# Presentation: 673869

## Vaccines and Related Biological Drug Products Advisory Committee MeetingFebruary 20, 2008

- RotarixTM
- (rotavirus vaccine, live, oral)
- GlaxoSmithKline Biologicals
- Paul Kitsutani, MD, MPH
- (Steven Rosenthal, MD, MPH)
- CBER/FDA

## Product Information - RotarixTM

- Live, attenuated, oral, human monovalent RV vaccine
- Derived from human 89-12 strain which belongs to G1P[8] type
- Prepared as a lyophilized formulation
- End-of-shelf-life potency of ≥ 106.0 median Cell Culture Infective Dose (CCID50) per dose after reconstitution with liquid diluent
- Contains no preservatives

## Proposed Indication and Administration

- Prevention of RV gastroenteritis (GE) caused by G1 and non-G1 types (including G2, G3, G4, and G9)
- Orally administered as a 2-dose series to infants 6 to 24 weeks of age
- First dose beginning at 6 weeks of age
- Second dose by 24 weeks of age
- Interval of at least 4 weeks between doses

## Regulatory History – RotarixTM

- RotarixTM under U.S. IND since July 2000
- Non-IND studies conducted thereafter outside the U.S., including pivotal efficacy and safety studies submitted to BLA
- Pre-BLA meetings held from July to September 2006
- Based on FDA-sponsor agreement,10 of the completed Phase II and III studies were to be submitted in BLA
- Additional Phase III immunogenicity study in U.S.(Rota-060) was to be submitted to BLA after completion
- BLA submitted on June 1, 2007

## Question 1

- Are the available data presented adequate to support the efficacy of RotarixTM in preventing rotavirus gastroenteritis caused by serotypes G1, G2, G3, G4, and G9, when the first dose of vaccine is administered beginning 6 weeks of age, followed by a second dose separated by at least 4 weeks?
- If not, what additional information should be provided?

## Question 2

- Are the available data presented adequate to support the safety of RotarixTM when used in a 2 dose series beginning with the first dose at 6 weeks of age, followed by a second dose separated by at least 4 weeks?
- If not, what additional information should be provided?

## Question 3

- Are there additional issues that should be addressed in post-marketing studies beyond the applicant’s proposed U.S. post-licensure safety study

## Presentation Overview - RotarixTM

- Clinical overview
- Efficacy – Pivotal Studies
- Safety – Serious Adverse Events
- Co-administration of RotarixTM with routine childhood vaccines
- Post-marketing commitments
- Questions for the Advisory Committee

## Clinical Overview – RotarixTM

- Complete results of 11 clinical studies submitted to BLA
- 2 pivotal Phase III efficacy studies: Rota-023, Rota-036
- 2 supportive Phase II efficacy studies: Rota-004, Rota-006
- 1 Phase III concomitant childhood vaccination study: Rota-060
- 1 Phase III lot-to-lot consistency study: Rota-033
- Safety and RV immunogenicity evaluated in all studies
- Rota-023 also considered pivotal safety study for IS
- All studies randomized, double-blinded, placebo-controlled

## Slide 10

| Study #
(Phase) | Countries | # RotarixTM 
/placebo
subjects | Dose
potency
(CCID50) | Age  at
1st dose/
mean (wks) | Vaccine 
interval
 (months) | Male:
Female
ratio | Ethnicity | Co-admin
of infant
vaccines |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Rota-004 (II) | Finland | 270 / 135 | 105.3 | 6-12 / 8.3 | 2 | 214:191 | 99% White | No |
| Rota-005 (II) | US, Canada | 421 / 108 | 105.6
106.8 | 6-12 / 8.7 | 2 | 260:269 | 75% White | Yes |
| Rota-006 (II) | Brazil, Mexico, Venezuela | 1709 / 567 | 105.3
105.6
106.6 | 6-12 / 8.3 | 2 | 1197:
1079 | 73% Mixed
24%White  | Yes,
except 
OPV |
| Rota-007 (II) | Singapore | 1811 / 653 | 105.3
105.6
106.6 | 11-17 / 13.3 | 1 | 1226:
1238 | 93% Asian | Yes |
| Rota-014 (II) | South Africa | 297 / 150 | 105.6 | 5-10 (P I)
8-17 (P II)/
6.2 (PI)
11.1 (PII) | 1 | 225:225 | 83% Black
15% White | Yes,
Including
OPV |
| Rota-023 (III) | Argentina, Brazil, Chile,
Colombia, Dominican
Republic, Finland*, 
Honduras, Mexico, 
Nicaragua, Panama, 
Peru**, Venezuela | 31,673 / 31,552 | 106.5 | 6-12
(Chile: 6-13)/
8.2 | 1 or 2 | 32,255:
30,970 | 81% Hisp
11% White | Yes,
except 
OPV |
| Rota-033 (III) | Colombia, Mexico, Peru | 730 / 124 | 106.5 | 6-12 / 8.5 | 2 | 439:415 | 98% Hisp | Yes, 
except  
OPV |
| Rota-036 (III) | Czech Republic, Finland,
France, Germany, Italy, Spain | 2646 / 1348 | 106.5 | 6-14 / 11.5 | 1 or 2 | 2107:
1887 | 98% White | Yes |
| Rota-039 (III) | Thailand | 398 / 52 | 106.5 | 6-12 / 8.7 | 2 | 235:215 | 99% Asian | Yes |
| Rota-048 (II) | Finland | 200 / 50 | 106.5 | 6-12 / 9.1 | 1 | 119:131 | 98%White | No |
| Rota-060 (III) | US | 459 / 0 | 106.7 | 6-12 / 8.7 | 2 | 256:228 | 76% White
13% Black | Yes
(1 group) |

## Clinical Overview – RotarixTM

- From the BLA 11 studies:
- 40,614 RotarixTM and 34,739 placebo recipients received at
- 	least one study dose
- 78,980 RotarixTM and 67,349 placebo doses given
- 37,214 infants received RotarixTM at the potency, formulation, and storage conditions intended for commercial use (≥ 106.0 median CCID50 per dose, lyophilized, buffered,  stored at 2° to 8°C)
- Across studies, 90.5-99.1% of RotarixTM and 90.3-100% of placebo recipients received 2 study doses

## Efficacy – Pivotal Studies

## Efficacy – Pivotal Studies

- Vaccine efficacy measured in 2 pivotal Phase III studies:
- Rota-023 (Latin America)
- Rota-036 (Europe)
- Year 1 According to Protocol (ATP) efficacy cohort used for primary efficacy analyses in each study
- Vaccination with 2 doses of RotarixTM or placebo
- No RV other than vaccine strain in GE stool samples between Dose 1 and 2 weeks post-Dose 2
- Entry into Year 1 efficacy follow-up period

## Efficacy – Pivotal Studies

| Study | Phase | # Total subjects | # RotarixTM subjects | # placebo subjects |
| --- | --- | --- | --- | --- |
| Rota-023 | III | 17,867 | 9009 | 8558 |
| Rota-036 | III | 3874 | 2572 | 1302 |

- Year 1 ATP efficacy cohort

## Pivotal Efficacy Studies - Demographics

| Study | Countries | # RotarixTM 
/ placebo
subjects | Mean (Median) Age in weeks
Dose 1, Dose 2  | Mean (Median) 
Duration of follow-up in months | Male/
Female
ratio | Ethnicity |
| --- | --- | --- | --- | --- | --- | --- |
| Rota-023 | Argentina, Brazil, Chile, Colombia, DR, Honduras, Mexico, Nicaragua, Panama, Peru, Venezuela | 9009 / 8858 | D1 – 8.4 (8.0)
D2 – 16.3 (16.0) | 8 (8) | 8750 /
9117 | 85.8% Hisp
7.9% White
5.2% Other |
| Rota-036 | Czech Republic, Finland, France, Germany, Italy,
Spain | 2572 / 1302 | D1 – 11.5 (12.0)
D2 – 19.7 (20.0) | 6 (6) | 1883 /
2041 | 98.3% White |

- Year 1 ATP efficacy cohort

## Pivotal Efficacy Studies – Inclusion Criteria

- Free of obvious health problems
- Parents/guardians able to comply with study procedures
- Age range at Dose 1
- Rota-023: 6 to 12/13 weeks
- Rota-036: 6 to 14 weeks
- Birth weight > 2000 grams (Rota-036)

## Pivotal Efficacy Studies – Exclusion Criteria

- History of chronic GI disease or other serious medical condition
- Immunocompromised condition, including HIV
- >14 days on immunosuppressive drugs

## Pivotal Efficacy Studies – Other Characteristics

- No feeding restrictions
- Co-administration of infant vaccines allowed in Rota-023, except OPV which was administered 2 weeks apart from study vaccination
- Choice of vaccines determined according to national recommendations in each country
- DTwP, DTaP, HBV, IPV, OPV, MMR

## Pivotal Efficacy Studies – Other Characteristics

- Co-administration of infant vaccines allowed in Rota-036
- DTaP-Hib-HepB-IPV: Czech Republic, Finland, Germany, Italy, Spain
- DTaP-Hib-HepB-IPV (Dose 1, 3), DTaP-Hib-IPV: France
- Meningococcal group C conjugate: Spain
- Prevnar®: France, Germany

## Pivotal Efficacy Study – Rota-023

- Primary efficacy objective
- Determine if 2 doses of RotarixTM can prevent severe wild-type RV GE during Year 1 efficacy period (2 weeks post-Dose 2 to 1 year of age)
- Secondary efficacy objectives:
- Determine Year 1 efficacy  of RotarixTM against
- Severe G1 wild-type RV GE
- Severe non-G1 wild-type RV GE, pooled
- Severe non-G1 wild-type RV GE, by individual type
- Severe RV GE (Vesikari scale case definition)

## Pivotal Efficacy Study – Rota-036

- Primary efficacy objective:
- Determine efficacy of 2 doses of RotarixTM given with childhood vaccines against any wild-type RV GE during Year 1 efficacy period (2 weeks post-Dose 2 until end of 1st RV season)
- Secondary efficacy objectives:
- Determine Year 1 efficacy of RotarixTM against
- Severe wild-type RV GE
- Any/severe G1 wild-type RV GE
- Any/severe non-G1 wild-type RV GE
- Hospitalization for RV GE
- Any medical attention for RV GE

## Pivotal Efficacy Studies – Case Definitions

- Diarrhea: ≥ 3 looser than normal stools within a day
- Vomiting: ≥ 1 episode of forceful emptying of partially digested stomach contents ≥ 1 hour after feeding within a day
- Gastroenteritis (GE): diarrhea with or without vomiting
- Medical attention: medical provider contact, advice or visit; emergency room contact or visit or hospitalization

## Pivotal Efficacy Studies – Case Definitions

- RV GE: an episode of GE in which RV other than vaccine strain identified in a stool sample collected no later than 7 days after GE symptom onset
- Severe RV GE (Rota-023): an episode of RV GE requiring hospitalization and/or re-hydration therapy (equivalent to WHO plan B or C) in a medical facility
- Severe RV GE (Vesikari scale, Rota-036): an episode of RV GE with a Vesikari score of ≥ 11 points

## Vesikari Scale

| Adverse Experience |  | Points |
| --- | --- | --- |
| Duration of looser than normal stools (days)
1-4
5
≥ 6 |  | 
1
2
3 |
| Maximum # of looser than normal stools per 24 hours
1-3
4-5
≥ 6 |  | 
1
2
3 |
| Duration of vomiting (days)
1
2
≥ 3 |  | 
1
2
3 |
| Maximum # of episodes of vomiting per 24 hours
1
2-4
≥ 5 |  | 
1
2
3 |
| Fever (highest temperature recorded during episode) |  |  |
| Rectally
37.1 – 38.4°C
38.5 – 38.9°C
≥ 39°C | Axillary
36.6 – 37.9°C
38.0 – 38.4°C
≥ 38.5°C | 
1
2
3 |
| Dehydration
1-5%
≥ 6% |  | 
2
3 |
| Treatment
Rehydration
Hospitalization |  | 
1
2 |

## Pivotal Efficacy Studies – RV GE Case Ascertainment

- Rota-023
- Hospitals and other medical facilities in study areas contacted at least twice a week
- Subjects also contacted or visited at least every 4 days to identify severe cases not picked up by routine medical facility surveillance
- Rota-036
- Subjects contacted weekly (by telephone) from 1 week post-Dose 1 until the end of the 1st RV season (end of May 2005)
- Diary cards collected temperature, stool, emesis data

## Pivotal Efficacy Studies – Stool Collection & Laboratory Diagnosis

- Parents instructed to collect, label, store, and submit stool samples for each GE episode
- All collected stools tested for RV antigen by ELISA at applicant’s laboratory in Belgium
- RV antigen-positive stools analyzed for G and P type by RT-PCR followed by Reverse Hybridization Assay or optional sequencing (Delft Diagnostic Laboratory, the Netherlands)

## Pivotal Efficacy Studies – Vaccine Efficacy Calculation

- Vaccine Efficacy = 1 – Relative Risk = 1 – (ARV/ARU)
- ARV = attack rate in RotarixTM group
-          = # subjects with at least one episode of RV GE endpoint ÷
- 	total # subjects in RotarixTM group
- ARU = attack rate in placebo group
-          = # subjects with at least one episode of RV GE endpoint ÷
- 	total # subjects in placebo group

## Efficacy Results – Rota-036

| 

Clinical endpoint | Number of cases (n) |  | 

Vaccine Efficacy
(%) | 

95% CI |
| --- | --- | --- | --- | --- |
|  | RotarixTM 
(N=2572) | Placebo
(N=1302) |  |  |
| Any RV GE | 24 | 94 | 87.1 | 79.6, 92.1 |
| Severe RV GE | 5 | 60 | 95.8 | 89.6, 98.7 |

- ATP efficacy cohort, Year 1

- N= total number of subjects in ATP efficacy cohort, Year 1
- n= number of subjects reporting at least one clinical endpoint event caused by circulating wild-type RV

## Efficacy Results – Rota-036

- VE against any RV GE, ATP efficacy cohort, Year 1

| RV Type | Number of cases (n) |  | Vaccine efficacy (%) | 95% CI |
| --- | --- | --- | --- | --- |
|  | RotarixTM
(N=2572) | Placebo
(N=1302) |  |  |
| G1 | 4 | 46 | 95.6 | (87.9, 98.8) |
| G2 | 3 | 4 | 62.0 |   (-124.4, 94.4) |
| G3 | 1 | 5 | 89.9 |   (9.5, 99.8) |
| G4 | 3 | 13 | 88.3 | (57.5, 97.9) |
| G9 | 13 | 27 | 75.6 | (51.1, 88.5) |
| Pooled (G2,G3,G4,G9) | 20 | 49 | 79.3 | (64.6, 88.4) |

## Efficacy Results – Rota-036

- VE against severe RV GE, ATP efficacy cohort, Year 1

| RV Type | Number of cases (n) |  | Vaccine efficacy (%) | 95% CI |
| --- | --- | --- | --- | --- |
|  | RotarixTM
(N=2572) | Placebo
(N=1302) |  |  |
| G1 | 2 | 28 | 96.4 | (85.7, 99.6) |
| G2 | 1 | 2 | 74.7 |   (-386.2, 99.6) |
| G3 | 0 | 5 | 100 |  (44.8, 100) |
| G4 | 0 | 7 | 100 | (64.9, 100) |
| G9 | 2 | 19 | 94.7 | (77.9, 99.4) |
| Pooled (G2,G3,G4,G9) | 3 | 33 | 95.4 | (85.3, 99.1) |

## Efficacy Results – Rota-036

| 

Clinical endpoint | Number of cases (n) |  | 

Vaccine Efficacy
(%) | 

95% CI |
| --- | --- | --- | --- | --- |
|  | RotarixTM 
(N=2572) | Placebo
(N=1302) |  |  |
| Hospitalization for RV GE | 0 | 12 | 100 | 81.8, 100 |
| Any medical attention for RV GE
 | 10 | 62 | 91.8 | 84.0, 96.3 |

- ATP efficacy cohort, Year 1

## Efficacy Results – Rota-023

| 

Clinical endpoint | Number of cases (n) |  | 

Vaccine Efficacy
(%) | 

95% CI |
| --- | --- | --- | --- | --- |
|  | RotarixTM 
(N=9009) | Placebo
(N=8858) |  |  |
| Severe RV GE (main definition) | 12 | 77 | 84.7 | 71.7, 92.4 |
| Severe RV GE (Vesikari scale)  | 11 | 71 | 84.8 | 71.1, 92.7 |

- ATP efficacy cohort, Year 1

## Efficacy Results – Rota-023

- VE against severe RV GE (main definition), ATP efficacy cohort, Year 1

| RV Type | Number of cases (n) |  | Vaccine efficacy (%) | 95% CI |
| --- | --- | --- | --- | --- |
|  | RotarixTM
(N=9009) | Placebo
(N=8858) |  |  |
| G1 | 3 | 36 | 91.8 | (74.1, 98.4) |
| G2 | 6 | 10 | 41.0 | (-79.2, 82.4) |
| G3 | 1 | 8 | 87.7 | (8.3, 99.7) |
| G4 | 1 | 2 |    Not calculated |  |
| G9 | 2 | 21 | 90.6  | (61.7, 98.9) |
| Pooled (G2,G3,G4,G9) | 10 | 40 | 75.4  | (50.0, 89.0) |

## Efficacy Results –FDA Analysis

- FDA considers it more appropriate to use the “time-to-first-episode” analysis than using attack rates in each arm
- Time-to-event approach accounts for differential follow-up of subjects, while the latter approach does not
- FDA inclined to place more importance on efficacy results based on the Cox proportional-hazards model
- Using the Cox-proportional-hazard model, VE against
- Severe RV GE (Rota-023): 84.8%; 95% CI=72.0, 91.7%
- Any RV GE (Rota-036): 87.4%; 95% CI=80.3, 91.9%

## Safety – Intussusception Study (Rota-023)

## Intussusception (IS) Study – Rota-023

- Primary safety objective:
- Determine the safety of RotarixTM with respect to intussusception (IS) within 31 days (Days 0 to 30) after each dose
- Primary safety endpoint:
- Occurrence of definite IS within 31 days after each dose
- The Brighton Collaboration IS Working Group case definition for IS used

## IS Study – Rota-023

| Surgical criteria
The demonstration of invagination of the intestine at surgery,

AND/OR

Radiological criteria 
The demonstration of invagination of the intestine by either gas or liquid contrast enema,

Or

The demonstration of an intra-abdominal mass by abdominal ultrasound with specific characteristic
features* that is proven to be reduced by hydrostatic enema on post-reduction ultrasound

AND/OR

Autopsy criteria 
The demonstration of invagination of the intestine.

* target sign or doughnut sign on transverse section and a pseudo-kidney or sandwich sign on
longitudinal section |
| --- |

- The Brighton Collaboration IS Working Group case definition for “Definite IS”

## IS Study – Rota-023

- To capture all IS events, IS cases reported irrespective of whether they met the Brighton case definition
- Clinical Events Review Committee (CEC) performed blinded objective reviews of all IS cases occurring from Dose 1 to Visit 3*
- CEC consisted of physicians acting as consultants who were not study investigators or medical care providers to study subjects
- *Visit 3 = 1-2 months post-Dose 2 or 2-4 months post-Dose 1

## IS Study – Rota-023

- Rota-023 specifically designed and powered to assess the risk of IS following RotarixTM vaccination
- 31,673 subjects vaccinated with at least 1 dose of RotarixTM
- 31,552 subjects vaccinated with at least 1 dose of placebo
- Original criterion for meeting primary safety objective
- UL of 90% CI of IS risk difference (RotarixTM minus placebo) less than 2/10,000 subjects
- Criterion based on consensus estimate of Rotashield® attributable risk of 1/10,000 vaccinees

## IS Study – Rota-023

- 9 months after study initiation, blinded overall IS incidence rate 31 days post-vaccination was 2-4/10,000
- Exceeded anticipated rate of 0.3/10,000 in placebo group
- UL of 90% CI exceeded 2/10,000
- Background incidence rate of 5/10,000 calculated from concurrent, prospective, multi-center epidemiologic study in the same countries

## Intussusception Study – Rota-023

- Criteria for meeting primary safety objective revised
- UL of 95% CI of risk difference for definite IS < 6/10,000
- 	(limit based on IS incidence of 3-5/10,000 in placebo group and 30,000 subjects in each group)
- LL of 95% CI of the risk difference < 0
- Study had >86% power to meet primary objective if the risk difference was truly 0

## IS Study Results– Rota-023

|  | Study group |  |  |  |  |  | Risk Difference
(RotarixTM – Placebo) |  |  | Relative Risk (RR)
(RotarixTM / Placebo) |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | RotarixTM |  |  | Placebo |  |  | per
10,000 | 95% CI |  | RR | 95% CI |  |  |
| 31 days  after: | N | n | n/
10,000 | N | n | n/
10,000 |  | LL | UL |  | LL | UL | p-value |
| Any dose | 31,673 | 6 | 1.9 | 31,552 | 7 | 2.2 | -0.32 | -2.91 | 2.18 | 0.85 | 0.30 | 2.42 | 0.776 |
| Dose 1 | 31,673 | 1 | 0.3 | 31,552 | 2 | 0.6 | -0.32 | -2.03 | 1.20 | 0.50 | 0.07 | 3.80 | 0.561 |
| Dose 2 | 29,616 | 5 | 1.7 | 29,465 | 5 | 1.7 | -0.01 | -2.48 | 2.45 | 0.99 | 0.31 | 3.21 | 0.994 |

**N = # subjects in the cohort; n = # subjects with definite IS**

- Definite IS diagnosed 31 days (Days 0 to 30) post-vaccination

## IS Study Results– Rota-023

- Applicant noted that when original criterion for primary safety objective used (UL of 90% CI of risk difference < 2/10,000), objective still met
- UL = 1.71/10,000
- 25 definite IS cases diagnosed from Dose 1 until Visit 3
- RotarixTM = 9, placebo = 16
- Risk difference = -2.23/10,000 (95% CI: -5.70, 0.94)
- RR = 0.56 (95% CI: 0.25, 1.24)

## IS Study Results– Rota-023 (FDA analysis)

- One definite IS case had onset on Day 29 but diagnosed on Day 31
- Analysis of IS risk within 31 days after any dose based on onset date rather than diagnosis date
- RotarixTM = 7, placebo = 7
- Risk difference = -0.008/10,000 (95% CI: -2.63, 2.61)
- RR = 0.996 (95% CI: 0.36, 2.72)

## IS Study Results– Rota-023(FDA analysis)

- Definite IS by onset interval after each dose

| Vaccination – IS onset interval | RotarixTM IS cases
(N = 31,673) | Placebo IS cases
(N = 31,552) |
| --- | --- | --- |
| Post-Dose 1 |  |  |
| Day 0 - Day 30 | 1 | 2 |
| > Day 30 | 1 | 6 |
| Post-Dose 2 |  |  |
| Day 0 - Day 30 | 6 | 5 |
| > Day 30 | 5 | 7 |
| Total | 13 | 20 |

## IS Study Results– Rota-023(FDA analysis)

- Definite IS by onset interval after each dose

| Vaccination – IS onset interval | RotarixTM IS cases
(N = 31,673) | Placebo IS cases
(N = 31,552) |
| --- | --- | --- |
| Post-Dose 1 |  |  |
| Day 3 - 7 | 0 | 0 |
| Day 3 - 14 | 0 | 0 |
| Post-Dose 2 |  |  |
| Day 3 - 7 | 2 | 1 |
| Day 3 - 14 | 2 | 2 |

## IS Study Results– Rota-023 (FDA analysis)

- Criteria to meet the primary safety objective was revised during the conduct of the study
- Such change while the trial is ongoing could potentially compromise the integrity of the study
- Because FDA did not discuss this change with applicant (study was not performed under US IND), more detailed information has been requested to ensure that proper procedure was followed

## Safety – Serious Adverse Events (SAEs)

## Safety – Integrated Safety Summary (ISS)

- Integrated Safety Summary (ISS) analyses conducted
- Based on Total Vaccinated Cohort (TVC) data from 10 studies
- Involved pooling of subjects into Core ISS and Supplementary ISS analysis groups
- Core ISS analysis group: pooled subjects who received RotarixTM at potency of ≥ 106.0 CCID50 per dose or placebo
- Supplementary ISS analysis group: pooled subjects who received RotarixTM at potency of < 106.0 CCID50 per dose or placebo

## Safety – ISS Analyses

- Core ISS analysis group
- 36,755 RotarixTM subjects (71,320 doses)
- 34,454 placebo subjects (66,765 doses)
- 8 studies
- Supplementary ISS analysis group
- 3076 RotarixTM subjects (6037 doses)
- 1613 placebo subjects (3177 doses)
- 5 studies
- For studies included in both ISS analysis groups, the same numbers of placebo subjects used

## Safety – ISS Analyses

- ISS analyses endpoints
- Fatal and non-fatal SAEs: Days 0-30 post-vaccination, entire length of studies
- SAEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA)
- Relative risk (RR; % in RotarixTM group divided by % in placebo group) and 95% CI calculated
- Adjusted for study effect
- Multiplicity adjustment not performed

## Safety – Pivotal Study Analyses

- Rota-023, Rota-036
- SAEs throughout study period (~2 years)
- Risk difference (RotarixTM minus placebo) and 95% CI calculated
- Rota-023
- 31,673 RotarixTM subjects (61,289 doses)
- 31,552 placebo subjects (61,017 doses)
- Rota-036
- 2646 RotarixTM subjects (5267 doses)
- 1348 placebo subjects (2686 doses)

## Deaths – ISS Analysis Groups

- 128 post-vaccination deaths reported from 10 studies in the ISS analyses (also: no deaths in Rota-060)

| Study | ≥ 106.0 CCID50 (Core ISS) |  | < 106.0 CCID50 (Supp ISS) |  | placebo |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | N | n (%) | N | n (%) | N | n (%) |
| Rota-004 | - | - | 270 | 0 | 135 | 0 |
| Rota-005 | 209 | 0 | 212 | 0 | 108 | 0 |
| Rota-006 | 570 | 1 | 1139 | 1 | 567 | 1 |
| Rota-007 | 653 | 2 | 1158 | 1 | 653 | 0 |
| Rota-014 | - | - | 297 | 3 | 150 | 5 |
| Rota-023 | 31,673 | 62 | - | - | 31,552 | 49 |
| Rota-033 | 730 | 3 | - | - | 124 | 0 |
| Rota-036 | 2646 | 0 | - | - | 1348 | 0 |
| Rota-039 | 174 | 0 | - | - | 52 | 0 |
| Rota-048 | 100 | 0 | - | - | 50 | 0 |
| All studies  | 36,755 | 68 (0.184) | 3076 | 5 (0.163) | 34,739 | 55 (0.158) |

**N = number of subjects that received at least one dose; n = number of fatal cases **

## Deaths – Core ISS Group

- 53 deaths reported from Days 0-30 post-dose
- RotarixTM = 33 (0.09%), placebo = 20 (0.06%)
- RR = 1.64; 95% CI = 0.92, 3.02
- Notable imbalances not observed for each MedDRA PT
- PT Pneumonia most common death code
- RotarixTM = 7 (0.02%), placebo = 5 (0.01%),
- 	RR=1.39; 95% CI = 0.38-5.57

## Deaths – Core ISS Group

- 118 deaths reported throughout study periods
- RotarixTM = 68 (0.19%), placebo = 50 (0.15%)
- RR = 1.31; 95% CI = 0.89, 1.93
- PT Pneumonia most common death code
- RotarixTM = 19 (0.05%), placebo = 10 (0.03%),
- 	RR=1.74; 95% CI = 0.76-4.23

## Deaths – Supplementary ISS Group

- 7 deaths reported from Days 0-30 post-dose
- RotarixTM = 3 (0.10%), placebo = 4 (0.25%)
- RR = 0.38; 95% CI = 0.06, 2.27
- 11 deaths reported throughout study periods
- RotarixTM = 5 (0.16%), placebo = 6 (0.37%)
- RR = 0.42; 95% CI = 0.10, 1.67

## Deaths – Rota-023

- 111 post-vaccination deaths reported
- RotarixTM = 62 (0.20%), placebo = 49 (0.16%)
- 99 of the 111 deaths reported from Dose 1 to Visit 3
- RotarixTM = 56 (0.18%), placebo = 43 (0.14%)
- Risk difference = 4.05/10,000; 95% CI = -2.15, 10.4
- Deaths within 31 days post-dose
- Post-Dose 1: RotarixTM = 22 (0.07%), placebo = 11 (0.03%),
- RD = 3.46/10,000; 95% CI: -0.11, 7.39
- Post-Dose 2: RotarixTM = 2 (0.006%), placebo = 5 (0.016%)
- RD = -1.02/10,000; 95% CI: -3.37, 0.95

## Deaths – Rota-023

- Among 99 deaths from Dose 1 to Visit 3, PT Pneumonia reported more in RotarixTM than placebo group
- RotarixTM = 14 (0.04%), placebo = 5 (0.02%),
- RD = 2.84/10,000; p=0.04
- 7 PT Pneumonia deaths had onset from Days 0 to 30 post-dose
- RotarixTM = 5 (0.02%), placebo = 2 (0.01%)
- Applicant performed ad-hoc pneumonia deaths analysis
- Pooled PTs Pneumonia, Bronchopneumonia, Pneumonia CMV
- Dose 1 to Visit 3: RotarixTM = 16 (0.05%), placebo = 6 (0.02%)
- RD = 3.15/10,000; p=0.054
- Days 0 to 30: RotarixTM = 7 (0.02%), placebo = 3 (0.01%)
- No clear temporal association by week of onset

## Deaths – Rota-023 (FDA Analysis)

- For ad-hoc pneumonia deaths analysis, exact p-value of risk difference calculated by FDA different than applicant’s calculations
- Deaths during period: RotarixTM = 16 (0.05%), placebo = 6 (0.02%)
- RD = 3.15/10,000
- Applicant’s p-value = 0.054
- FDA’s p-values = 0.0345, 0.0354

## SAEs – Core ISS Group

- 1286 subjects with at least one SAE from Days 0-30 post-dose
- RotarixTM = 627 (1.71%), placebo = 659 (1.91%)
- RR = 0.90; 95% CI = 0.81, 1.01
- Rates of PTs Diarrhoea, Gastroenteritis, Dehydration significantly less in RotarixTM group
- Rates of PTs Pneumonia, Convulsions same or very similar between groups
- 4519 subjects reported at least one SAE throughout study periods
- RR = 0.89; 95% CI = 0.84, 0.94
- Results of PT analyses similar to those from Days 0-30

## Intussusception – Core ISS Group

- IS onset from Days 0-30 post-dose
- RotarixTM = 9 (0.024%), placebo = 7 (0.020%)
- RR = 1.23; 95% CI = 0.41, 3.90
- No cases from Days 0-14 post-Dose 1
- IS onset throughout study periods
- RotarixTM = 16 (0.04%), placebo = 22 (0.06%)
- RR = 0.69; 95% CI = 0.34, 1.37

## Intussusception – Supplementary ISS Group

- IS onset from Days 0-30 post-dose
- RotarixTM = 1 (0.033%), placebo = 0 (0.0%)
- LL of 95% CI for RR = 0.01
- Case occurred 6 days post-Dose 1
- IS onset throughout study periods
- RotarixTM = 2 (0.07%), placebo = 1 (0.06%)
- RR = 1.08; 95% CI = 0.06, 63.94

## SAEs – Rota-023

- Significantly less RotarixTM than placebo recipients reported at least 1 SAE from Dose 1 to Visit 3
- RotarixTM = 928 (2.93%), placebo = 1047 (3.32%);
- RD = -38.8/10,000; p=0.005
- PTs Diarrhea, Vomiting, Gastroenteritis, and Dehydration reported significantly less in RotarixTM group
- No notable imbalances in pneumonia-related PTs
- Dose 1 to Visit 3:
- RotarixTM = 280 (0.88%), placebo = 277 (0.88%)
- Hospitalizations from Dose 1 to Visit 3
- RotarixTM = 277 (0.87%), placebo = 273 (0.87%)

## SAEs – Rota-023

- PT Convulsions reported significantly more in RotarixTM group from Dose 1 to Visit 3
- RotarixTM = 16 (0.05%), placebo = 6 (0.02%)
- RD=3.15/10,000; p=0.034
- Applicant performed ad-hoc convulsion analysis
- Combined PTs Convulsions, Epilepsy, Grand mal convulsions, Tonic convulsions, Status epilepticus
- RotarixTM = 20 (0.06%), placebo = 12 (0.04%)
- RD=2.51/10,000; p=0.219
- Days 0 to 30: RotarixTM = 7 (0.02%), placebo = 9 (0.03%)
- Post-Dose 1:  RotarixTM = 5 (0.02%), placebo = 5 (0.02%)
- Post-Dose 2:  RotarixTM = 2 (0.01%), placebo = 4 (0.01%)

## SAEs – Rota-036

- Less RotarixTM than placebo recipients reported at least 1 SAE from Dose 1 to Visit 7 (end of 2nd RV season)
- RotarixTM = 290 (11.0%), placebo = 176 (13.1%); p-value=0.051
- PTs Gastroenteritis and Gastroenteritis rotavirus reported significantly less in RotarixTM group
- PT Pneumonia reported significantly more in RotarixTM group from Dose 1 to Visit 7
- RotarixTM = 24 (0.91%), placebo = 4 (0.30%)
- RD=61/10,000; p=0.029
- After Visit 5: RotarixTM = 17 (0.64%), placebo = 2 (0.15%)
- Days 0 to 30 post-dose: RotarixTM = 1, placebo = 0

## SAEs – Rota-036 (FDA Analysis)

- Frequency of combined convulsion-related PTs (Convulsions, Epilepsy, Infantile spasms, Myoclonus, Partial seizures) from Days 0 to 30 post-vaccination similar between groups
- RotarixTM = 1 (0.04%), placebo = 1 (0.07%)

## SAEs – Rota-036 (FDA Analysis)

- Frequency of combined pneumonia-related PTs (Pneumonia, Bronchopneumonia, Lobar pneumonia, Pneumonia viral) were higher RotarixTM group
- Dose 1 to Visit 7: RotarixTM = 31 (1.2%), placebo = 7 (0.5%)
- Days 0 to 30 post-dose: RotarixTM = 2 (0.08%), placebo = 0 (0%)

## Safety – Kawasaki Disease

- At ACIP meeting on June 28, 2007, FDA presented data on occurrence of Kawasaki disease (KD) within 30 days after RotaTeq® vaccination during Phase III clinical trials
- 5 out of 36,150 RotaTeq® subjects
- 1 out of 35,536 placebo subjects
- Unadjusted RR = 4.9; 95% CI: 0.6-239.1
- Causal relationship between RotaTeq®  and KD not established, post-licensure studies ongoing

## Safety – Kawasaki Disease

- Upon request by FDA, applicant submitted an analysis report of KD following RotarixTM on July 20, 2007
- Report included all cases of KD from completed and ongoing clinical trials
- Information amendment in response to FDA comments submitted on February 1, 2008

## Safety – Kawasaki Disease

- 27 unblinded cases of KD reported in RotarixTM trials
- Rota-023 (Mexico): 1 case  (RotarixTM; total exposed = 31,673)
- 2 yr female, Hispanic,19 months post-Dose 2 Rotarix, 17 months post-DTwP-HBV-Hib-OPV, 7 months post-HepA
- Lack of clinical information to assess whether KD criteria met
- Rota-006 (Brazil): 1 case (RotarixTM; total exposed = 1709)
- 13 mo male, Mixed, 7 months post-Dose 2 Rotarix,  5 months after DTwP-HepB-Hib
- Rota-061 (Finland): 1 case (RotarixTM; total exposed = 1200)
- 3 mo male, White,12 days post-Dose 2 Rotarix, 12 days after DTaP-IPV-HepB-Hib

## Safety – Kawasaki Disease

- 27 cases of KD reported in RotarixTM clinical trials
- Rota-007 (Singapore), Rota-028 (Singapore), Rota-029 (Hong Kong), Rota-030 (Taiwan): 24 cases
- RotarixTM – 15 (0.21%), placebo – 9 (0.15%)
- Male:female = 15:9; Asian = 100%
- Median onset after Rotarix/placebo: 5.5 months (3 days – 19 months)
- Median onset after routine vaccinations (DTaP-IPV-Hib with/without HepB): 3.5 months (3 days-18 months)
- Days 0 to 30 post-Rotarix/placebo: RotarixTM = 1, placebo = 1
- 1 case (RotarixTM, 55 days post-Dose 2) lacked clinical information to assess whether KD criteria met

## Co-Administration of RotarixTM with Other Childhood Vaccines(Rota-060)

## Co-administration with Other Childhood Vaccines

- Co-administration of other routine childhood vaccines with RotarixTM allowed in 9 of the 11 BLA studies
- Only Rota-060 specifically designed to evaluate non-inferiority of immune responses to routine U.S. childhood vaccine antigens when these vaccines were co-administered with RotarixTM
- All subjects given 3 doses each of Pediarix® (DTaP-HepB-IPV), Prevnar® (pneumococcal 7-valent conjugate), and ActHIB® (*Haemophilus b* conjugate) on a 0, 2, 4-month schedule

## Co-administration Study – Rota-060

- Subjects randomized to one of 2 groups
- Co-ad group: RotarixTM administered with first 2 sets of routine vaccine doses
- Sep-ad group: RotarixTM administered 1 month after Dose 1 and 1 month after Dose 2 of routine vaccines
- 180 Co-ad subjects and 137 Sep-ad subjects in ATP immunogenicity cohort

## Co-administration Study – Rota-060

- Antibody responses to D, T, P (PRN, FHA, PT), hep B (HBs), poliovirus (1, 2, 3), Hib (PRP), and *S. pneumoniae* (4, 6B, 9V, 14, 18C, 19F, 23F) antigens measured at one month post-Dose 3 of routine vaccinations
- GMC or GMT measured for all antigens
- Definitions of seroprotection
- Anti-PRP:	≥ 1.0 μg/mL
- Anti-HBs:		≥ 10 mIU/mL
- Anti-polio (1,2,3):	≥ 1:8
- Anti-D:		≥ 0.1 IU/mL
- Anti-T:		≥ 0.1 IU/mL

## Co-administration Study – Rota-060

- Demonstration of non-inferiority of immune response to routine vaccine antigens in Co-ad group required meeting all of the following criteria:
- LL of 95% CI for difference* in seroprotection rate ≥ -10% for:
- Anti-PRP, anti-HBs, anti-polio (types 1, 2, 3), anti-D, anti-T
- LL of 95% CI for GMC ratio* ≥ 0.67 for:
- Anti-P (PT, FHA, PRN)
- LL of 95% CI for GMC ratio* ≥ 0.5 for:
- Anti*-S. pneumoniae* (serotypes 4, 6B, 9V, 14, 18C, 19F, 23F)

- *Difference = rate in Co-ad minus rate in Sep-ad
- **GMC ratio = GMC in Co-ad ÷ GMC in Sep-ad

## Co-administration Study – Rota-060

- Non-inferiority of seroprotection rates in Co-ad group compared to Sep-ad group demonstrated for Anti-PRP, anti-HBs, anti-polio (types 1, 2, 3), anti-D, anti-T
- LLs of 95% CI on difference in seroprotection rates all ≥ -10%
- Non-inferiority of GMCs in Co-ad group compared to Sep-ad group demonstrated for Anti-P (PT, FHA, PRN) and Anti*-S. pneumoniae* (serotypes 4, 6B, 9V, 14, 18C, 19F, 23F)
- LLs of 95% CI on GMC ratios all ≥ 0.5

## Co-administration Study – Rota-060(FDA Analysis)

- When the LL of 95% CI for difference in the anti-polio seroprotection rate was increased from ≥ -10% to ≥ -5%, non-inferiority criterion for each poliovirus type was still met

## Summary 

- RotarixTM was effective in preventing any RV GE and severe RV GE during the 1st year of life
- Protection demonstrated against wild-type G1, G3, G4, G9 types individually, and non-G1 types when pooled together

## Summary

- RotarixTM did not increase post-vaccination risk of intussusception
- Increased rates of pneumonia-related deaths and convulsion-related SAEs in RotarixTM group from Dose 1 to Visit 3, Rota-023

## Summary

- Co-administration of RotarixTM with other routine vaccines in the U.S. did not interfere with immune responses to each of these vaccine antigens

## Post-marketing Commitments

- Applicant will conduct a U.S. post-licensure observational safety study:
- Cohort of infants vaccinated in routine pediatric health care setting
- Safety data collected prospectively
- Total number of vaccinated infants calculated in order to provide 80% power to detect a RR of intussusception ≥ 2.5 at a 5% significance level
- Other measured outcomes:
- Deaths from all causes
- Hospitalizations due to acute lower respiratory tract infections (including pneumonia)
- Convulsions
- Kawasaki disease

## Acknowledgements

- FDA Review Team
- Pete Amin
- Vladimir Chizhikov
- Dino Feigelstock
- Steve Feinstone
- Anthony Hawkins
- Gale Heavner
- Laraine Henchal
- Hector S. Izurieta
- Jingyee Kou
- Chris Lynch
- Sandra Menzies
- Jonathan Mcinnis
- Karen Meysick
- Steve Rosenthal
- Lev Sirota
- Lisa Stockbridge
- Luba Vujcic

- Other FDA members
- Norman Baylor
- Amelia Dale Horne
- Douglas Pratt
- Loris McVittie
- Rosemary Tiernan

## Questions for the Advisory Committee

## Question 1

- Are the available data presented adequate to support the efficacy of RotarixTM in preventing rotavirus gastroenteritis caused by serotypes G1, G2, G3, G4, and G9, when the first dose of vaccine is administered beginning 6 weeks of age, followed by a second dose separated by at least 4 weeks?
- If not, what additional information should be provided?

## Question 2

- Are the available data presented adequate to support the safety of RotarixTM when used in a 2 dose series beginning with the first dose at 6 weeks of age, followed by a second dose separated by at least 4 weeks?
- If not, what additional information should be provided?

## Question 3

- Are there additional issues that should be addressed in post-marketing studies beyond the applicant’s proposed U.S. post-licensure safety study