# Presentation: 094215

## Vaccines and Related Biological Drug Products Advisory Committee MeetingDecember 14, 2005

**Rosemary Tiernan, MD, MPH**
**CBER/FDA**
**RotaTeq****TM**
**(rotavirus vaccine, live, oral, pentavalent****)**
**Merck & Co., Inc**.

## Overview

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

## 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**

## Product

**RotaTeq****TM**** 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**.

## 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

## Regulatory History for RotaTeqTM

** **
**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**July  1999****	****	****RotaShield****® withdrawn**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****	****60,000****th**** subject randomized (REST)**
**Sept  2004****	****70,000****th**** subject enrolled (REST)**
**Nov   2004****	****DSMB recommends stopping REST ****	****	****	****enrollment**
**April  2005****	****BLA submitted to FDA**

## Clinical Studies

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

## The Phase 3 Studies 

| Number of subjects vaccinated | RotaTeqTM
    (N) | Placebo
    (N) |
| --- | --- | --- |
| Study 006 |    35,027 |   34,978 |
| Study 007 |         650 |         660 |
| Study 009 |         679 |         112 |
| Total |    36,356 |    35,750 |

**Notes:**
*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

## 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**

**Notes:**
- White 				69.0%
- Hispanic American 			14.2% 
- Black 				 8.2%
- Multiracial 				  5.2%
- Asian				 1.5%
- Native American			  1.5%
- Other 				  0.4%

## 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

**Notes:**
These are inclusion criteria of note or highlighted.

## Phase 3 Exclusion Criteria 

**Rectal temperature > 38.1****0****C**
**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**

**Notes:**
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

## 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

## 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****TM or placebo were included.**

## 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 RotaTeqTM

## Study 006  

- Primary objectives of Study 006:
- Evaluate efficacy of 3 dose regimen of RotaTeqTM against rotavirus gastroenteritis caused by serotypes G1,G2, G3 and G4 occurring at least 14 days following the third vaccination and
- Evaluate safety of RotaTeqTM with respect to intussusception within 42 days following any vaccination.

## Study 006 Efficacy 

- Primary Null Hypothesis:
- 	Efficacy of RotaTeqTM 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%.

## Efficacy (FDA)

| Study 006 |  RotaTeqTM |  |   Placebo |  |
| --- | --- | --- | --- | --- |
| Subjects vaccinated |     2834 |  |     2839 |  |
| Subjects in Efficacy Analysis |     2207 |  |     2305 |  |
|  | FDA | Merck | 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) |  |  |

## Study 007 End Expiry

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

## Study 007 

**Primary objectives:**
**Evaluate efficacy of 3 dose regimen of RotaTeq****TM 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 RotaTeqTM 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%. **

## Efficacy (FDA)

| Study 007 |  RotaTeqTM |  |   Placebo |  |
| --- | --- | --- | --- | --- |
| Subjects vaccinated |     650 |  |     660 |  |
| Subjects in Efficacy Analysis |     551 |  |     564 |  |
|  | FDA | Merck | 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) |  |  |

## 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**

## 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.

## 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.

**Notes:**
-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. 

## Primary Safety Hypothesis

- RotaTeqTM 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. **

## 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.

## 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.

## 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.

## 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 |  |  |  |  |  |  |

**Notes:**
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

## 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)

## 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.

**Notes:**
No increased risk of IT at  Day  60 post-vaccination

## IT Cases Requiring Surgical Reduction

| Study 006 | RotaTeqTM 
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 |

**Notes:**
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 #
43717	96/99	3
64286	121	3
65484	38	3
76380	22/40	3
79306	2	2

Placebo IT cases that went to OR
AN		Day 	Vaccine dose #
01210	122	3
09934	404	3
22289	121	3
38225	49	2
47937	336	3

## Positively Adjudicated Cases of IT with Hematochezia Reported 

| Study 006 | RotaTeqTM
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 | Post- Dose 1 | Post- Dose 2 | Post- Dose 3 |
| 0-21 |  |    3 |  |  |  |  |
| 22-42 |  |    1 |    2 |  |    1 |    1 |
| > 42 |    1 |    1 |    2 |  |    1 |    4 |

**Notes:**
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)

## Negatively Adjudicated Cases IT with Hematochezia  Reported (Merck)

|  | RotaTeqTM
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
 | Post- Dose 1 | Post- Dose 2
 | Post- Dose 3
 |
| 0-21 |    5 |    1 |    1 |    2 |  |  |
| 22-42 |  |  |  |  |  |  |
| > 42 |  |    1 |    2 |  |  |    1 |

**Notes:**
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 2.7.4.11 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

## Negatively Adjudicated Cases IT with Hematochezia  Reported (FDA)

|  | RotaTeqTM

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 |

**Notes:**
 This data is derived using the Merck Table 2.7.4.11 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 1 	4			4
PD 2	3 (2 of these kids had Salmonella)------	1
PD 3	1			1

## 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.

## Deaths (Phase 3 Studies)

- No deaths in Phase 1 and Phase 2
- 52 deaths in the Phase 3 studies:
- RotaTeqTM	25
- Placebo	27
- Most common cause of death was SIDS
- RotaTeqTM	8
- Placebo	9

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

## Death with IT

- White male randomized to RotaTeqTM 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.

**Notes:**
Narrative

## 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:
- RotaTeqTM 2.1% vs Placebo 2.2%
- Discontinuations at _<_42 days post vaccine dose due to SAEs in Phase 3:
- RotaTeqTM 0.23% vs Placebo 0.20%

## Most Frequent Serious Adverse Events in Phase 3 Trials

|  | RotaTeqTM
(N=36,356) | Placebo
(N=35,750) |
| --- | --- | --- |
| Bronchiolitis |      233 |     268 |
| Gastroenteritis |       76 |    129 |
| Pneumonia |       59 |     62 |
| Pyrexia |       50 |     50 |
| Urinary Tract Infection |       39 |     31 |

## Most Frequent  SAEs that Led to Discontinuation in Phase 3 Trials

|  | RotaTeqTM
(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 |

## 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 |

**Notes:**
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 RotaTeqTM 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 RotaTeqTM 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 RotaTeqTM 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 

## Hematochezia (Phase 3)

|  | RotaTeqTM
(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
 |

##  Hospitalizations at <7 days Vaccine Dose(Safety Cohort)

| Hospitalizations< 7 days post vaccine dose
 |    RotaTeqTM
   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 |

**Notes:**
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: 

## Most Common Reasons for Hospitalizationat <7 days Any Vaccine Dose (Safety Cohort)

|  |   RotaTeqTM
    N = 36,356 |    Placebo
   N = 35,750 |
| --- | --- | --- |
| Bronchiolitis |            54 |           59 |
| Gastroenteritis |           18 |           25 |
| Pyrexia |             8 |           15 |
| UTI |           14 |             9 |
| Pneumonia |           11 |           14 |

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

|  Post -Dose 1 |    RotaTeqTM
   (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%)    |

**Notes:**
Fever at < 7 days for detailed safety after any dose:

Rota 1901/5751 = 32%
Placebo 1652/5209 = 33%

## 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 RotaTeqTM and 696 Placebo) received concomitant COMVAX®, INFANRIX®, IPOL®, and PREVNAR® and evaluated for immune responses

## 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

## Concomitant Vaccines

| Antigen | Comparison | Non-inferiority |
| --- | --- | --- |
| Polio 1, 2, 3
HBsAg
PRP
Diphtheria 
Tetanus | Seroprotection rate (placebo minus RotaTeqTM) | UL of 2-sided 95% CI for difference <10% |
| PT, FHA, PRN
Pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F, 23F | GMT ratio
(RotaTeqTM/
placebo) | LL of 2-sided 95% CI for ratio >0.5 |

**Notes:**
 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. 

## Concomitant vaccines (Results)

- Non-inferiority criteria RotaTeqTM versus placebo met for all antigens except tetanus, diphtheria and pertussis antigens
- Assay validation under review for anti-FHA, PT, PRN, tetanus and diphtheria

**Notes:**
LL of 95% CI for anti-pertactin GMT ratio RotaTeq /placebo 

## 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 RotaTeqTM is co-administered with childhood vaccines to prevent pertussis and diphtheria/tetanus

## 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**

## Questions for the Advisory Committee

- Are the available data adequate to support the efficacy of RotaTeqTM 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?

## Questions for the Advisory Committee

- Are the available data adequate to support the safety of RotaTeqTM 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?

## 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.

## All Hospitalizations in Phase 3

| Study |    RotaTeqTM
N = 36,356 |    Placebo
N = 35,750 |
| --- | --- | --- |
|  006 |        849 |        934 |
|  007 |          20 |          27 |
|  009 |            4 |            3 |
| Total |        873 |        964 |

## 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

**Notes:**
Quantity of shedding 
Kids before they leave the hospital

## 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
        5 to 7 |    
        > 8
       > 8 |
| Vomiting 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 |

**Notes:**
-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

## 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, RotatTeqTM
- 	- No intussusception

## Gestational Age < 36 weeks

|  | RotaTeqTM
(N =987) | Placebo
(N=1052) |
| --- | --- | --- |
| AEs |   17% |   20% |
| SAEs |   5.4 % |   6.4% |
| Deaths |    2 |   2 |

## 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

## 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.

## 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**

## Fever at < 7 days (Detailed Safety Cohort)

|  
 | RotaTeqTM
(N= 6153) | Placebo
(N=5589) |
| --- | --- | --- |
| Post-Dose 1 |    786 (13%) |    647 (12%) |
| Post-Dose 2 |    906  |    801  |
| Post-Dose 3
 |    816  |    729  |

**Notes:**
Fever at < 7 days for detailed safety after any dose:

Rota 1901/5751 = 32%
Placebo 1652/5209 = 33%

## Respiratory AEs <7 days of vaccine dose

| Study  | RotaTeqTM
N = 36,356 | Placebo
N = 35,750 |
| --- | --- | --- |
| 006 |     565 |     558 |
| 007 |       70 |        72 |
| 009 |         |         11 |
| Total |      717 |       641 |

**Notes:**
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 1	180	186
PD2	208	198
PD3	212	212
Study 007
PD1	14	21
PD2	25	25
PD3 	38	31
Study 009	
PD1	34	5	
PD2	30	3
PD3	17	3

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

|  Post -Dose 1 |    RotaTeqTM
   (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%)    |

**Notes:**
Fever at < 7 days for detailed safety after any dose:

Rota 1901/5751 = 32%
Placebo 1652/5209 = 33%

## Irritability at < 7 days (Detailed Safety Cohort)

|  | RotaTeqTM
(N=6153)
 | Placebo
(N=5589)
 |
| --- | --- | --- |
| Post-Dose 1 |    500 ( 8%) |  444 (7.9 %)
 |
| Post-Dose 2
 |    421 
 |  402 
 |
| Post-Dose 3
 |   310 
 |  286 
 |

## Vomiting at < 7 days (Detailed Safety Cohort)

|  | RotaTeqTM
(N=6153) | Placebo
(N=5589) |
| --- | --- | --- |
| Post-Dose 1 |   426 (7.0%) |   321 (5.4%)
 |
| Post-Dose 2 |   298 
 |   243 
 |
| Post-Dose 3 |   206 
 |   168 
 |

## Diarrhea at < 7days(Detailed Safety Cohort)

|  | RotaTeqTM
(N=6153) | Placebo
(N=5589) |
| --- | --- | --- |
| Post-dose 1 |   676 (11%) |   559 (10%) |
| Post-dose 2 |   503 |   371 |
| Post-dose 3 |   352 |   287 |