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Vaccines and Related Biological Drug Products Advisory Committee Meeting

December 14, 2005

Rosemary Tiernan, MD, MPHCBER/FDA

RotaTeq™(rotavirus vaccine, live, oral, pentavalent)

Merck & Co., Inc.

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Overview

Epidemiology Product Proposed Indication/UsageRegulatory HistoryOrganization of Clinical Studies EfficacySafetyRotaShield® ExperienceQuestions for the Advisory Committee

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Rotavirus Disease

Almost all children are infected within the firstfew years of life.

Rotavirus infection in the U.S.:-50,000 hospitalizations per year -20 deaths annually

Rotavirus infection worldwide:-2 million hospitalizations per year -352,000 to 592,000 deaths per year in children less than 5 years of age

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Product

• RotaTeq™ is a live, oral, pentavalent, human-bovine reassortant (Serotypes: Human G1, G2, G3, G4, P1a & Bovine G6, P7) vaccine.

• Liquid formulation stored at 2-8 degrees centigrade.

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Proposed Indication and Usage

• Prevention of rotavirus gastroenteritis in infants and children caused by serotypes G1, G2, G3, G4 and G serotypes that contain P1 (e.g. G9)

• Administered as 3 dose series with the first

dose given to healthy infants at 6-12 weeks of age followed by two additional doses administered at 4-10 week intervals

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Regulatory History for RotaTeq™

• June l993 Phase 1 Study 001 initiated• Aug l998 RotaShield® approved• July 1999 RotaShield® withdrawn• May 2000 AC meeting to discuss REST design• Jan 2001 Study 006 (REST) initiated• Nov 2003 60,000th subject randomized (REST)• Sept 2004 70,000th subject enrolled (REST)• Nov 2004 DSMB recommends stopping REST

enrollment• April 2005 BLA submitted to FDA

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Clinical Studies

Phase 1 and 2 trials:

– Studies 001, 002, 003, 004 and 005

– 2470 infants and 30 adult subjects

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The Phase 3 Studies

Number of subjects vaccinated

RotaTeq™

(N)

Placebo

(N)

Study 006 35,027 34,978

Study 007 650 660

Study 009 679 112

Total 36,356 35,750

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Phase 3 Studies: DemographicsAcross the treatment arms:• Gender

– Approximately 50% male and 50% female• Race

– 69% white

Subjects participated from the following countries:

- 48% U.S. and Puerto Rico

- 33% Finland

- 19% Costa Rica, Guatemala, Mexico, Jamaica,

Taiwan, Belgium, Italy, Germany, Sweden

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Phase 3 Inclusion Criteria

• Healthy infants aged 6 weeks through 12 weeks of age

• Healthy, premature infants (<36 weeks of age) enrolled according to chronological age

• No restrictions on breast-feeding• No restrictions on concomitant vaccines except

OPV was not allowed

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Phase 3 Exclusion Criteria

• Rectal temperature > 38.10C• Congenital abdominal disorder• Intussusception or abdominal surgery• Immune deficiency• Living in household with immunocompromised

person• Chronic diarrhea, history of rotavirus disease• Receipt of blood products, immunoglobulins or

immunosuppressive therapy• Receipt of OPV

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Important Cohorts in the Phase 3 Studies

• Large Safety Cohort (N = 72,324)

- Study 006, Study 007 and Study 009 • Detailed Safety Cohort (N = 11,753)

- Subset of Study 006 subjects and

- All subjects in Studies 007 and 009 • U.S. Concomitant Use Cohort (N = 1358)

- Subset of the Efficacy Cohort

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Efficacy: Case Definition

• Case definition of rotavirus gastroenteritis:– 3 or more watery or looser-than-normal stools

within a 24 hour period and/or forceful vomiting and

– Rotavirus antigen detected by enzyme immunoassay (EIA) in a stool specimen taken within 14 days of symptom onset.

– For the primary efficacy analysis, only G1-, G2-, G3- or G4- specific rotavirus gastroenteritis cases naturally occurring through the first full rotavirus season that began at least 14 days after the third dose of RotaTeq™ or placebo were included.

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Study 006 Rotavirus Efficacy and Safety Trial

(REST)

• Phase 3 double-blinded, randomized, placebo-controlled, international, multi-center study to evaluate the efficacy, immunogenicity and safety of RotaTeq™

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Study 006

Primary objectives of Study 006:• Evaluate efficacy of 3 dose regimen of

RotaTeq™ against rotavirus gastroenteritis caused by serotypes G1,G2, G3 and G4 occurring at least 14 days following the third vaccination and

• Evaluate safety of RotaTeq™ with respect to intussusception within 42 days following any vaccination.

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Study 006 Efficacy

Primary Null Hypothesis:

Efficacy of RotaTeq™ against all G1-, G2-,

G3- or G4- specific cases of rotavirus

gastroenteritis occurring through the first

rotavirus season that begins 14 or more

days post-dose 3 would be < 35%.

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Efficacy (FDA)Study 006

RotaTeq™ Placebo

Subjects vaccinated

2834 2839

Subjects in Efficacy Analysis

2207 2305

FDA Merck FDA MerckDays of Follow-up

626,666 623,880 633,438 622,399

Gastroenteritis Cases 60 82 232 315Efficacy Estimate and 95% CI

73.9(65.1,80.7)

74(66.8,79.9)

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Study 007 End Expiry

• Phase 3 double-blinded, randomized, placebo-controlled study to evaluate the efficacy of RotaTeq™ at end expiry.

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Study 007

Primary objectives:• Evaluate efficacy of 3 dose regimen of RotaTeq™ at

expiry potency against naturally occurring rotavirus disease caused by composite of the serotypes contained within the vaccine (G1,G2, G3 and G4) occurring at least 14 days following the third dose.

Primary null hypothesis:• Efficacy of RotaTeq™ at expiry potency against all

G1-, G2-,G3-, or G4-specific cases of rotavirus gastroenteritis occurring at least 14 days post dose 3 through one rotavirus season would be less than or equal to 0%.

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Efficacy (FDA)Study 007 RotaTeq™ Placebo

Subjects vaccinated

650 660

Subjects in Efficacy Analysis

551 564

FDA Merck FDA MerckDays of Follow-up

78128 77929 77759 77037

Gastroenteritis Cases

13 15 46 54

Efficacy Estimate and 95% CI

71.9(47.1,86.1)

72.5(50.6,85.6)

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The Safety Cohorts

• Large Safety (Study 006, 007, 009) – 72,324 infants randomized– 7 days detailed safety and monitored q 6 weeks

for SAEs and IT to 365 days post vaccine dose 1

• Detailed Safety (Subset study 006, all study subjects 007 & 009)

– 11,753 infants randomized– 42 days detailed safety (SAEs and AEs) and

monitored q 6 weeks for SAEs and IT to 365 days post vaccine dose 1

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Safety Endpoint Adjudication Committee (SEAC)

- 3 physicians with expertise in pediatric surgery, pediatric radiology and clinical diagnosis of IT

- Adjudication was blinded to treatment assignment using pre-specified case definitions and adjudication guidelines.

- If disagreement, a majority ruling was made.

- All adjudications made by the committee were final.

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Data Safety Monitoring Board (DSMB)

• Experts in operational, medical, biostatistical aspects of clinical trials.

• Not involved in the conduct of the study. • Considered all SAEs and specifically

intussusception cases.• Unblinded the treatment arm of positively

adjudicated IT cases and made recommendations regarding ongoing conduct of study.

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Primary Safety Hypothesis

• RotaTeq™ would not increase the risk of IT relative to placebo within 42 days of any vaccine dose. The statistical criteria included:– Distribution of IT cases between vaccine and

placebo (case split) would not reach predefined safety boundary for any of the two overlapping day ranges (1 to 7 or 1 to 42 days following any dose) being monitored by the DSMB and

– Upper bound on the 95% CI estimate of the RR of IT had to be <10.

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Intussusception

• Most frequent cause of intestinal obstruction in the first 2 years of life.

• Uncommon illness with estimated annual incidence of 1 out of 2000 among infants less than 2 years of age.

• Symptoms: irritability, abdominal pain, vomiting, lethargy, bloody or mucous-containing or “currant jelly” stools; may be fatal if left untreated.

• Cases confirmed by contrast enema, ultrasound, surgery or autopsy. Some cases may spontaneously reduce.

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Intussusception

Case of IT had to be diagnosed radiographically,at surgery or at autopsy.• IT case definition similar to Brighton

Collaboration Intussusception Working Group except Brighton definition calls for initial ultrasound diagnosed cases of IT to be followed up with another ultrasound to demonstrate resolution/reduction of IT. The Merck definition permitted ultrasound cases alone in order to avoid missing IT cases that could have spontaneously reduced.

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Intussusception

• For the pre-specified 42-day post-vaccination endpoint, results demonstrated 6 cases of IT versus 5 cases of IT in the placebo group.

• Estimated RR of 1.2 with a 95% CI of (0.3, 5.0) was obtained. The upper bound of the 95% CI of the RR is less than 10, which satisfies the prospectively specified primary safety objective of REST.

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Intussusception (REST)

All cases of IT

Vaccine Dose #1

Vaccine Dose #2

Vaccine Dose #3

Days Post Dose

Rota Pla Rota Pla Rota Pla Rota Pla

0-7 1 1

0-14 1 1 1 1

0-21 3 1 3 1

0-42 6 5 1 4 1 2 3

0-60 8 6 1 1 5 2 2 3

0-462 13 19

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Exploratory Analysis with IT Case from Study 005

• 7 month old Caucasian male• Received low dose pentavalent vaccine• Developed hematochezia, vomiting and IT

diagnosed at surgery on day 9 post-dose 1• Benign lymphoid hyperplasia • Merck exploratory analysis:• RR 1.4, 95% (CI: 0.4 - 5.6)

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Intussusception

- No increased risk of IT at day 42 post-vaccination compared to placebo.

- No clustering of IT cases within 7 day

or 14 day window post-vaccination.

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IT Cases Requiring Surgical Reduction

Study 006

RotaTeq™ Total # IT Cases (N =13)

Placebo Total # IT cases (N = 19)

IT Cases to Surgery (N = 5) IT Cases to Surgery (N = 5)

Days post- dose

Post- Dose 1

Post -Dose 2

Post -Dose 3

Post- Dose 1

Post- Dose 2

Post- Dose 3

0-21 1

22-42 2

> 42 2 5

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Positively Adjudicated Cases of IT with

Hematochezia Reported

•Study 006

RotaTeq™Total # IT cases (N = 13)

PlaceboTotal # IT cases (N =19)

Hematochezia (N = 10) Hematochezia (N = 7)

Days post- dose

Post- Dose 1

Post- Dose 2

Post- Dose 3

Post- Dose 1

Post- Dose 2

Post- Dose 3

0-21 3

22-42 1 2 1 1

> 42 1 1 2 1 4

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Negatively Adjudicated Cases IT with Hematochezia Reported (Merck)

RotaTeq™Total # Negatively Adjudicated Cases (N=45)

PlaceboTotal # Negatively Adjudicated Cases (N= 47)

Hematochezia (N=10) Hematochezia (N= 3)

Days post- dose

Post- Dose 1

Post- Dose 2

Post- Dose 3

Post- Dose 1

Post- Dose 2

Post- Dose 3

0-21 5 1 1 2

22-42

> 42 1 2 1

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Negatively Adjudicated Cases IT with Hematochezia Reported (FDA)

RotaTeq™

Total # Negatively Adjudicated Cases (N=45)

Placebo

Total # Negatively Adjudicated Cases (N=47)

Hematochezia (N=17) Hematochezia (N= 9)

Days post- dose

Post- Dose 1

Post- Dose 2

Post- Dose 3

Post- Dose 1

Post- Dose 2

Post- Dose 3

0-21 7 3 1 4 2

22-42 1 1

> 42 2 3 2

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Intussusception Results do not address use in infant populationswho were not studied such as:• children with HIV• underlying gastrointestinal disorders• infants who reside in areas outside the U.S. where

the standard of care is to give live oral polio vaccine. Limited data regarding administration of 1stdose to infants at age >12 weeks or administrationof 3rd dose beyond approximately 34 weeks ofage.

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Deaths (Phase 3 Studies)

• No deaths in Phase 1 and Phase 2

• 52 deaths in the Phase 3 studies:– RotaTeq™ 25– Placebo 27

• Most common cause of death was SIDS– RotaTeq™ 8– Placebo 9

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Death with IT

White male randomized to RotaTeq™ arm.

On day 96 post dose 3, subject developed

abdominal pain, vomiting, bloody stools and

barium enema confirmed IT. Subject

underwent surgery, had necrotic bowel

resected, developed septicemia and died

on day 99 post-dose 3 of vaccine.

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Serious Adverse Events (SAEs)

• Serious Adverse Events in phase 1 and 2

- IT case in study 005 already discussed.• Incidence SAEs in Phase 3 at < 42 days:

– RotaTeq™ 2.1% vs Placebo 2.2%

• Discontinuations at <42 days post vaccine dose due to SAEs in Phase 3:

– RotaTeq™ 0.23% vs Placebo 0.20%

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Most Frequent Serious Adverse Events in Phase 3 Trials

RotaTeq™

(N=36,356)

Placebo

(N=35,750)

Bronchiolitis 233 268

Gastroenteritis 76 129

Pneumonia 59 62

Pyrexia 50 50

Urinary Tract Infection

39 31

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Most Frequent SAEs that Led to Discontinuation in Phase 3 Trials

RotaTeq™

(N= 36,356)

Placebo

(N= 35,750)

Gastroenteritis 4 9

SIDS 7 7

Inguinal Hernia 6 7

Bronchiolitis 5 7

Convulsion 6 2

Vomiting 3 0

Pyrexia 2 2

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Seizures in the Phase 3 Trials

Phase 3 < 7 days post vaccine dose

< 14 days post vaccine dose

< 42 days post vaccine dose

RotaTeq(N= 36,356)

Placebo(N= 35,750)

RotaTeq(N= 36,356

Placebo(N= 35,750)

RotaTeq(N= 36,356)

Placebo(N= 35,750)

Dose 1 3 1 4 2 9 7

Dose 2 4 2 6 2 12 9

Dose 3 3 2 5 4 12 8

Total 10 5 15 8 33 24

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Hematochezia (Phase 3)

RotaTeq™

(N=36,356)

Placebo

(N=35,750)

< 7 days post any vaccine dose

13 21

< 14 days post any vaccine dose

29 30

< 21 days post any vaccine dose

40 33

< 42 days post any vaccine dose

45 39

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Hospitalizations at <7 days Vaccine Dose(Safety Cohort)

Hospitalizations< 7 days post vaccine dose

RotaTeq™

N =36,356

Placebo

N =35,750

Post Dose 1 133 114

Post Dose 2 66 81

Post Dose 3 40 53

Total 239 248

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Most Common Reasons for Hospitalizationat <7 days Any Vaccine Dose

(Safety Cohort) RotaTeq™

N = 36,356

Placebo

N = 35,750

Bronchiolitis 54 59

Gastroenteritis 18 25

Pyrexia 8 15

UTI 14 9

Pneumonia 11 14

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Solicited Adverse Events at <7 days (Detailed Safety Cohort)

Post -Dose 1 RotaTeq™ (N= 6153)

Placebo (N=5589)

Fever 786

(12.8%)

647

(11.6 %)Irritability 500

(8.1%)

444

(7.9%) Diarrhea 676

(11.0%) 559

(10.0%)Vomiting 426

(6.9%)

321

(5.7%)

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Concomitant Vaccines

• All subjects in Phase 3 permitted to receive licensed pediatric vaccines on same day or within 42 days of vaccination

• Subset of 1358 infants (662 RotaTeq™ and 696 Placebo) received concomitant COMVAX®, INFANRIX®, IPOL®, and PREVNAR® and evaluated for immune responses

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Concomitant Vaccines

-Responses measured at age 7-8 months after 3 doses of vaccine:

-Diphtheria, tetanus, pertussis and pneumococcal serotypes

-Responses measured at age 5-6 months

after 2 doses of vaccine:-PRP, Hepatitis B and polio

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Concomitant Vaccines

Antigen Comparison Non-inferiority

Polio 1, 2, 3

HBsAg

PRP

Diphtheria

Tetanus

Seroprotection rate (placebo minus RotaTeq™)

UL of 2-sided 95% CI for difference <10%

PT, FHA, PRN

Pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F, 23F

GMT ratio

(RotaTeq™/placebo)

LL of 2-sided 95% CI for ratio >0.5

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Concomitant vaccines (Results)

• Non-inferiority criteria RotaTeq™ versus placebo met for all antigens except tetanus, diphtheria and pertussis antigens

• Assay validation under review for anti-FHA, PT, PRN, tetanus and diphtheria

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Summary• There was no increased risk of IT at day 42 post-

vaccination when compared to placebo.• Clinical study data not sufficient to support:

- administration of a first dose at an age less than 6 weeks or a third dose beyond approximately 34 weeks

- use in immunosuppressed patients• Unable to rule out interference of immune responses

when RotaTeq™ is co-administered with childhood vaccines to prevent pertussis and diphtheria/tetanus

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FDA Review Team• Chintamani D. Atreya, PhD• Christine Drabick, MS • Gale Heavner, CAPT, USPHS• Laraine Henchal, MS• Amelia Dale Horne, DrPH• Hector S. Izurieta, MD, MPH• Jingyee Kou, PhD• Loris McVittie, PhD• Douglas Pratt, MD, MPH• Angela Shen, MPH• Lev Sirota, PhD • Rosemary Tiernan, MD, MPH• Luba Vujcic, MS

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Questions for the Advisory Committee

• Are the available data adequate to support the efficacy of RotaTeq™ in preventing rotavirus gastroenteritis caused by serotypes G1, G2, G3, G4 and G serotypes that contain P1 (e.g. G9), when the first dose of vaccine is administered at 6-12 weeks of age, followed by two subsequent doses separated by 4-10 week intervals?

• If not, what additional information should be provided?

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Questions for the Advisory Committee

• Are the available data adequate to support the safety of RotaTeq™ when used in a 3 dose series beginning with the first dose at 6 -12 weeks of age, followed by two additional doses separated by 4 to 10 week intervals.

• If not, what additional information should be provided?

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Questions for the Advisory Committee

• Please identify any other issues that should be addressed, including post-licensure studies. In particular please address:

• Assessment of intussusception.• Applicant’s proposed pharmacovigilance plan.• Concomitant use with other routinely

administered childhood vaccines.• Use of the vaccine in immunocompromised

children, such as those with HIV, or children taking steroids or other chronic immuno-suppressive therapies, or other special populations.

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All Hospitalizations in Phase 3

Study RotaTeq™

N = 36,356

Placebo

N = 35,750

006 849 934

007 20 27

009 4 3

Total 873 964

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Shedding

• 300 tested (150 U.S. and 150 Finnish)

• Single stool sample at 4-6 days post vaccine visits 1, 2 and 3

• 13 % shed at days 4-6 following visit 1

• Strains were vaccine or re-assortants

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Efficacy: The AGE ScoreScore Summed by Evaluation of Symptoms & Duration

1 2 3

Diarrhea

# Stools /day

Duration in days 2 to 4

1 to 4

5 to 7

5 to 7

> 8

> 8Vomiting No. of Emeses/day and Duration in Days

1 to 3

2

4 to 6

3 to 5

> 7

> 6

Rectal Temp. (oC)

Duration in Days 38.1 to 38.2

1 to 2

38.3 to 38.7

3 to 4

> 38.8

> 5

Behavioral Symptoms

Duration in Days

Irritable/ less playful

1 to 2

Lethargic / listless

3 to 4

Seizure

> 5

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Cross-Treated

76 infants in the phase 3 studies.

- 16/76 had AEs(21%)

- No specific problem in infants who received RotaTeq “late” i.e. may have received Placebo,Placebo, RotatTeq™

- No intussusception

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Gestational Age < 36 weeks

RotaTeq™(N =987)

Placebo(N=1052)

AEs 17% 20%

SAEs 5.4 % 6.4%

Deaths 2 2

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Gestational Age < 36 weeks

• Most common AEs were pyrexia URI, diarrhea, irritability, vomiting, bronchiolitis

• Most common SAEs were bronchiolitis, pneumonia, RSV bronchitis, vomiting, viral syndrome and UTI

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Efficacy

• Definition of the rotavirus season:

- Rotavirus season varied according to study site location (in U.S., the season was 01 Dec to 30 Jun).

- Primary Efficacy Analysis considered only those cases that occurred after the 14

days of follow-up-post-dose 3 and through the first entire rotavirus season.

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Safety Monitoring

Large Safety and Detailed Safety Cohort• Active surveillance for IT

– Telephone or home visit on days 7, 14 and 42 days post vaccination and every 6 weeks until 365 days post vaccination visit #1or end of study date

• Vaccine Report Card (VRC): 7 days post -vaccination – Recorded daily temperature– Solicited adverse events: diarrhea, vomiting,

other complaints or illnesses; not hematocheziaDetailed Safety Cohort

– Solicited adverse events to 42 days post vaccination

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Fever at < 7 days (Detailed Safety Cohort)

RotaTeq™(N= 6153)

Placebo(N=5589)

Post-Dose 1 786 (13%) 647 (12%)

Post-Dose 2 906 801

Post-Dose 3 816 729

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67

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Respiratory AEs <7 days of vaccine dose

Study RotaTeq™

N = 36,356

Placebo

N = 35,750

006 565 558

007 70 72

009 11

Total 717 641

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Solicited Adverse Events at <7 days (Detailed Safety Cohort)

Post -Dose 1 RotaTeq™ (N= 6153)

Placebo (N=5589)

Fever 786

(12.8%)

647

(11.6 %)Irritability 500

(8.1%)

444

(7.9%) Diarrhea 676

(11.0%) 559

(10.0%)Vomiting 426

(6.9%)

321

(5.7%)

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Irritability at < 7 days (Detailed Safety Cohort)

RotaTeq™

(N=6153)

Placebo

(N=5589)

Post-Dose 1 500 ( 8%) 444 (7.9 %)

Post-Dose 2 421 402

Post-Dose 3 310 286

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Vomiting at < 7 days (Detailed Safety Cohort)

RotaTeq™

(N=6153)Placebo(N=5589)

Post-Dose 1 426 (7.0%) 321 (5.4%)

Post-Dose 2 298 243

Post-Dose 3 206 168

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Diarrhea at < 7days(Detailed Safety Cohort)

RotaTeq™

(N=6153)

Placebo

(N=5589)

Post-dose 1 676 (11%) 559 (10%)

Post-dose 2 503 371

Post-dose 3 352 287