative to the system. I think that the way we evaluate Kawasaki in
this country is fairly extensive. I mean, the amount of serologic data,
the exclusionary tests that we use may not be accessible to all of the
systems in IMMS, so I\'m not sure that you\'re going to get a lot of
\"bang\" for your buck on this particular aspect. I think that the issue
of pneumonia, though, is clearly something that could be evaluated in
that country under that system.

DR. MODLIN:  Thanks, Jose. Melinda.

DR. WHARTON:  Yes. I have two questions about seasonality. In the large
Phase III efficacy trials, although I don\'t remember reading this, I
would guess that there was an effort to deliver vaccine, both doses, the
complete vaccine series prior to the expected onset of the Rotavirus
transmission season in the countries in which the trials were being
performed, rather than vaccination being ongoing throughout the year,
but I don\'t know that. What was the seasonality of vaccine distribution
relative to the Rotavirus transmission season?

DR. FRIEDLAND:  Yes, I can address that question. In Study-O36, the
study in Europe where Rotavirus is anticipated to have a seasonal
exposure, the Rotavirus season was defined as December-May, so there was
an attempt to vaccinate before the Rotavirus season. Although, as I
mentioned, not everybody had received both doses before Rotavirus season
started.

In the study in Latin America, where it\'s felt that Rotavirus is not
necessarily seasonal, but year-round, there was no defined season in
Latin America.

DR. WHARTON:  Okay. And that\'s \--thank you. And that\'s a prelude to
my second question, which has to do with seasonality of Rotavirus
disease compared to respiratory disease in tropical countries, and
temperate climates like the United States, Rotavirus season, and what we
usually think of as the respiratory disease season coincide. And what
about in tropical countries, where seasonality may differ? You already
mentioned the Rotavirus disease, so I guess there isn\'t seasonality of
Rotavirus in tropical settings?

DR. FRIEDLAND:  My colleague, Eduardo Ortega, who is a physician from
Latin America, and works for GlaxoSmithKline would like to address that
question.

DR. ORTEGA:  Thank you very much. I am from Panama. I am currently the
Vice President for Clinical R&D for Latin America. Before that, I was a
principal investigator for Rota O-23 in Panama, and for one year I was
responsible of Carica Modena, the area in which 50 percent of the
children were recruited. Basically, Latin America will depend on the
hemisphere in which you are. You\'re in the northern hemisphere, in
Mexico, for example, you will have a very varied pattern of respiratory
diseases, and it will coincide a little bit with the North American
season. And you will see respiratory diseases starting October,
November, December, and January. If you are in the southern hemisphere,
Brazil and other countries, then you have the reverse, and it will
depend of the hemisphere in which you are.

In Rota O-23, we have subjects in northern hemisphere, and the southern
hemisphere, and also in the middle of the Central American countries.

DR. WHARTON:  Thank you.

DR. MODLIN:  I have just a couple, myself, if you don\'t mind. We
haven\'t really heard any information about the particular sensitivity,
but also the specificity of the ELISA assays that have been used in all
these trials to detect Rotavirus disease. And I guess I have a corollary
question to that, and that is, we saw impressive reduction in
gastroenteritis due to all causes. What do you see when you look at the
effect of vaccination on ELISA negative gastroenteritis?

DR. FRIEDLAND:  Well, to start with, I can say the Rotaclone assay was
the assay used in the Phase III programs for the ELISA. There is no
reference, recognized reference standard which the assay is based. It\'s
a commercially available assay for use in the United States and
elsewhere.

We did look at the Rotaclone assay and compare it to the ELISA assay
developed by Drs. Bernstein and Ward, which was used in our Phase II
program. And compared to the Bernstein and Ward ELISA assay, the
Rotaclone assay sensitivity is 85 percent, and the specificity is 100
percent.

With regards to your comment about reduction for all-cause
gastroenteritis, I don\'t have an answer to your question about ELISA
negative. I can say that, for example, in Study O-36 where there was a
75 percent reduction in all-cause gastroenteritis, if we look at
\-- this was gastroenteritis causing hospitalizations. If we look at the
percentage of placebo subjects who had gastroenteritis who are
hospitalized in that study, 55 percent of those infants had Rotavirus.
And the reduction was 75 percent.

DR. MODLIN:  David, did you want to say anything more about the
sensitivity of the assay, David Bernstein? The ELISA assay, because my
understanding is it may be a little less sensitive than, say, PCR and
others. It\'s important because the question is are you \-- how does it
affect \-- would affect the results of the trial.

DR. BERNSTEIN:  Yes. Dick Ward actually does most of this, and his
home-grown ELISA, uses home-grown reagents. But in the studies that
compare the commercial assays, Rotaclone compares very favorably with
any other commercial assays. It is less sensitive than PCR. In fact, we
have a paper that was just accepted where we compared PCR to both
Dick\'s ELISA and to Rotaclone, and the problem was that when we
collected healthy infants as a control group, I think it\'s something
like 20 percent of those were positive, so you actually can\'t predict
that an illness is due to that Rotavirus if they use PCR.

If you Rotaclone or Dick\'s assay, there was actually zero in the
negative control group, because once you get so sensitive, either these
kids had an infection a month ago, and still had enough virus to be
positive by PCR, or they had a sub-clinical infection, so it actually
was not useful doing that. So I think Rotaclone is about as good as we
can do.

DR. MODLIN:  Thank you. One other question. The seroconversion rates in
developing countries across the board was somewhat less than it is in
industrialized countries. And I guess, I just wonder if you have any
information that would give us a little bit more information about the
basis for that. Is that a higher titer of passive acquired maternal
antibody in these infants, the time they\'re immunized, or are we
looking at the possibility of increased risk of interfering
gastrointestinal pathogens in this population, or a combination of the
two? Do we have any sense of what the reason for the lower
seroconversion rates happen to be?

DR. FRIEDLAND:  I have my sense of what I\'ve read in the literature,
and there might be others who can contribute to this conversation. But
lower immunogenicity and lower efficacy has been seen with live oral
vaccines, with poliovirus vaccines, with cholera vaccines, and also with
Rotavirus vaccines, including RotaShield, and also Rotavirus vaccines
that were in development in which development had stopped. Speculation
as to why this may be includes interference of enteric pathogens,
presence of maternal antibodies, are two of the etiologies that are
given. There might be others in the room who have more information about
this, but this was not an unexpected finding.

I think it\'s important to point out that while vaccine efficacy in the
Latin American study, O-23, was somewhat lower than that in O-36,
vaccine efficacy was still quite robust in Study O-23; 85 percent
protection against severe Rotavirus gastroenteritis.

DR. MODLIN:  Okay. Dr. Debold, do you have further questions?

DR. DEBOLD:  Yes, actually I do. I\'m still concerned about the
pneumonia-related deaths, and the convulsions. And I\'m concerned partly
because I notice that a primary inclusion criteria for the study was
that the child be healthy. So part of the explanation for why some of
this may have happened was because we had children who are hyponetrimic,
or had some other underlying problem. So now what happens when this
vaccine is given to children in the real world, what happens when it\'s
given to preemies, what happens when it\'s given to children who have
feeding difficulties, gastrointestinal problems? Do we have any evidence
of not only efficacy, but safety, in giving this in vulnerable infant
populations, particularly those who may be immuno suppressed?

DR. FRIEDLAND:  Good question.

DR. VERSTRAETEN:  So as I mentioned in my presentation, there is a
number of additional, what we call Phase IV studies, which are ongoing
right now. So one of them looks specifically at the question of
prematures. In that study, there\'s two group of premature children.
There\'s a group of severe premature, less than 30 weeks of age, and
then the other group is, I believe, between 30 and 36 weeks of age, so
we\'re specifically testing the immunogenicity and safety of Rotarix in
that group. So we will have that answer shortly.

Another study, which is ongoing in South Africa is looking specifically
at HIV-infected children. Now these children, some may be or some are
not immuno compromised depending on their status. So, again, it\'s a
very difficult study. It\'s not easy to find those children, and
there\'s a lot of deaths, unfortunately, occurring in that study, but we
will have that answer, also, shortly.

So, in general, when we develop our clinical development program,
there\'s always a balance to make between enrolling healthy children,
because you\'re worried about natural effects and making sure we have as
pure data as possible. And, therefore, usually, we will set up these
Phase IV studies trying to answer these questions.

Of course, in addition to that, we have our pharmaco vigilance program
in which we will try to see if there\'s any undue effects in populations
that were in studies in the clinical trials.

DR. FRIEDLAND:  I\'d like to add, as mentioned in the briefing
materials, in the study in Latin America, Study O-23, we know that there
were 254 infants enrolled in that study, small numbers, but still 254
infants enrolled who were gestational age less than 36 weeks; 134 of
those infants received Rotarix, and 120 had received placebo. And the
adverse event profile between those two groups was comparable, so there
was no evidence of any increased adverse events in premature infants in
Study O-23.

DR. MODLIN:  Thank you. Yes, Dr. Belay?

DR. BELAY:  How many, again on the pneumonia cases, if I remember
correctly, cases of pneumonia were also observed in Study 36, which is
the one that was conducted in Europe. In two of the countries, France
and another country, if I remember correctly, used Prevnar as part of
the routine childhood immunization program. In your analysis, did you
separate out the two countries that use Prevnar and the countries that
do not, and look at the pneumonia issue?

DR. FRIEDLAND:  You can start, and then I can look up the answer.

DR. VERSTRAETEN:  Okay. That\'s a very good question, thank you. And,
actually, it\'s one of the considerations we made. We also noted, this
one country where Prevnar was given, could there have been an
interference with Prevnar? So we tried to tease that out. However, we
did not see a specific effect limited to France, or to the countries
where Prevnar was not given, so as far as the data allowed us, we
couldn\'t tease that out. It didn\'t look like that was what was
happening.

DR. FRIEDLAND:  All right. And I do remember now, there was no country
effect seen when we looked at countries in the pneumonia deaths, either.

DR. MODLIN:  Yes, Pablo?

DR. SANCHEZ:  Getting back to the vulnerable population and premature
babies, do you have any \-- in the premature studies that you will be
conducting, will you be evaluating its use in short gut infants, or
full-term babies who\'ve had short gut secondary to gastro \-- 

DR. FRIEDLAND:  The question is in the premature study, or I would say
even in other studies, are we specifically enrolling children with short
gut or other gastrointestinal malformations? The answer is no, that is
not a specific population that is being specifically studied at this
moment.

DR. MODLIN:  I think Dr. Sanchez\'s question is an important one, and it
raises the issue of \-- it\'s a very practical one when it comes to
making \-- when you make a universal recommendation for use of a
vaccine, and then you need to understand how it\'s going to be applied
to all different types of populations, and what the risk-benefit ratio
may be. And I know that the past working groups at the ACIP, for both
RotaShield and for Rota Teq have struggled with these issues. In some
respects, they\'re a little bit different from the labeling issue,
because the label, necessarily, needs to be based on the data that are
brought to bear on safety and efficacy, and doesn\'t often go beyond
that.

It largely comes down to ultimately being an issue for the ACIP until
such data are generated that specifically address safety and efficacy in
these specific populations, Pablo. And those often take a fair amount of
time, and almost always occur as they\'re occurring in this case, after
licensure, as part of a Phase IV program. So it\'s difficult for us, as
this Committee, to weigh-in a lot on those issues, even though they\'re
critically important. But they\'re a little bit tangential to what our
primary role is here today, if that\'s a fair way to put it. I don\'t
know if Norm or Dr. Rosenthal want to speculate as to what the label may
say on these issues, or whether or not it will be any different than the
Rota Teq label. I\'m not forcing your hand, but I\'m not going to get
very far.

DR. BAYLOR:  No, you\'re not. It\'s too early to make that speculation,
John.

DR. MODLIN:  Are there other questions? Pablo, did you have other
questions? Dr. Hetherington?

DR. HETHERINGTON:  One basic question, maybe too simple, and that is,
just to make sure we understand how pneumonia-related death cases were
identified. Were these cases where the investigator needed to state the
pneumonia was either related to the death, caused primarily or secondary
as a cause, or were they deaths that occurred when pneumonia was a
concurrent adverse event that was active, or were they deaths that
occurred in patients that had had pneumonia at any time during their
participation in the studies, or some other method?

DR. FRIEDLAND:  Yes, thank you. It\'s important to mention that when
Study O-23 was conducted, there was no reason to be specifically looking
at fatalities in that study, and the study was not designed to look at
fatalities. So all fatalities that were reported in that study were as
per our standard instructions to investigators; and that is, when a
serious adverse event occurs, which fatality being part of that group,
investigators are instructed to report the diagnosis of the serious
adverse event. So these cases that \-- these were cases where the
children died, and the serious adverse event diagnosis given by the
investigator to the company included pneumonia as a preferred term.

In that study, the Independent Data Monitoring Committee appointed a
special Safety Review Committee to review all of the fatalities, and
assign a primary cause of death after their assessment. And the cases
that I presented to you today, the 16 pneumonia-related cases in the
Rotarix group, and the 6 in the placebo group, were with a primary cause
of death assigned as pneumonia by the Safety Review Committee.

DR. HETHERINGTON:  But just as a follow-up, usually, when you record an
SAE, you record an outcome. And one of the outcomes you can record is
death, so is it true, then, that all cases that this subsequent Endpoint
Committee declared as related to pneumonia, had they all been reported
as an SAE by the investigator with an outcome of death?

DR. FRIEDLAND:  Yes, that is true.

DR. MODLIN:  Jose?

DR. ROMERO:  John, one more question, if I may. So I\'m sorry if I
missed this when you presented it, but given the wide confidence
intervals for efficacy that were shown on the O-23 study for G2-P4
Rotavirus, how many cases were there? I mean, how many actual cases were
in that, and in the O-36 case?

DR. FRIEDLAND:  Yes. So if I could bring back up from the Core
presentation Slide A-38. If you could put it up on the screen. Thank
you. In this study, G2-P4 was reported by two vaccine recipients and
seven placebo recipients, so small numbers of cases.

DR. MODLIN:  Does that answer your question?

DR. ROMERO:  Yes. Sorry.

DR. MODLIN:  I think it does.

DR. ROMERO:  Thanks.

DR. MODLIN:  Are there any further questions for either the Sponsor, or
for the Agency from members of the Committee? Yes, Dr. Debold?

DR. DEBOLD:  Okay. Sorry to keep after this, but the death statistics
are still upsetting. And I\'m not comfortable with the explanation so
far, in the sense that we\'ve talked about a portion of the deaths being
related to pneumonia. That\'s only a fraction of the deaths that were
reported. The FDA said they identified 128, there were, as I\'m looking
at the graph, it says there were 73 in the vaccine group, and 55 in the
placebo group. And while I realize the confidence interval includes one,
the confidence interval was basically .9 something to \-- it was .92 to
3.02. The point estimate being at 1.64, which means that the vaccine
group was 64 percent more likely to experience death than was the
control group.

Can you please explain what these other causes of deaths were? Pneumonia
was only what, 16 of them? What are the other 100 due to?

DR. FRIEDLAND:  Yes, I certainly can. The list is quite extensive, as
you can imagine, with so many fatalities. If you\'d like, I can go
through each one with you. What I can say is an exploratory analysis, we
looked at each cause of death comparing the Rotarix group compared to
the placebo group to see if there was an imbalance. And the only
imbalance that there was when looking at the preferred terms was for
pneumonia death.

DR. DEBOLD:  I guess I don\'t know what to \-- I\'m not that familiar
with MEDRA terms. I\'m sorry to have my back to you, but I think I\'m
supposed to talk in the mic. I\'m not sure what to make of the coding
issue, because it seems like even with the convulsions, I\'m not sure
that I would have put epilepsy and coded some of these other terms into
\-- with the convulsion terms the way that you did. But was there any
sort of pattern? I mean, what was on the list? I just know that this is
going to be come up in parent groups, so it would be better to discuss
it here.

DR. FRIEDLAND:  Right. I don\'t have the list in front of me, so I\'m
going to go through my memory. But there were cases of accidents, for
example, sudden death. I\'d have to pull out the list. I\'m sorry I
don\'t remember off-hand, but there\'s a wide variety of list of
fatalities. And if there\'s a break, I can come back and share the list
with you. I\'m sorry, I just don\'t remember.

DR. MODLIN:  Probably not a bad idea.

DR. FRIEDLAND:  Oh, I have \-- well, I do have the list in front of me.
So within 30 days after vaccination, I can read down the list of these.
Thank you whoever put this up for me. I can read down the list of those
in the Rotarix group; Leukemia, gunshot wound, congenital patent ductus
ateriosus, septicemia, renal tubular acidosis, appendimoma, suffocation,
death due to unknown cause. It\'s that sort of list.

DR. MODLIN:  Do you have further questions, Dr. Debold? I\'m sure we can
provide more specificity on a piece of paper for you; although it\'s
probably not wise use of the time right now to get into great detail.
Yes?

DR. BREUER:  Maybe making one more comment. I mean, death is, obviously,
of high concern to any country. I just want to reiterate that these
studies were performed in countries where infant mortality is much, much
higher than, fortunately, in the U.S., so you expect to see hundreds of
death in, for example, the studies in Africa. The main point is that
except for pneumonia, all these were balanced, so the same proportion
happened in the placebo group, and a similar proportion happened in the
group which received Rotarix. So this should comfort you, and that
comfort us that you don\'t have any imbalance.

The other question you had was around the P-value, and maybe \-- I want
to make a general comment. When you have a primary endpoint, obviously,
you apply statistics up front, and these statistics mean something when
you evaluate these results. However, when you then go into a data mining
exercise in your safety data based on hundreds of analysis, they\'re two
schools of thought; one is that you simply report the proportions and
eye them by yourself, and decide this is something which looks cautious,
and I want to go deeper into it, and you look at it. You look at the
clinical cases, and you try to make an assessment.

The other school of thought says, and this was followed in this study.
However, there is no consensus, we do it sometimes this way, sometimes
that way, depending on who is the statistician on the team, that we say
okay, we define what is defined as an imbalance. And to do that, we
apply a statistical test.

However, the P-values and the confidence interval in that setting do
mean something totally different than a P-value or a confidence interval
as a primary endpoint. And I just wanted to make that point, that we
don\'t get mixed up on these things. This was just a tool to highlight
potential issues, and then we dig further into it, so thank you.

DR. MODLIN:  If there are no further questions, I think what we\'ll do
is go on and move towards consideration of the questions that have been
put before us. Why don\'t we put the first question back up on the
screen again, if we could. And keeping in mind that it\'s not just our
individual votes as members that\'s important, but the basis for our
votes. We are trying to provide as much detail to our opinions for our
purpose of giving advice to the Agency.

I think I will go ahead and - while we\'re getting the question up, go
ahead and open up the discussion, which has to do with are the data
sufficiently convincing regarding efficacy of the human Rotavirus
vaccine to recommend to the Agency that it be licensed. Here we go. And
I\'m also assuming that this will include use of the vaccine with the
first dose being given no later than 13 weeks of age.

Thoughts, questions? How about the CDC side here, are there any further
specific thoughts about this, concerns? Melinda?

DR. WHARTON:  Well, of course, we got less data on the G2 type than we
do for the other serotypes, so that and the constraint around when
vaccine is administered I think are the two issues I would raise related
to effectiveness. But, certainly, the data seem quite robust other than
the G2 serotype issue.

DR. FRIEDLAND:  Dr. Modlin, is it possible that I could add something to
that?

DR. MODLIN:  Certainly.

DR. FRIEDLAND:  If I could go back to Slide A-28 in the Core set. I just
wanted to show again the data on G2-P4 in O-36, just trying to point out
to you that the confidence interval that was seen was 86 percent, with a
confidence interval of 24-99. But, in addition, we have a integrated
analysis of G2-P4 in the first year from a series of the clinical
studies where we pooled the numbers just to get larger cases. So if I
could bring up that slide. So just an additional analysis to show you
additional cases of G2-P4. And that would be Slide E-6. There it is.
Thank you.

So what we\'ve done here is following standard procedures for integrated
analyses, we\'ve looked at our vaccine efficacy studies, Studies 4 and
6, where two Phase II vaccine efficacy studies, and you\'ve already
heard about Study O-23 and O-36. And this is within the first year after
vaccination. And when we pooled the G2-P4 cases across these four
studies in an integrated analysis, the vaccine efficacy for G2-P4 is
71.4 percent with statistical significance. So just additional data on
G2-P4.

DR. MODLIN:  It may very well be that the concern is in the larger study
you have the lowest efficacy, if that\'s a concern. I understand what
Melinda is saying. It actually comes down to the actual numbers of cases
of G2 illness and in two groups it\'s important on how much confidence
we have around that. Dr. Jackson?

DR. JACKSON:  Do you have a similar slide for all Rotavirus GE?

DR. FRIEDLAND:  No, I don\'t have a similar slide for all Rotavirus
gastroenteritis. You mean pooling all the types?

DR. JACKSON:  Looking for G2 for the outcome of Rotavirus GE not severe.
I believe the FDA \-- 

DR. FRIEDLAND:  Oh, yes.

DR. JACKSON:  Yes.

DR. FRIEDLAND:  I\'m sorry, I don\'t have that slide, but that analysis
has been done, and it also is statistically significant.

DR. JACKSON:  But lower?

DR. FRIEDLAND:  My statistician is here. I don\'t know. Bridgette, if
you know the number off-hand?

(Off microphone comment.)

DR. MODLIN:  Please use the microphone. And introduce yourself, if you
would, please.

MR. DEBRUS:  So I\'m Sergio Debrus from GlaxoSmithKline. I was working
in R&D developing this vaccine before. Just what I can tell you by heart
is the fact that the data we have for the meta analysis is pooling for
any gastroenteritis. We have pretty similar number that what we have
seen for the severe diseases, and we have a good confidence interval, so
it\'s pretty the same number for any and severe disease for the meta
analysis in G2-P4.

DR. KOU:  Excuse me. Can I \-- 

DR. MODLIN:  Yes.

DR. KOU:  My name is Jingyee Kou. I\'m a FDA statistician, and I\'m a
statistical reviewer for this product. And we have looked at each
individual serotypes, and to us, the \-- we wanted to see is clear
evidence on the control, well-controlled study. And the G2, in this case
they\'re combining all of the studies, and they\'re not all \-- have the
same condition when they enrolled the subject, and so we don\'t consider
this is enough evidence to support G2.

DR. MODLIN:  Thank you.

DR. FRIEDLAND:  And if I could just, we could bring back up again, in an
individual study, as a reminder, in Study O-36, statistical significant
efficacy is seen is an isolated single study through the two years.

DR. MODLIN:  Fair enough. It sounds like this is going to be an issue
between the Sponsor and the Agency with respect to labeling. I don\'t
think it\'s likely to have a major effect on how we feel about its
efficacy against the other types, if that\'s a fair summary. Lisa?

DR. JACKSON:  Potentially, it could influence the post-licensure
considerations, however.

DR. MODLIN:  It could, if you can find enough cases some place. Any
other thoughts? Is there anyone on the Committee who feels that \-- who
have \-- let me say, is not disposed to being positive towards this
question? And if so, why? Jose, you\'ve got your finger up.

DR. ROMERO:  I guess I need a little bit of clarification here, because,
again, I hate to use this first meeting as a crutch excuse. I mean, I
agree with everything except the G2. And the question that you\'re
asking is, is it approved \-- are you going to vote yes for everything
but one of those, or how does that work, John?

DR. MODLIN:  I don\'t think that we \-\-\-\-- I\'ll just take the
prerogative, the Chair\'s prerogative of saying I think we don\'t have
to settle that issue. Is that fair, Norm? I don\'t \-- it\'s thrown in
there, but that\'s going to be an issue between the Agency and GSK in
terms of what the final label actually says.

DR. ROMERO:  Right. And that\'s what my question about the G2 was early
on.

DR. MODLIN:  Right. I think they would like to know our general
enthusiasm for including it, but I think they\'ve heard it.

Well, is there any further discussion on this question at all? If not,
I\'ll entertain a motion to call the question.

DR. ROMERO:  So moved.

DR. MODLIN:  So moved.

DR. DAVIS:  Second.

DR. MODLIN:  Seconded. Any further discussion?

Okay. We are under a new procedure, and that is rather than going around
and asking each member\'s vote, voting member in the past, we will be
voting all simultaneously. So I\'m going to ask those who would be
voting yes on Question One, if you would raise your hand, and keep it
raised. And Dr. Wharton, DeStefano, Dr. Stapleton, Dr. Davis, Dr. Belay,
Dr. Modlin, Dr. Debold, Dr. Romero. Everybody around to me, Dr. Debold,
Dr. Romero, Dr. McInnes, Dr. Self, Dr. Sanchez, and Dr. Jackson. I
believe there are no nos, or no abstentions, because everyone voted yes
on this question.

Let\'s move on to Question Two, if we might. And, again, I\'m assuming
that \-- for the safety purposes that we\'re assuming that this means
that the first dose will be given by 13 weeks of age. Let me open this
up to questions, or not to questions, questions or discussion. Why
don\'t we start over on this side of the table, if anyone has any
specific issues, questions, discussion regarding safety? We\'ve heard an
awful lot about it today. This side. Melinda?

DR. WHARTON:  Well, I am not highly concerned about the pneumonia issue,
but it is a little concerning seeing a respiratory disease signal in
multiple studies. And in thinking about, is there any biological
mechanism that one can possibly come up with? What the studies suggest
is that Rotavirus disease as developed in the placebo group, may protect
from respiratory infection, which I think might be biologically
plausible if, in fact, the immune system tends to only get one viral
infection at a time. And this is why I was asking the earlier questions
about seasonality.

If, in fact, the vaccinated group got Rotavirus vaccine outside of
respiratory disease season, and the unvaccinated group got Rotavirus
disease during respiratory disease season, perhaps they had a slightly
decreased risk of getting a viral respiratory infection, which then
might predispose them to serious viral or bacterial outcomes. And I
don\'t know if this makes any sense from the immunological point of
view, but it\'s the only thing I could come up with in thinking about
this.

DR. MODLIN:  It does, and I was thinking about the same thing, and
whether or not there might be yet ways to probe whether there\'s
actually a statistical interaction between protection against Rotavirus
disease; in other words, less disease, and risk of pneumonia. But we\'re
really not looking at risk of pneumonia, we\'re looking at risk of
pneumonia deaths, when you think about it, which is a different animal
here. But I would agree with Melinda. I would think that any efforts to
try to understand this better, whatever way we can, given the existing
database, and it may be possible to do that. Where those kids \-- well,
see whether actually there\'s a statistical interaction between
protection and subsequent pulmonary disease with death would be very
interesting. Yes, sir?

DR. IZURIETA:  My name is Hector Izurieta. I\'m a reviewer for FDA. I
had a question which might be interesting, if GSK would address it. When
we read the list of deaths on Rota O-23, which is the main one
implicated in the pneumonia deaths issue, if you just run the numbers
for aspiration deaths, deaths that include the phenomenon of aspiration
by the child, you might find an imbalance probably, around 7-2. The
intervals may be very far away, there could be some that are very near
to the vaccination date, but I\'d like to see you comment on that.

DR. MODLIN:  There is a specific cause of pneumonia death, which is
aspiration. Can you tease that out between the two groups?

DR. IZURIETA:  Not necessarily coded as pneumonia, any death that is
coded as aspiration, either pneumonitis, pneumonia, chest aspiration,
gastric fluids aspiration, any of those phenomenon, because this is an
oral vaccine. I just want the clarification.

DR. FRIEDLAND:  There were deaths that were coded as aspiration. Of
course, for each preferred term there was no imbalance between the
groups. I think it\'s an excellent suggestion, and we can certainly go
and do those analyses, pooling those preferred terms to see if there\'s
an imbalance.

DR. MODLIN:  Any other concerns about safety information that has been
presented today? Dr. Self?

DR. SELF:  Not so much a concern, but a comment about adequate safety
\-- data being adequate, support safety. And while the signals are
important, and should be attended to, we should probably just point out
that the attributable risk associated with these safety terms is one or
two orders of magnitude below the risk associated with the primary
efficacy endpoint. And there are issues about comparing how severe the
different endpoints are, and all of that, but that should be the
context, I think, that we use to answer this question. It wasn\'t quite
brought out maybe as well as it could be in the presentations, but that
information is there, and we should attend to it.

DR. MODLIN:  That\'s an excellent point.

DR. DAVIS:  Can I follow-up on that, because I was wondering about the
same thing. Because if you think that the protection against death
overall from the primary endpoint is immediate, if the protection is
immediate, you should actually see a reduction in death within the very
confined time points we\'re looking at, and for various reasons.

But I\'m wondering whether they\'ve actually extended their analyses
\-- this is unfair, because as an ad hoc on an ad hoc, but whether you
can actually \-- whether there is any data that looks at this over a
longer term to see whether there is reduction of death due to natural
Rotavirus, any overall reduction of death which one would presume would
be primary driven by the reduction of natural disease. I think I got
that out right. That\'s actually a question. I mean, feel free to \-- 

DR. MODLIN:  I hear your question. Would the company like to respond
with data that you don\'t have?

DR. VERSTRAETEN:  Could you clarify, Bob? We\'re not sure we understood.

DR. DAVIS:  Well, Steve was making a point that overall, even though
\-- let\'s assume that the data is, in fact, real, that there might be a
small blip increase in pneumonia-related deaths, and I don\'t think any
of us are willing to go that far quite yet, but let\'s \-- for the
purpose of argument, let\'s assume that\'s real. Over time, it will be
compensated for many times over by the reduction in death due to natural
Rotavirus disease. And I was just wondering, do you have any evidence
that, in fact, demonstrates that?

DR. VERSTRAETEN:  As far as I know, we don\'t have additional follow-up
data that would help us in that. Of course, mortality rates go down
quickly as these kids age, so the highest mortality, of course, is in
the earlier age group.

DR. BREUER:  So as we have pointed out in our initial presentation,
death due to Rotavirus is still very common in countries, even in
countries where we have performed the studies, so since it seems we all
agree, including the Committee, that this is a highly efficacious
vaccine, so it will have a major impact on Rotavirus death.

However, in clinical studies you will never find this, because these are
settings which are sort of artificial. We are taking good care of our
placebo group, and we take good care of our variant group, so this kind
of effects you will not find in clinical studies. However, with a high
efficacious vaccine, you can fully expect that in a setting where
children die from Rotavirus disease, that you will have a major impact
on Rotavirus death.

DR. MODLIN:  Yes?

DR. BELAY:  From the dates that you\'ve already identified, you could
potentially compare deaths associated with diarrhea, or dehydration. You
can see there are differences in the two groups.

DR. MODLIN:  Thank you. Any other discussion? If not, I assume that the
Committee is ready to vote on this question. I will ask for a vote
\-- ask you if you would raise your hand if your vote on this question
is yes, the available data are adequate to support the safety of Rotarix
when used as described on the slide. Those who vote yes?

DR. BELAY:  A question.

DR. MODLIN:  Yes?

DR. BELAY:  Are we allowed to qualify our answers, or a show of hands?

DR. MODLIN:  Yes, you are, but why don\'t we go ahead and take the vote,
and then I\'ll come back. You\'re certainly permitted to qualify your
vote. Okay. Those voting yes are Dr. Wharton, Dr. DeStefano, Dr.
Stapleton, Dr. Davis, Dr. Belay, Dr. Modlin, Dr. Romero, Dr. McInnes,
Dr. Self, Dr. Sanchez, and Dr. Jackson. Those voting no, Dr. Debold, and
I believe that\'s everyone, that no one is abstaining. And yes, we are
permitted to go back afterwards and explain your vote, if you would like
to.

DR. BELAY:  My qualification is there would be continued post-marketing
surveillance for some of the safety issues that were raised, including
the safety concerns associated with previous Rota vaccines, such as
intussusception, Kawasaki, and the others. And, also, the new situation
that unrolls during the studies which would include the pneumonia death
and the convulsions.

DR. MODLIN:  Okay. Should we move on to question three, please? Are
there additional issues that should be addressed in the post-marketing
studies beyond the applicant\'s proposed study? And, specifically, Dr.
Belay\'s last comment gets right at this. We\'ve already had a fair
amount of discussion about this, already. Is there further discussion?

Dr. Jackson?

DR. JACKSON:  Well, I wonder if Tom might want to comment on the
methodology, because I\'m struggling with how you could possibly use a
self-controlled method. I mean, the difference between this and the
previous experience that Trudy Murphy analyzed was that you\'re going to
have very little heterogeneity in the timing of your exposure, meaning
that you\'re only to give the first dose during a certain age, pretty
narrow window, and consequently the second dose.

And then I assume there\'s going to be some risk window, 90 days, or 30
days. So, unavoidably, you\'re going to be comparing older age with
younger age, and since this outcome, or many of the outcomes are
age-dependent, and there\'s a huge difference between a two-month old
and a five-month old, I just don\'t know how you can do it. And I\'m
sure you\'ve thought about this a lot more than I have, Tom.

DR. VERSTRAETEN:  Yes. Thanks, Lisa. Yes, we have thought quite a bit
about it. We actually talked to Paddy Farrington, who\'s the guy who
pretty much invented, or at least applied it to vaccine safety, and has
been a little bit the godfather of this method. And he was a little bit
puzzled at first, as well, because this is obviously a non-recurring
event, both intussusception, and certainly deaths. So the only way we
could do it is actually do it by dose, and we cannot combine the two
doses, because once you\'ve had one of the events, you will not have
another dose.

We were concerned about whether we would have enough heterogeneity.
However, the risk period is one month, and there is heterogeneity at the
age of vaccination. We see that. We see that in Europe, we see that in
Latin America, sufficient that we can actually adjust for age even
within that method. So I think that will be okay.

We will not have a control period before vaccination, so that will be
the limitation here, the control period will be after the risk period.
So the only concern we actually have is, if by any chance our vaccine
protects against any of the outcomes, then we will have to take care of
that, as well. But as for the age effect, we\'re confident that we will
be taking care of it.

DR. MODLIN:  Further questions or comments? I might just say for myself
\-- go ahead, Frank.

DR. DeSTEFANO:  I guess, just following up on this self-control
methodology. So you\'re going to say, let\'s say, intussusception cases.
You restrict this to vaccinated intussusception cases? I mean, because
of this age \-- 

DR. VERSTRAETEN:  Yes.

DR. DeSTEFANO:  \-- issue, and needing to control finely for age, you
might be well-served to include all cases, or non-vaccinated cases to
get a better distribution by age, or other factors.

DR. VERSTRAETEN:  You\'re right. Theoretically, you don\'t need them,
but if you have them, they help you to take care of the background, to
better define the impact of age. Yes. We will use them, but we don\'t
necessarily need them.

DR. MODLIN:  I have to admit that I have a fairly high degree of
confidence in the data that I\'ve seen with respect to intussusception.
I think the data are very robust. I know that we can never prove the
null hypothesis and say that the vaccine never causes intussusception.

But, on the other hand, we have a whole lot more data here than we have
over many, many other adverse events that we\'re concerned about, for
good reason. But that\'s just a comment. I\'m not actually looking to
see a whole lot more. I don\'t know how others feel about that. I do
think that some of these other signals are very, very important to
follow-up on, that we\'ve already discussed, but I\'m fairly confident
in this.

Dr. Davis?

DR. DAVIS:  I can\'t help myself. Lisa got me thinking, which is that if
you do a self-control group, a self-control analysis for death, I\'m
just sort of harping on that, we\'ve already sort of expressed the fact
that the concern may be one of a biologic phenomenon that extends way
passed 30 days, so the exposed group is really almost forever after the
exposure \-- the time window could go out for three, four, five, six
months after the exposure starts.

So I\'m not really sure that \-- I guess I\'m quite concerned that
whether a self-control group study is actually possible to examine
death.

DR. VERSTRAETEN:  We\'ve thought about that, as well. To go beyond one
month would be very difficult in a self-controlled. I mean,
theoretically it\'s possible, and Farrington claims that you can
actually check for autism after MMR using this method, following up for
even longer periods. I think we do have to go back to what we believe is
really plausibly possible, so to say, and it brings us back to the
question in biological plausibility.

It really doesn\'t make sense that there would be an effect later, much
later than the actual infection, and any symptoms that have been
described, respiratory symptoms around Rotavirus infection have always
been around the time of the infection, or even before, having some
people suggest that may be a respiratory transmission of Rotavirus.

So we\'re pretty sure if there is anything, it should be really around
the time of vaccination. So that will be a limitation, I agree, but I
think it\'s the most sensible period to be looking at.

DR. MODLIN:  Any other questions or comments?

Norm, maybe I could ask either you, or Dr. Leventhal if you felt that
there\'s other issues or items that you\'d like the Committee to touch
upon that we haven\'t? If not, I think we can consider this meeting
adjourned. Thank you, everyone.

(Whereupon, the proceedings went off the record at 2:37:58 p.m.)