# Presentation: 094213

## Vaccine and Related Biologics Products Advisory Committee December 14, 2005

- Merck & Co., Inc.

- RotaTeqTM
- Rotavirus vaccine, live, oral, pentavalent

- k

## RotaTeqTM Proposed Indication

- RotaTeqTM is an oral pentavalent vaccine indicated for the prevention of rotavirus gastroenteritis in infants and children caused by the serotypes G1, G2, G3, G4, and G-serotypes that contain P1a (e.g., G9)
- RotaTeqTM may be administered to infants as young as 6 weeks of age

## RotaTeqTM Agenda

- Mark Bagarazzi, MD, FAAP
- Global impact of rotavirus gastroenteritis
- Overview of RotaTeqTM clinical development program

## RotaTeqTM Agenda

- Mark Bagarazzi, MD, FAAP
- Global impact of rotavirus gastroenteritis
- Overview of RotaTeqTM clinical development program
- Penny Heaton, MD
- Rotavirus gastroenteritis in the US
- Clinical trial results
- Overall benefit/risk profile

## Rotavirus: Leading Cause of Severe Diarrhea in Infants and Young Children Worldwide

- Virtually all children are infected by 5 years of age
- Worldwide, approximately 1,000 children die every day from rotavirus
- Rotavirus accounts for over 2 million hospitalizations worldwide annually (55,000-70,000 in US)
- Rotavirus affects all children equally
- Regardless of socioeconomicstatus, environmental conditions, geographic area
- Severe symptoms equally commonin developed and developing world

- Parashar et al., *Emerging Infect Dis.* 2003; 9:565-72.
- Parashar et al., 2005 IDSA; Abstract 579.

## RotaTeqTM Development

## RotaTeqTM Development

**Proof-of- **
**Concept Study ****(G1-3, P1) (002)**

## RotaTeqTM Development

**Proof-of- **
**Concept Study ****(G1-3, P1) (002)**

**Study of**
**Different Buffers (G1-2) (003)**

## RotaTeqTM Development

**Monovalent (P1), Quadrivalent (G1-4), Pentavalent (G1-4, P1) (005)**

**Proof-of- **
**Concept Study ****(G1-3, P1) (002)**

**Study of**
**Different Buffers (G1-2) (003)**

## RotaTeqTM Development

**Monovalent (P1), Quadrivalent (G1-4), Pentavalent (G1-4, P1) (005)**

**Proof-of- **
**Concept Study ****(G1-3, P1) (002)**

**Study of**
**Different Buffers (G1-2) (003)**

## RotaTeqTM Development

**Dose-ranging Study,**
**Monovalent (P1), Quadrivalent (G1-4), Pentavalent (G1-4, P1) (005)**

**Proof-of- **
**Concept Study ****(G1-3, P1) (002)**

**Study of**
**Different Buffers (G1-2) (003)**

**Study Design Endorsed by FDA Advisory Committee**

## RotaTeqTM Development

**Proof-of- **
**Concept Study ****(G1-3, P1) (002)**

**Dose-ranging Study,**
**Monovalent (P1), Quadrivalent (G1-4), Pentavalent (G1-4, P1) (005)**

**Study Design Endorsed by FDA Advisory Committee**

**Study of**
**Different Buffers (G1-2) (003)**

## RotaTeqTM Phase III Program

- Safety
- Intussusception (REST)

**Large-Scale **
**(**_**R**_**otavirus **_**E**_**fficacy and **_**S**_**afety **_**T**_**rial ; REST) **
**(006)**

## RotaTeqTM Phase III Program

- Safety
- Intussusception (REST)

**Dose Confirmation Efficacy**
**(007)**

**Large-Scale **
**(**_**R**_**otavirus **_**E**_**fficacy and **_**S**_**afety **_**T**_**rial ; REST) **
**(006)**

## RotaTeqTM Phase III Program

- Safety
- Intussusception (REST)

**Dose Confirmation Efficacy**
**(007)**

**Consistency Lots Study ****(009)**

**Large-Scale **
**(**_**R**_**otavirus **_**E**_**fficacy and **_**S**_**afety **_**T**_**rial ; REST) **
**(006)**

## RotaTeqTM Phase III Program

- Safety
- Intussusception (REST)
- Generally well tolerated
- AEs of special interest (Fever, vomiting, diarrhea, and irritability)

**Dose Confirmation Efficacy**
**(007)**

**Consistency Lots Study ****(009)**

**Large-Scale **
**(**_**R**_**otavirus **_**E**_**fficacy and **_**S**_**afety **_**T**_**rial ; REST) **
**(006)**

## RotaTeqTM Phase III Program

- Efficacy (REST, Protocol 007)

## RotaTeqTM Phase III Program

- Efficacy (REST, Protocol 007)
- RV gastroenteritis due to vaccine-virus serotypes

## RotaTeqTM Phase III Program

- Efficacy (REST, Protocol 007)
- RV gastroenteritis due to vaccine-virus serotypes
- Prevents 98% of severe disease

## RotaTeqTM Phase III Program

- Efficacy (REST, Protocol 007)
- RV gastroenteritis due to vaccine-virus serotypes
- Prevents 98% of severe disease
- Prevents 74% of all disease

## RotaTeqTM Phase III Program

- Efficacy (REST, Protocol 007)
- RV gastroenteritis due to vaccine-virus serotypes
- Prevents 98% of severe disease
- Prevents 74% of all disease
- Reduction in hospitalizations and emergency department visits by 94%

## RotaTeqTM Phase III Program

- Immunogenicity

## RotaTeqTM Phase III Program

- Immunogenicity
- Consistency of manufacturing process (Protocol 009)

## RotaTeqTM Phase III Program

- Immunogenicity
- Consistency of manufacturing process (Protocol 009)
- Integration of RotaTeqTM into immunization schedule of 2- to 6-month olds (REST)

## Experts in Attendance

- H Fred Clark, DVM, PhD – Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine
- Paul Offit, MD  - Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine
- King Holmes, MD, PhD - University of Washington School of Medicine, (Chairman REST DSMB)
- Janet Wittes, PhD – Statistics Collaborative (Statistician, REST DSMB)
- Gary S. Marshall, MD – University of Louisville
- David O. Matson, MD, PhD – Eastern Virginia Medical School (Principal Investigator, REST, US sites)

## RotaTeqTM Agenda

- Mark Bagarazzi, MD, FAAP
- Global impact of Rotavirus gastroenteritis
- Overview of RotaTeqTM clinical development program
- Penny Heaton, MD
- Rotavirus gastroenteritis in the US
- Clinical trial results
- Overall benefit/risk profile

## Objectives

- Brief review of rotavirus epidemiology
- Description of the pentavalent human-bovine reassortant rotavirus vaccine, RotaTeqTM
- Overview of Phase III clinical trials
- Results from Phase III clinical trials supporting licensure of RotaTeqTM
- Safety
- Efficacy
- Immunogenicity

## Public Health Burden of Rotavirus Disease in the United States

- Rotavirus accounts for 4% to 6% of all pediatric hospitalizations
- Risk of developing rotavirus gastroenteritis and associated outcomes does not vary by geographic region
- Updated estimates of rotavirus morbidity and mortality show no change over the last decade

- Parashar et al., 2005 IDSA; Abstract 579.

## US Annual Burden of Rotavirus Disease 

**Risk by **
**5****th**** birthday**

**Annual Burden**

**AGE Episodes**

**Emergency (ED)/****Outpatient (OPD) ****Department **
**Visits  **

**Hospitalizations**

**Deaths**

- 1:129,000
- 1:65
- 1:171:10
- 2:3

- 20 - 60
- 55,000 - 70,000
- 205 - 272,000 ED410,000 OPD
- 2.7 million

- Parashar et al., 2005 IDSA; Abstract 579.

## Structure of Rotavirus

- Nonenveloped icosahedral particle
- 11 segments of double-stranded RNA enclosed in a triple layer capsid
- Outer layer consists of VP7 and VP4, which are important for immunity
- Induce serotype-specific neutralizing antibodies
- Rotaviruses are classified by their G- and P-types
- VP7 determines G-type
- VP4 determines P-type

- Figure adapted from Estes MK, *J Infect Dis. *1996;174(Suppl 1):S37-S46.

-  **VP4 (P serotype)**

**VP7 (G serotype**)

## G1, G2, G3, and G4 Account for >90% of Rotavirus Cases*

- Prevalent G- and P-types in US,1996-2002

- * Griffin et al., *J Clin Microbiol* 2000; 38:2784-7 and Santos et al., *Rev. Med. Virol.* 2005; 15:29-56.

- P1a is Most Common P-Type

## Rotavirus Gastroenteritis is Characterized by Fever, Vomiting, and Watery Diarrhea

- Average duration 6 days (3 to 9 days)
- Extended duration of vomiting with diarrhea may cause dehydration
- Hospitalization may be required
- Death may occur if supportive care unavailable

- Rodriguez et al., *J Pediatrics* 1977; 91(2):188-193 and Santos et al., *Rev. Med. Virol*. 2005; 15:29-56.
- * Statistically significant.

## Basis for Prevention of Rotavirus Gastroenteritis Through Vaccination

- Wild-type rotavirus infection induces immunity against subsequent rotavirus gastroenteritis
- Greatest protection against severe disease
- Substantial protection against mild gastroenteritis
- Natural immunity is largely serotype-specific
- We developed a multivalent rotavirus vaccine directed against the most prevalent rotavirus serotypes

- Velazquez et al., *N Engl J Med* 1996; 335:1022-8.

## Characteristics of RotaTeqTM

- Oral vaccine suspended in a liquid buffer/stabilizer
- Protected from gastric acid
- Stored refrigerated with 24-month shelf life
- Administered directly from tube
- 3-dose regimen that will integrate into pre-established immunization schedules
- First dose age 6 to 12 weeks
- Subsequent doses at 1- to 2-monthintervals
- Contains 5 human-bovine rotavirus reassortants
- Serotypes:	Human G1, G2, G3, G4, and P1a
- 	Bovine G6, P7

## Bovine (WC3) Rotavirus

## Overview of Development of RotaTeqTM

- concept (efficacy)
- study (G1-3, P1)(002)

- Clinical study of
- different buffers (G1-2)(003)

- Study to establish dose
- and serotype composition
-  (pentavalent; G1-4, P1)(005)

## Characteristics ofNaturally-Occurring Intussusception

- Etiology not well defined
- Uncommon: Incidence ~1/2000 infant-years
- Peak incidence is between 5 and 9 months of age
- Male to female case ratio = 1.5-4:1
- Treated with enema or surgery
- Morbidity and mortality low iftreated early; however, delay in diagnosis may be fatal

## Cases of Intussusception Associated with RRV-TV Clustered During the 2 Weeks After Doses 1 and 2

- Murphy et al., *New Engl J Med* 2001; 344:564-72.

## Basis for Decision to Continue Developmentof RotaTeqTM in the Face of Concerns About Intussusception (IS)

- Public health need for a safe and effective rotavirus vaccine
- Phase II studies showing that the vaccine was well tolerated and prevented rotavirus gastroenteritis
- Single case of IS in 2470 vaccine recipients
- RRV-TV associated with IS may be rhesus strain-specific
- Wild-type rotavirus does not appear to cause IS
- Pre-clinical/clinical differences between RotaTeqTM and RRV-TV
- FDA Advisory Committee approved design for large-scale Rotavirus Efficacy and Safety Trial (REST) in May 2000

## Developmentof RotaTeqTM

- Proof-of-
- concept study (G1-3, P1) (002)

- Study to establish dose
- and reassortant composition
-  (pentavalent; G1-4, P1) (005)

- 1993

- 1997

- 1998

- 2001

- 2002

- 2003

- 2000

- 1999

- Reports of intussusception
- with RRV-TV

- Large-Scale Trial
- (_R_otavirus _E_fficacy and _S_afety _T_rial ; REST) (006)

- Dose Confirmation Efficacy
- (007)

- 2004

- 2005

- Consist-ency Lots Study (009)

- Filed for
- licensure

- Phase III  (RotaTeqTM)

- Clinical study of
- different buffers (G1-2) (003)

- FDA Advisory Committee Meeting

## Evaluation of Safety withRespect to Intussusception:  Rotavirus Efficacy and Safety Trial (REST)

## REST Study Design

- Sample size:	≥60,000 (randomized 1V:1P)	Additional groups of 10,000 subjects 	enrolled until primary safety criteria 	met or 100,000 subjects enrolled
- Age:	6 to 12 weeks at first dose
- Regimen:	3 oral doses, 1 every 4 to 10 weeks
- Sites:	Areas with good standard of care for	intussusception
- Duration:	January 2001 to April 2005

## REST Primary Safety Hypothesis

- RotaTeqTM will not increase the risk of intussusception (IS) relative to placebo within 42 days of any dose
- To satisfy the primary safety hypothesis, 2 criteria must be met:
- 1.		Interim monitoring:  No increased IS risk (LB 95% CI >1) in vaccine recipients following any dose
- 1 to 7 days
- 1 to 42 days
- 2.		End of study:  Upper bound of the 95% CI estimate of the relative risk of IS ≤10
- RR point estimates ≤2 would be needed to satisfy the safety criteria

## Comprehensive Interim Monitoring for Intussusception (IS)

- Active Surveillance at Study Sites
- Contacts on days 7, 14, and 42
- Up to 1 year after first dose

- Independent SafetyEndpoint AdjudicationCommittee
- - Adjudicated cases using specific case definition

- Independent Data andSafety Monitoring Board (DSMB)
- - Unblinded each case and made recommendations for continuation
- - Reviewed safetydata every 6 months

## Comments on Statistical Propertiesof REST Study Design

- Goals of REST study design and the extensive safety monitoring were to provide:
- High probability that a study of a vaccine with increased intussusception risk would stop early; and simultaneously
- High probability that a safe vaccine would meet the end-of-study criteria
- The statistical operating characteristics of REST were estimated using Monte Carlo simulation

## Statistical Operating Characteristics of REST

- * Murphy et al., *New Engl J Med* 2001; 344: 564-72.
- Probabilities based on two different risk profiles reported by CDC.

- Risk Scenario

- Safe Vaccine (RR=1)
- RRV-TV Risk Profile*

- Probability of Stopping Early Because Unsafe

- 6%
- ~90%

- Probability of Meeting End of StudySafety Criteria

- 94%
- ~10%

- Probability of Meeting End of StudySafety Criteria

## 71,799 Subjects in 11 Countries Vaccinated36,203 in RotaTeqTM Group35,596 in Placebo Group

- 71,799 Subjects in 11 Countries Vaccinated36,203 in RotaTeqTM Group35,596 in Placebo Group

## Safety Follow-up: Phase III Trials

- 5,497(89.5)

- 3rd Dose + 42 days

- Placebo
- n=5,579
- n (%)

- 4,995(89.5)

- Vaccine
- n=36,203
- n (%)

- 33,115(91.5)

- Placebo
- n=35,596
-  n (%)

- 32,531(91.4)

## REST Intussusception Results

- No intussusception cases in Protocols 007 and 009

- 35 Investigator-Diagnosed
- Intussusception Cases

- 0V:2P

- 11 caseswithin
- 42 daysof a dose

- 4 casesreported  after study
- completed

- 17 cases>42 daysof a doseand ≤1 yrof dose 1

- 0V:4P

- 6V:5P

- 7V:10P

- 32 positively-adjudicatedcases

- 2 negatively- adjudicatedcases

- 1 unadjudicatedcase

- 0V:1P

## Confirmed Intussusception Cases in REST Within 1 Year of Dose 1

- 13 Vaccine : 15 Placebo
- RR=0.9; 95% CI=0.4, 1.9

## Confirmed Intussusception Cases in REST Within 42 Days of Each Dose

- 6 Vaccine : 5 Placebo
- RR=1.2; 95% CI=0.3, 5.0*

- * Unadjusted for multiplicity.

- Day 42

## Characteristics of Intussusception Cases Were Similar to Those of Naturally-Occurring Intussusception

- Incidence, gender, and age of cases were similar to naturally-occurring intussusception
- Incidence (infant-years):
- 1:2253 overall; 1:2101 in placebo recipients
- Gender: 19 male, 13 female
- Peak age at diagnosis: 5 to 9 months
- No shift of vaccine cases to younger infants 2 to 3 months old

## REST Data Provide a High Level of Confidence in the Safety of RotaTeqTM

- Primary safety hypothesis was satisfied
- Relative risk of intussusception met pre-specified statistical criteria for clinical acceptability
- RR=1.6; 95% CI=0.4,6.4 (multiplicity adjusted)
- Intussusception cases occurred sporadically
- No clinical evidence of an increased intussusception risk among vaccine recipients within 7 and 14 days of any dose
- Characteristics of cases in REST were similar to those of naturally-occurring intussusception

## Additional Safety Datafrom the Phase III Studies (REST, Protocol 007, Protocol 009)

## Overview of Safety Evaluationsin Phase III Studies

- Overview of Safety Evaluationsin Phase III Studies

**Detailed Safety**
**Cohort**
**N=11,722****(6143V:5579P)**

**All serious adverse events (SAEs) including intussusception**
- Vaccine-related SAEs and deaths were to be reported until study’s end

**All adverse events (AEs)**
- Other AEs of clinical interest
- Fever (temp ≥100.5°F rectal equivalent), vomiting, diarrhea, irritability, and hematochezia

**Large-Scale Cohort**
**N=71,799**
**(36,203V:35,596P)**

- +

- Fecal vaccine-strain shedding was evaluated in 2 ways
- Pre-specified time interval
- All rotavirus-positive potential acute gastroenteritis cases

- N=Number vaccinated.

## Summary of Serious Adverse Events (SAEs) Within 42 Days of Any Dose

- Large-Scale Cohort

- No SAEs
- SAEs
- Dose-related SAEs
- Deaths
- Discontinued due to an SAE

- Number (%) of Subjects

- 35,289 (97.6)
- 861   (2.4)
- 49   (0.1)
- 15 (<0.1)
- 83   (0.2)

- RotaTeqTM

- 34,614 (97.4)
- 922   (2.6)
- 79   (0.2)
- 13 (<0.1)
- 72   (0.2)

- Placebo

## Most Frequently Reported SAEsWithin 42 Days of Any Dose

- Most frequent SAEs overall	Bronchiolitis	Gastroenteritis
- Most frequent dose-related SAEs(blinded investigator-assessment)	Gastroenteritis	Fever	Dehydration

- Number (%) of Subjects

- 226 (0.6)73 (0.2)
- 17 (<0.1)8 (<0.1)3 (<0.1)

- RotaTeqTM

- 257 (0.7)117 (0.3)
- 33 (0.1)12 (<0.1)13 (<0.1)

- Placebo

- Large-Scale Cohort

## Percent of Infants with Fever Within Week of Dose by Vaccination Group and Dose Number

- Detailed Safety Cohort

## Percent of Infants with Vomiting, Diarrhea,and Irritability Within Week of First Doseby Vaccination Group

- * p-Value (2 sided) <0.05.

- Detailed Safety Cohort

## Percent of Infants with Hematochezia* Within6 Weeks of Dose by Vaccination Groupand Dose Number

- Percent of Infants with Hematochezia* Within6 Weeks of Dose by Vaccination Groupand Dose Number

- Detailed Safety Cohort

## Evaluation of Fecal Shedding of Vaccine-Virus Strains

- Phase II studies of fecal shedding of vaccine-virus strains:
- Low (<10%) proportion of subjects
- Low (<103 PFU/mL) quantities
- Almost exclusively after dose 1
- Vaccine-virus strain fecal shedding peaked during 4- to 6-day period after the first dose
- Fecal shedding of vaccine-virus strains evaluated in REST and Protocol 007
- Prospectively defined subset of ~300 subjects 4 to 6 days after each dose (REST)
- Potential acute gastroenteritis episodes that were rotavirus EIA-positive (REST and Protocol 007)

## Fecal Shedding of Vaccine-Virus Strains in REST and Protocol 007 Occurred Almost Exclusively After Dose 1

- Latest shedding postdose was 15 days from dose 1
- One subject shed 4 days from dose 3
- Low quantities (5101 to 1.88104 PFU/mL)

## Summary of General Safety

- RotaTeqTM was generally well tolerated
- RotaTeqTM was well tolerated with respect to the adverse events of special clinical interest (fever, vomiting, diarrhea, irritability, and hematochezia)
- Small risk (1.3%) of mild diarrhea and vomiting after vaccination
- Vaccine-virus strain fecal shedding occurred infrequently and almost exclusively during the week after the first dose
- Suggests that risk of transmission of vaccine-virus strains is low

## Efficacy Objectives and Resultsfrom the Phase III Studies(REST and Protocol 007)

## Efficacy Evaluations in the Phase III Studies

**Large-Scale Cohort**
**(REST)**
**N=68,038**
**(34,035V:34,003P)**

- Efficacy against hospitalizations and emergency department visits for rotavirus acute gastroenteritis (RV AGE)

- Efficacy against all RV AGE (REST and Protocol 007)
- Efficacy against office visitsfor RV AGE (REST)

**Efficacy Cohort **
**(REST and 007)**
**N=6983**
**(3484V:3499P)**

- N=Number vaccinated.

- REST, Protocol 007

## Primary Efficacy Hypotheses

- Oral RotaTeqTM will be efficacious against rotavirus disease caused by serotypes G1, G2, G3, and G4 that occurs following a 3-dose regimen

- Efficacy against moderate and severe rotavirus disease caused by G1-4 serotypes (REST and 007)
- Efficacy against rotavirus gastroenteritis caused by the individual G serotypes in the vaccine (G1, G2, G3, G4) and not in the vaccine (e.g., G9) (REST and 007)
- Efficacy during a second rotavirus season postvaccination (REST)

- REST and Protocol 007

- Other Efficacy Objectives

## Case Definitionfor Rotavirus Gastroenteritis

- Clinical Case Definition
- Forceful vomiting and/or ≥3 loose stools in 24 hours
- Severity of cases assigned using a clinical scoring system
- Based on intensity and duration of  fever, vomiting, diarrhea, and behavioral changes:     ≤8=mild; >8 ≤16=moderate; >16=severe
- Laboratory Case Definition
- Rotavirus detection by EIA
- Serotype identification by PCR
- Vaccine-virus strain identification by plaque and electropherotyping

- Clinical and Laboratory Criteria

## Efficacy Endpoints

- Primary efficacy analysis
- Efficacy against hospitalizations, emergency department visits, and office visits for rotavirus gastroenteritis
- Intention-to-treat (ITT) efficacy analyses
- Serotype-specific efficacy
- Second season efficacy

## Primary Efficacy Hypotheses Were MetRotaTeqTM Was Efficacious Against G1-4 Rotavirus Gastroenteritis 

- Primary Efficacy Hypotheses Were MetRotaTeqTM Was Efficacious Against G1-4 Rotavirus Gastroenteritis

- N=number vaccinated.

## RotaTeqTM Was Efficacious Against Hospitalizations, Emergency Department Visits & Office Visits for G1-4 Rotavirus Gastroenteritis

- † N=34,035 vaccinated in vaccine group and 34,003 vaccinated in placebo group.
- ‡ N=2834 vaccinated in vaccine group and 2839 vaccinated in placebo group.

- REST

## Intention-to-Treat Analysis: Efficacy of RotaTeqTM Against G1-4 Rotavirus Gastroenteritis

- Disease Severity

- Any
- Severe

- % Efficacy

- 59.7
- 96.8

- 95% CI

- 51.9,66.4
- 88.1,99.6

- Number of Cases

- 177
- 2

- Vaccine
- (N=3484)

- 435
- 62

- Placebo
- (N=3499)

- From First Day of Vaccination Among All Subjects Who Received at Least One Dose
- Efficacy Cohort

- N=number vaccinated.

## Intention-to-Treat Analysis:Efficacy of RotaTeqTM Against Hospitalizations, Emergency Department Visits, and Office Visitsfor G1-4 Rotavirus Gastroenteritis

- † N=34,035 vaccinated in vaccine group and 34,003 vaccinated in placebo group.
- ‡ N=2834 vaccinated in vaccine group and 2839 vaccinated in placebo group.

- From First Day of Vaccination Among All Subjects Who Received at Least One Dose
- REST

## RotaTeqTM Was Efficacious Against Rotavirus Gastroenteritis Caused by Serotypes G1-4 & G9

- Efficacy Cohort

## RotaTeqTM Was Efficacious Against Hospitalizations and Emergency Department Visits for Rotavirus Gastroenteritis Caused by G1-4 & G9

- REST

## Efficacy of RotaTeqTM Persisted During the Second Rotavirus Season Postvaccination

- REST

## Summary of Efficacy

- RotaTeqTM prevented G1-4 rotavirus gastroenteritis of any severity (74%) and severe disease (98%)
- RotaTeqTM prevented healthcare encounters for rotavirus gastroenteritis
- 96% reduction in hospitalizations
- 93% reduction in emergency department visits
- 86% reduction in office visits
- Serotype-specific data indicate that RotaTeqTM is efficacious against the G serotypes in the vaccine and against G9 strains containing P1
- Efficacy persisted during the second rotavirus season postvaccination

## Immunogenicity Objectives and Resultsfrom the Phase III Studies (REST, Protocol 007, and Protocol 009)

- Immunogenicity of RotaTeqTM
- Immunogenicity of Concomitant Vaccines

## Immunogenicity of RotaTeqTM

- No definitive immunologic surrogate for efficacy identified
- Studies of wild-type rotavirus suggest that serum and fecal anti-rotavirus IgA and G1 SNA titers correlate with protection
- Magnitude of antibody responses to RotaTeqTM correlates with potency (viral titer) but not efficacy
- Immunogenicity data from Phase III studies have been utilized for comparisons
- Demonstration of consistency of manufacturing process
- Concomitant use studies
- Pattern of antibody responses to RotaTeqTM has been consistent across different populations and studies
- High proportion (>90%) have significant rise in anti-rotavirus IgA
- Magnitude of serum neutralizing antibody responses to G and P types vary

-  Velazquez et al., *J Infect Dis* 2000; 182:1602-9 and Matson DO et al., *J Infect Dis* 1993; 167:577-83 andO’Ryan et al., *J Infect Dis* 1994; 169:504-11.

## Evaluation of Immunogenicity of Licensed Vaccines Given Concomitantly with RotaTeqTM

- Evaluated antibody responses to DTaP, IPV, Hib, Hep B, and pneumococcal conjugate vaccines
- Compared antibody responses to these vaccines when given with RotaTeqTM with the responses when given with placebo
- Statistical criteria for demonstrating noninferiority
- DT, IPV, Hib, and Hep B:  95% confident no more than a 10 percentage point decrease among vaccinees compared with placebo recipients for the proportion who achieve seroprotection
- Pertussis and pneumococcus: 95% confident no more than a 2-fold decrease among vaccinees compared with placebo recipients for the ratio of GMT

- (662V:696P)

- N= Number vaccinated.

## Concomitant Vaccination Schedule

- 3 doses of DTaP and pneumococcal conjugate vaccine
- GMT measured ~42 days postdose 3 at 7 to 8 months of age
- 2 doses of COMVAX® (Hib/Hep B) and IPV
- Subjects were required to receive a neonatal dose of hepatitis B within 2 weeks of birth
- Seroprotection measured on day of dose 3 at 5 to 6 months of age

## Antibody Responses to Diphtheria, Tetanus, Hep B, Hib, and Polio Were Similar in RotaTeqTM and Placebo Recipients

## Antibody Responses to Pneumococcal Conjugate Vaccine Were Similar in RotaTeqTM and Placebo Recipients

## Antibody Responses to Pertussis Toxoid,FHA, and Pertactin in RotaTeqTMand Placebo Recipients

- Note: Pertactin level >5 Eu/mL.  95% RotaTeq TM recipients vs. 96% placebo recipients.

## Summary of Immunogenicity

- RotaTeqTM was generally immunogenic
- No definitive immunologic surrogate for efficacy identified
- Administration of RotaTeqTM with licensed pediatric vaccines induced acceptable antibody responses to the concomitant vaccines

## Post-Licensure Plan to Monitor the Safety of RotaTeqTM

- Post-licensure surveillance is planned to monitor intussusception (IS) cases temporally associated with vaccination
- RotaTeqTM will be given on a 2-, 4-, 6-month schedule
- This schedule overlaps with the peak age of naturally-occurring IS

- Hospitalizations for Intussusception by Age in Months
- New York State, 1991 to 1995*

- * Rennels et al., *Ped Infect Dis J*  1998; 17: 924-5.

## Post-Licensure Plan to Monitor the Safety of RotaTeqTM

- Clinical studies
- Phase III studies (REST, 007, 009)
- Future clinical studies
- Merck-sponsored pharmacovigilance activities
- Active surveillance
- Prospective population-based study to assess IS and general safety
- Study design allows rapid detection of IS
- Enhanced passive surveillance
- IS: Telephone follow-up of all cases and prompt reporting to FDA
- All adverse events: Reporting to FDA on a monthly (vs. quarterly) basis
- Coordination and communication with public health agencies
- FDA / CDC (VAERS )
- CDC (VSD)

## Overall Assessment and Conclusionsfrom Studies of RotaTeqTM

## Overall Assessment and Conclusions

- Rotavirus is a significant cause of childhood morbidity in the US
- 55,000 to 70,000 hospitalizations/year
- Causes similar outcomes regardless of geography
- Only available therapy for rotavirus gastroenteritis in the US is supportive care
- Results of REST and other Phase III studies provide a high level of confidence in the safety of RotaTeqTM
- Well tolerated with respect to all AEs
- No signal of a safety concern with regard to IS

- RotaTeqTM prevents 74% of any severity of rotavirus gastroenteritis and 98% of severe disease
- RotaTeqTM reduces healthcare encounters for rotavirus gastroenteritis
- 96% ↓ hospitalizations
- 93% ↓ emergency department visits
- 86% ↓ physician office visits
- RotaTeqTM can be concomitantly administered with the licensed pediatric vaccines evaluated
- Given the absence of identified risk factors for severe rotavirus gastroenteritis and the universal nature of this disease, this vaccine is an important public health priority

- Overall Assessment and Conclusions(Cont’d)