1. Rosemary Tiernan, MD, MPH (rotavirus vaccine, live, oral, pentavalent)
Vaccines and Related Biological Drug Products Advisory Committee Meeting December 14, 2005
Rosemary Tiernan, MD, MPH
CBER/FDA
RotaTeq™
(rotavirus vaccine, live, oral, pentavalent)
Merck & Co., Inc.

2. Overview Epidemiology Product Proposed Indication/Usage
Regulatory History
Organization of Clinical Studies
Efficacy
Safety
RotaShield® Experience
Questions for the Advisory Committee

3. Rotavirus Disease Almost all children are infected within the first
few 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

4. 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.

5. 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

6. Regulatory History for RotaTeq™
June l993 Phase 1 Study 001 initiated
Aug l RotaShield® approved
July RotaShield® withdrawn
May AC meeting to discuss REST design
Jan Study 006 (REST) initiated
Nov ,000th subject randomized (REST)
Sept ,000th subject enrolled (REST)
Nov DSMB recommends stopping REST enrollment
April BLA submitted to FDA

7. Clinical Studies Phase 1 and 2 trials:
Studies 001, 002, 003, 004 and 005
2470 infants and 30 adult subjects

8. The Phase 3 Studies RotaTeq™ (N) Placebo Study 006 35,027 34,978
Number of subjects vaccinated
RotaTeq™
(N)
Placebo
Study 006
35,027
34,978
Study 007
650
660
Study 009
679
112
Total
36,356
35,750
*Dose not include the 76 cross treated
Does include the 382 excluded site subjects
My total is 72,106 v.accinated if minus the 382 excluded sites = 71,724 and then add in 76 cross treated =71, 800.
Merck says total vaccinated are 71,799
They do not include the excluded sites which have 382 subjects with 191 in Placebo and 191 in RotaTeq.
Phase 1 and 2 trials:
Studies 001, 002, 003, 004 and 005
2470 infants and 30 adult subjects

9. Phase 3 Studies: Demographics
Across 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
- White %
- Hispanic American %
- Black %
- Multiracial %
- Asian %
- Native American %
- Other %

10. 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
These are inclusion criteria of note or highlighted.

11. 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
These are exclusion criteria of note.
Include the numbers of kids in 006 who got OPV and no IT in this group---Merck sent down the dataset
Horizontal transmission potential phase 4

12. 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

13. 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.

14. 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™

15. 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.

16. 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%.

17. Efficacy (FDA) Study 006 RotaTeq™ Placebo 2834 2839 2207 2305 60 82
Subjects vaccinated
2834
2839
Subjects in Efficacy Analysis
2207
2305
FDA
Merck
Days of Follow-up
626,666
623,880
633,438
622,399
Gastroenteritis Cases 60 82
232
315
Efficacy Estimate and 95% CI
73.9
(65.1,80.7) 74
(66.8,79.9)

18. Study 007 End Expiry
Phase 3 double-blinded, randomized, placebo-controlled study to evaluate the efficacy of RotaTeq™ at end expiry.

19. 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%.

20. Efficacy (FDA) Study 007 RotaTeq™ Placebo 650 660 551 564 13 15 46 54
Subjects vaccinated
650
660
Subjects in Efficacy Analysis
551
564
FDA
Merck
Days 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)

21. The Safety Cohorts Large Safety (Study 006, 007, 009) Detailed Safety
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

22. 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.

23. 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.
-Graphs with predefined stopping boundaries that defined a statistically significant increase (lower bound of the 95% CI on the RR of IT >1.0) were provided as guides to be used along with their clinical judgment when making recommendations regarding the study. These stopping boundaries were designed such that the study would be stopped early if the RR of IT in any 2 overlapping day ranges (1 to 7 days and 1 to 42 days) after any vaccination was statistically significantly increased among vaccine recipients vs placebo recipients.
-Cases of IT that occurred among recipients of RotaTeq in either day range were compared to IT cases that occurred in the placebo arm.
-REST employed a group sequential design which called for a minimum enrollment of 60,000 infants with additional enrollment of groups of 10,000 infants if the statistical criteria for the primary safety hypothesis were not met to a maximum enrollment of 100,000 suvjects.

24. 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.

25. 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.

26. 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.

27. 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.

28. Intussusception (REST)
All cases of IT
Vaccine Dose #1
Vaccine Dose #2
Vaccine Dose #3
Days Post Dose
Rota
Pla
0-7 1
0-14
0-21 3
0-42 6 5 4 2
0-60 8
0-462 13 19
Extra case at day 9 post dose 1 study 005
This child was older at 7 months of age when he received his first dose and it was a lower dose formulation
If we add this 005 case the split is 2:1 rota to placebo in the 0-14 day window and the cases are
rota 1 post dose 1 and 1 post dose 2 vs
placebo 1 post dose 3

29. 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: )

30. 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.
No increased risk of IT at Day 60 post-vaccination

31. 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 2
Post- Dose 3
0-21 1
22-42 2
> 42 5
At 42 days there are 6 Rota cases and 3/6 went to the OR vs 0/5 for Pla
RotaTeq IT cases that required surgical reduction:
AN Day Vaccine dose #
/99 3
/40 3
Placebo IT cases that went to OR

32. Positively Adjudicated Cases of IT with Hematochezia Reported
Study 006
RotaTeq™
Total # IT cases (N = 13)
Placebo
Total # IT cases (N =19)
Hematochezia (N = 10)
Hematochezia (N = 7)
Days post- dose
Post- Dose 1
Post- Dose 2
Post- Dose 3
0-21 3
22-42 1 2
> 42 4
Positively Adjudicated IT cases RotaTeq (10/13 had hematochezia)
PD1 1
PD2 5
PD3 4
Positively adjudicated IT case RotTteq (3/13 without hematohezia report)
All PD3 3 (late at days 114, 121, 140 post dose 3)
Positively Adjudicated IT cases Placebo with hematochezia (7/19 had hematochezia reported)
PD1 0
PD2 2
PD3 5
Positively Adjudicated IT case Placebo (12/19without hematochezia)
PD1 1 (at 36 days)
PD2
PD3 11 (days are 9, 42, 87, 122, 139, 141,171, 336,337,404, 455)

33. Negatively Adjudicated Cases IT with Hematochezia Reported (Merck)
RotaTeq™
Total # Negatively Adjudicated Cases (N=45)
Placebo
Total # Negatively Adjudicated Cases (N= 47)
Hematochezia (N=10)
Hematochezia (N= 3)
Days post- dose
Post- Dose 1
Post- Dose 2
Post- Dose 3
0-21 5 1 2
22-42
> 42
Negatively Adjudicated Cases of IT
10/45 RotaTeq cases had hematochezia reported
3/47 Placebo cases had hematochezia reported
This data is derived using the Table on page 259 SUR
Rota cases are:
Post Dose 1 days 3,16,16,16 and 21
Post Dose 2 days 17 and 112
Post Dose 3 days 4, 107 and 128
Placebo Case
Post Dose 1 Days 7, 7
Post Dose 3 Days 50

34. 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
0-21 7 3 1 4 2
22-42
> 42
This data is derived using the Merck Table on page 259 SUR and the narratives so we have more cases of hematochezia includes “currant jelly”.
17 kids negatively adjudicated had hematochezia with Rota and
13 are < 60 days and 4 are greater than 60 days. The spread on the 13 kids:
PD1 6
PD2 6
PD3 1
9 kids negatively adjudicated had hematochezia with Placebo but 2 of the 9 had salmonella and these 2 occurred after the second dose of placebo.
8 ccurred at < 60 days and 1of the 9 cases occurred at > 60 days.
Spread on the 8 cases at less than or equal to 60 days PD
PD 2 3 (2 of these kids had Salmonella) PD

35. Intussusception Results do not address use in infant populations
who 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 1st
dose to infants at age >12 weeks or administration
of 3rd dose beyond approximately 34 weeks of
age.

36. 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
Intussusception and death at day 99 post dose 3
Other causes of death varied included injuries, accidents, cancer and infections and cardiovascular issues.

37. 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.
Narrative

38. 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%

39. 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
Urinary Tract Infection 39 31

40. Most Frequent SAEs that Led to Discontinuation in Phase 3 Trials
RotaTeq™
(N= 36,356)
Placebo
(N= 35,750)
Gastroenteritis 4 9
SIDS 7
Inguinal Hernia 6
Bronchiolitis 5
Convulsion 2
Vomiting 3
Pyrexia

41. Seizures in the Phase 3 Trials
< 7 days post vaccine dose
< 14 days post vaccine dose
< 42 days post vaccine dose
RotaTeq
(N= 36,356)
Placebo(N= 35,750)
(N= 36,356
Placebo
(N= 35,750)
Dose 1 3 1 4 2 9 7
Dose 2 6 12
Dose 3 5 8
Total 10 15 33 24
31 subjects placebo /20 kids RotaTeq who had a history of seizure ---none of these children developed a seizure within 42 days of a vaccine dose during the trial.
At 7 days post vaccine dose, there were more seizures in the RotaTeq™ arm when compared to placebo, post dose 1 ( 3 to 1), post-dose 2 ( 4 to 2 ) and post-dose 3 ( 3 to2 ).
At 14 days post vaccine dose, there were more seizures in the RotaTeq™ arm when compared to placebo, post dose 1 (4 to 2), post-dose 2 (6 to 2) and post-dose 3 (5 to 4).
At 42 days post vaccine dose, there were more seizures in the RotaTeq™ arm when compared to placebo, post-dose 1 (9 to 7), post-dose 2 (12 to 9) and post-dose 3 (12 to 8)
At < 14 days Rota-2 febrile seizures 2/15 , 2 kids 34 wks. GA and one of these kids was the febrile seizure, no narr on 1 rota kid, no narrative on 4 kids with placebo and 2/8 febrile seizure
Study 003 (G1,G2) 2 males with seizures at day 8 & 35 PD #1
Study 005 (G1G2G3G4 at 5 x 10*6) febrile seizure at 17 days

42. Hematochezia (Phase 3) RotaTeq™ (N=36,356) Placebo (N=35,750) 13 21 29
< 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

43. 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
Hospitalizations at 7 days or less:
RotaTeq 236
Placebo 246
Crosstreated 2
There were 5 kids with 2 hospitalizations: 3 in Rota and 2 in placebo.
Most common reasons for hospitalization at 7 days post vaccine dose:

44. Most Common Reasons for Hospitalization at <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

45. 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%)
Fever at < 7 days for detailed safety after any dose:
Rota 1901/5751 = 32%
Placebo 1652/5209 = 33%

46. 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

47. 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

48. 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
for seroprotection change it to Rota minus placebo; LL of 2-sided 95% CI for difference >-10 if that's how Merck presented it in BLA/briefing document, just for consistency.

49. 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
LL of 95% CI for anti-pertactin GMT ratio RotaTeq /placebo

50. 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

51. 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

52. 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?

53. 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 weeks of age, followed by two additional doses separated by 4 to 10 week intervals.
If not, what additional information should be provided?

54. 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.

57. 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

58. 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
Quantity of shedding
Kids before they leave the hospital

59. Efficacy: The AGE Score
Score Summed by Evaluation of Symptoms & Duration 1 2 3
Diarrhea
# Stools /day
Duration in days
2 to 4
1 to 4
5 to 7
> 8
Vomiting No. of Emeses/day and Duration in Days
1 to 3
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
Irritable/ less playful
Lethargic / listless
Seizure
> 5
-88% of the temperatures were collected rectally
-If a rectal equivalent was not used only 6 subjects would have been reclassified (all placebo) as not severe and this would have produced a case split for severe disease as:
1 vaccine to 45 placebo vs 1 vaccine to 51 placebo.
Rectal equivalent was adding 10F to otic and oral temperatures and 20F to axillary temperatures (24 pt. score)
Mild disease was < 8
Moderate disease was >8 but < 16
Severe disease was >16

60. 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

61. Gestational Age < 36 weeks
RotaTeq™
(N =987)
Placebo
(N=1052)
AEs
17%
20%
SAEs
5.4 %
6.4%
Deaths 2

62. 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

63. 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.

64. 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 hematochezia
Detailed Safety Cohort
Solicited adverse events to 42 days post vaccination

65. 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
Fever at < 7 days for detailed safety after any dose:
Rota 1901/5751 = 32%
Placebo 1652/5209 = 33%

68. 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
Respiratory AES inlcuded in decreasing frequency: URI, Bronchiolitis, croup,RSV, bronchospasmpm
Looked at this by dose and it is balanced per vaccine dose:
Rota Placebo
Study 006 PD PD PD
Study 007 PD PD PD
Study 009
PD1 34 5
PD2 30 3
PD3 17 3

69. 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%)
Fever at < 7 days for detailed safety after any dose:
Rota 1901/5751 = 32%
Placebo 1652/5209 = 33%

70. 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

71. 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

72. 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