FDA Briefing Document
Vaccines & Related Biological Products Advisory Committee Meeting
February 20, 2008
RotarixTM (rotavirus vaccine, live, oral, monovalent)
GlaxoSmithKline Biologicals
Paul Kitsutani, MD, MPH
Division of Vaccines and
Related Product Applications
OVRR/CBER/FDA
TABLE OF CONTENTS
PAGE
1.0 GENERAL INFORMATION 3
PRODUCT NAME
PRODUCT COMPOSITION
PROPOSED INDICATION
PROPOSED AGE GROUP
DOSING REGIMEN AND ROUTE OF ADMINISTRATION
EXECUTIVE SUMMARY 4
2.0 INTRODUCTION AND BACKGROUND 9
2.1 EPIDEMIOLOGY OF ROTAVIRUS INFECTIONS 9
2.2 REGULATORY BACKGROUND 10
2.3 BASIS FOR LICENSURE 11
3.0 CLINICAL OVERVIEW 11
3.1 EFFICACY – PIVOTAL STUDIES 15
3.2 IMMUNOGENICITY 20
3.3 SAFETY 21
3.4 CO-ADMINISTRATION
WITH OTHER CHILDHOOD VACCINES
39
4.0 REFERENCES 41
1.0
GENERAL
INFORMATION
Product name
Established name: Live Attenuated Human Rotavirus [HRV] Vaccine,
Oral
Proposed
trade name: RotarixTM
Product composition (from the Applicant’s proposed label):
RotarixTM is a live,
attenuated rotavirus vaccine derived from the human 89-12 strain which belongs
to G1P[8] type. The HRV strain is propagated
on Vero cells. After reconstitution, the final formulation (1 mL) contains
an end-of-shelf-life titer of at least 106.0 median Cell Culture
Infective Dose (CCID50) of live, attenuated HRV. RotarixTM, for oral administration, is available as a
single-dose vial of lyophilized vaccine to be reconstituted with a liquid
diluent in prefilled oral applicator. The lyophilized vaccine contains amino acids, dextran, Dulbecco’s
Modified Eagle Medium (DMEM), sorbitol, and sucrose; the liquid diluent
contains calcium carbonate, sterile water, and xanthan. The diluent
includes an antacid component to protect the vaccine during passage through the
stomach and prevent its inactivation due to the acidic environment of the
stomach. RotarixTM contains no preservatives.
Manufacturer: GlaxoSmithKline Biologicals
Proposed indication: Prevention of rotavirus gastroenteritis caused by G1 and non-G1 types
RotarixTM is an oral monovalent vaccine indicated for the prevention of rotavirus gastroenteritis in infants caused by G1 and non-G1 types (including G2, G3, G4, and G9) when administered as a 2-dose series to infants 6 to 24 weeks of age.
Dosing regimen: 2 doses, first dose beginning at 6 weeks of age, second dose administered by 24 weeks of age, interval of at least 4 weeks between doses
Route of administration: Oral
Potency: -------- CCID50 per dose (release specification potency)
≥ 106.0 CCID50 per dose (end-of-shelf-life potency)
EXECUTIVE SUMMARY
This briefing document contains a summary of efficacy, immunogenicity, and safety data provided by GlaxoSmithKline to support approval of RotarixTM, a live, oral, monovalent rotavirus (RV) vaccine indicated for the prevention of RV gastroenteritis (GE) caused by G1 and non-G1 types. RotarixTM is to be administered as a 2-dose series to healthy infants 6 to 24 weeks of age, with doses separated by a minimum interval of 4 weeks. The proposed release specification potency is ≥ 106.2 median Cell Culture Infective Dose (CCID50) per dose of live, attenuated human RV, with an end-of-shelf-life potency of
≥ 106.0 CCID50 per dose.
The Biologics Licensing Application (BLA) contains six Phase
II trials and five Phase III trials. Two of the Phase III trials are considered
pivotal efficacy studies: Rota-023, conducted in 11 Latin American countries,
and Rota-036, conducted in six European countries. Rota-023 was also
specifically designed and powered to evaluate the risk of definite intussusception
(IS), with over 63,000 infants from 11 Latin American countries plus
Efficacy
Two Phase III studies, Rota-023 and Rota-036, are considered pivotal to the efficacy claims in this BLA. The primary objective of Rota-036 was to assess vaccine efficacy (VE) against any RV GE during the first efficacy follow-up period from 2 weeks post-Dose 2 until the end of the first RV epidemic season. The primary objective of Rota-023 was to assess VE against severe RV GE during the first efficacy follow-up period from 2 weeks post-Dose 2 until 12 months of age. Both studies were prospective, randomized, double-blinded, placebo-controlled trials. In each study, the According to Protocol (ATP) efficacy cohort was used for the primary efficacy analyses, and consisted of 17,857 subjects (RotarixTM: 9009, placebo: 8558) in Rota-023 and 3874 subjects (RotarixTM: 2572, placebo: 1302) in Rota-036. VE for each endpoint was calculated using the following formula: 1 – (attack rate in the RotarixTM group ÷ attack rate in the placebo group).
In Rota-036, RV GE was defined as an episode of GE in which RV other than the vaccine strain was identified in a stool sample collected no later than 7 days after GE symptom onset, while severe RV GE was defined as an episode of RV GE with a score of ≥ 11 points using the Vesikari scale. In Rota-023, the primary case definition of severe RV GE was defined as an episode of RV GE requiring hospitalization and/or rehydration therapy (equivalent to WHO plan B or C) in a medical facility.
The sponsor demonstrated that RotarixTM, at 106.5 CCID50
per dose, was effective in preventing naturally occurring RV GE
of any grade of severity and severe RV GE during the first year of life. VE was
87.1%
(95% CI:
79.6, 92.1%) against any RV GE in Rota-036. VE against severe
RV GE was 95.8%
(95% CI:
89.6, 98.7%) in Rota-036 compared to 84.7% (95% CI: 71.7,
92.4%) in Rota-023, suggesting geographical and/or ethnic
differences in efficacy. Protection was
also demonstrated against any and severe RV GE caused by circulating G1 and
certain non-G1 types, as well as other clinical endpoints during the
first-year, second-year, and combined (first- and second-year) efficacy
follow-up periods.
Immunogenicity
Immunogenicity to RotarixTM
was assessed by measuring serum anti-RV IgA antibodies, considered a standard
measure of immunity in most field studies and vaccine trials, at pre- and
post-vaccination time points. Definitions of seropositivity and seroconversion were
uniform across studies. Seropositivity was defined as an anti-RV IgA
concentration ≥ 20 U/mL. Seroconversion was defined as an anti-RV IgA
concentration ≥ 20 U/mL in a subject seronegative for RV pre-Dose 1. Stool
samples were also collected to evaluate vaccine take, defined as anti-RV IgA
seropositivity in any post-vaccination blood sample or detection of RV antigen
in any post-vaccination stool sample in a RV-uninfected subject
pre-vaccination. Anti-RV IgA seroconversion rates and geometric mean concentrations (GMCs)
were measured in all or a pre-defined subset of subjects from all BLA studies,
while vaccine take was estimated in 7 studies, including Rota-033. In each
study, the ATP immunogenicity cohort was used for the primary immunogenicity
analyses.
In studies that
evaluated RotarixTM at 106.5
CCID50 to 106.8
CCID50 per dose (total number of RotarixTM subjects at these potencies in the ATP immunogenicity
cohorts = 2642), 2 doses of RotarixTM appeared immunogenic in
infants, as demonstrated by post-Dose 2 anti-RV IgA seroconversion rates, GMCs,
and vaccine take rates. At 1-2 months post-Dose 2, the anti-RV IgA
seroconversion rate was 86.5% (95% CI: 83.9, 88.8%) in Rota-036 compared to 76.8%
(95% CI: 72.4, 80.9%) in Rota-023. Similarly, 1-2 month post-Dose 2 GMC was
higher in Rota-036 (197.2 U/mL; 95% CI: 175.2, 222.0 U/mL) than in Rota-023
(102.6 U/mL; 95% CI: 86.3, 122.0 U/mL). These results suggest that geographical
and/or ethnic factors may impact the anti-RV IgA immune response to RotarixTM.
Safety
Intussusception (IS)
In Rota-023, the primary safety objective was to determine the safety of RotarixTM with respect to IS occurring within 31 days (Days 0-30) after each dose. The safety database consisted of the Total Vaccinated Cohort (RotarixTM: 31,673, placebo: 31,552) that was followed from Dose 1 to 1-2 months post-Dose 2. Definite IS was defined as a diagnosis of IS confirmed by intestinal invagination at surgery or autopsy, or by radiologic techniques (gas/liquid contrast enema or abdominal ultrasound). The primary safety objective was achieved if the following two criteria were met: upper limit of the 95% confidence interval (CI) of the risk difference (RotarixTM minus placebo) for definite IS was <6/10,000 and lower limit of the 95% CI of the risk difference was < 0. An increased risk of definite IS following RotarixTM vaccination was not observed within 31 days after any dose when the date of IS diagnosis was used to categorize cases (risk difference/10,000 = -0.32; 95% CI: -2.91, 2.18/10,000). An increased risk within 31 days was also not demonstrated in an FDA analysis that used the date of IS onset to categorize cases (risk difference = -8.48/107; 95% CI: -2.63, 2.61/10,000). Increased risk was not observed after Dose 1 or Dose 2. Temporal clustering after either dose was also not observed.
When pooled safety data from 8 BLA studies of subjects who received RotarixTM at the proposed licensure potency (≥ 106.0 CCID50 per dose; n = 36,755) were analyzed (Core Integrated Safety Summary [ISS] analysis), a statistically significant increased risk of IS within 31 days after RotarixTM was not observed (RotarixTM: 9 [0.024%], placebo: 7 [0.020%]; RR=1.23, 95% CI: 0.41, 3.90). Pooled safety data from 5 BLA studies of subjects who received RotarixTM at the less-than licensure potency (< 106.0 CCID50 per dose; n = 3076) (Supplementary ISS analysis) also did not demonstrate a significantly increased risk of IS within 31 days after RotarixTM (RotarixTM: 1 [0.033%], placebo: 0 [0%]; LL 95% CI: 0.01).
Serious adverse events - deaths
A total of 118 deaths (0.158% of all study subjects) were reported throughout the course of the studies. Overall death rates were 0.184% (68/36,755) in the RotarixTM (≥ 106.0 CCID50 potency) group, 0.163% (5/3076) in the RotarixTM (< 106.0 CCID50 potency) group, and 0.158% (55/34,739) in the placebo group. In the Core and Supplementary ISS analyses for deaths, there were no significant imbalances between treatment groups in the rates of fatalities during the 31 days post-vaccination or entire study follow-up periods. For either follow-up period, there were no significant imbalances in fatalities between groups for any Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term (PT).
In Rota-023, an FDA
analysis revealed statistically significant difference between treatment groups
in the rate of subjects with pneumonia-related deaths between Dose 1 and Visit
3 (1-2 months post-Dose 2 or 2-4 months post-Dose 1) (RotarixTM: 0.051%,
placebo: 0.019%; p = 0.0354). The applicant provided a p-value of 0.054. Pneumonia-related
death rates within 31 days post-vaccination were still higher in RotarixTM
compared to placebo recipients (0.022% [7/31,673] vs. 0.010% [3/31,552]). However,
there were no differences between the treatment groups in rates of non-fatal
pneumonia events and pneumonia hospitalizations (Dose 1 to Visit 3, within 31
days and beyond 31 days post-vaccination).
Non-fatal serious adverse events
In the Core and Supplementary ISS analyses for severe adverse events
(SAEs), there were no significant imbalances between treatment groups in the rates
of subjects with at least 1 SAE during the 31 days post-vaccination or during the
entire study follow-up period. In the Core ISS analysis, PTs Diarrhea, Gastroenteritis, Dehydration,
and Ileus were reported significantly
less during the entire study follow-up periods in the RotarixTM
group than in the placebo group. There were no significant imbalances for any
other specific PT except Foreign body
trauma (RotarixTM: 11/36,755 [0.035%], placebo: 1/34,739 [0.003%]; RR = 9.11, 95% CI:
1.31, 394.8). However, all cases involved swallowing a foreign body between 48-483
days post-dose, and were assessed by the applicant as not related to
vaccination.
Convulsions – Rota-023
In Rota-023, a
statistically significant difference between treatment groups was observed in
the rate of PT Convulsions between
Dose 1 and Visit 3 (RotarixTM: 16/31,673 [0.051%], placebo: 6/31,552
[0.019%]; p = 0.034). However, when convulsion-related PTs (Convulsions, Epilepsy, Grand mal convulsion,
Status epilepticus, and Tonic
convulsion) were pooled in a
post-hoc analysis, a statistically significant difference between groups was
not demonstrated (RotarixTM: 20/31,673 [0.063%], placebo: 12/31,552
[0.038%]; p = 0.219). Furthermore, convulsion-related episodes within 31 days
after any dose occurred less in RotarixTM recipients than placebo
recipients. Among subjects who experienced a convulsion-related event within 31
days after any dose, 7 (0.022%) were RotarixTM and 9 (0.029%) were
placebo recipients. Within 43 days post-vaccination, 12 (0.04%) RotarixTM
and 9 (0.03%) placebo recipients reported a convulsion-related event.
Imbalances between groups in convulsion-related PTs within 31 or 43 days
post-vaccination were not observed in Rota-036.
Pneumonia – Rota-036
In Rota-036, rates
of PT Pneumonia were significantly higher
in the RotarixTM compared to the placebo group from Dose 1 to Visit
7 (end of the second RV epidemic season) (24 vs. 4, p = 0.029). Of the 28
cases, only one (RotarixTM group) was reported within 31 days after
vaccination. CBER’s analysis showed that 3 cases in the RotarixTM
group compared to 0 in the placebo group reported PT Pneumonia within 43 days after vaccination. Furthermore, when the
CBER reviewer combined the pneumonia-related PTs (Pneumonia, Bronchopneumonia, Lobar pneumonia, Pneumonia viral), an
imbalance was still seen from Dose 1 to Visit 7 (RotarixTM: 31,
placebo: 7), within 31 days post-vaccination (RotarixTM: 2, placebo:
0) and within 43 days post-vaccination (RotarixTM: 5, placebo: 0).
Imbalances between groups in pneumonia-related PTs within 31 or 43 days
post-vaccination were not observed in Rota-023.
Unsolicited adverse events
(non-SAEs)
In the Core and
Supplementary ISS analyses for unsolicited AEs 31 days post-vaccination, there
were no significant imbalances between groups in the rates of subjects with at
least 1 AE of any intensity or Grade 3 intensity after any dose. In the Core
ISS analysis, there were small but statistically significant increases in
RotarixTM compared to placebo recipients in rates of PTs Irritability (11.4% vs. 8.7%) and Flatulence (2.2% vs. 1.3%). However, no
significant imbalances in Grade 3 Irritability
and Flatulence were observed. In the Supplementary ISS analysis, there was
a statistically significant increase in rates of PT Bronchitis in RotarixTM compared to placebo recipients
(1.85% vs. 0.74%, RR=2.39, 95% CI: 1.27, 4.90%). Grade 3 Bronchitis occurred in 6 RotarixTM compared to 0 placebo
recipients. The applicant stated that this imbalance was driven by an imbalance
of Bronchitis in Rota-006. FDA
calculated a total of 44 (3.9%) RotarixTM recipients (< 106.0 CCID50
groups) compared to 10 (1.8%) placebo recipients in Rota-006 who
reported PT Bronchitis during Days 0
to 30 post-vaccination. Grade 3 Bronchitis occurred in 1 RotarixTM
compared to 0 placebo recipients. In Rota-006, the rate of any Bronchitis in the RotarixTM
group receiving the licensure potency was higher than in the placebo
group during this same interval (3.7% vs. 1.8%); no Grade 3 Bronchitis was reported in this RotarixTM
group. In the Core ISS analysis, when PTs Bronchitis
and Bronchitis acute were combined,
116 (2.3%) RotarixTM recipients compared to 45 (1.6%) placebo
subjects reported an AE. Grade 3 AE rates were comparable (RotarixTM:
0.16%, placebo: 0.14%).
Solicited adverse events
In the Core and Supplementary ISS analyses for solicited symptoms 8 days
(Days 0-7) post-vaccination, there were no significant imbalances in rates of
fever, irritability, loss of appetite, vomiting, or diarrhea, of any severity
or Grade 3 severity, between the RotarixTM and placebo groups after
any dose. The exception was Grade 3 cough/runny nose after any dose in the Core
ISS analysis (RotarixTM: 3.6%, placebo: 3.2%, RR=1.41, 95% CI: 1.01,
1.99). However, imbalances in rates of cough/runny nose after each dose were
not observed.
Shedding and Transmission
Post-vaccination RV antigen shedding in stools was evaluated in all or a
subset of subjects from 7 BLA studies. In all studies (total number of RotarixTM subjects in the ATP immunogenicity cohorts = 1086), samples were
collected on Day 7 after each dose, while in 4 studies, samples were also
collected on Day 15 post-dose. In addition, 4 studies collected samples at 30
days post-Dose 1 (pre-Dose 2), while 4 studies collected samples at 60 days
post-Dose 1 (pre-Dose 2).
Among RotarixTM treatment groups from studies that administered vaccine
at 106.5 CCID50 to
106.8 CCID50 per
dose, post-Dose 1 RV antigen shedding ranged from 50.0% to 80.0% of subjects at Day 7, 19.2% to 64.1% at Day 15,
0% to 24.3% at Day 30, and 0% to 2.6% at Day 60. The highest rates of post-Dose
1 shedding at Days 7, 15, and 30 occurred in subjects from Rota-007, a Phase II
study conducted in
In 2 BLA studies that administered RotarixTM at 106.5
CCID50 per dose, an estimated 25.6% to 26.5% of subjects shed live
RV at Day 7 post-Dose 1. In addition, data from 4 other studies combined
demonstrated that among RV antigen-positive samples, live RV was detected in fewer
samples from RotarixTM
vaccinated subjects than samples from wild-type RV GE episodes (14.6% vs.
68.6%)
Transmission of RotarixTM was not formally evaluated in any of the BLA
studies.
Co-Administration
with Other Childhood Vaccines
Concomitant administration of other routine childhood
vaccines with RotarixTM or
placebo was allowed in 10 of the 12 BLA studies. Only one study (Rota-014,
Phase II,
Only Rota-060 was specifically designed to
evaluate non-inferiority of immune responses to diphtheria, tetanus, pertussis, hepatitis B, poliovirus, Haemophilus
influenza type b
(Hib), or S. pneumoniae antigens when
these routine vaccines were co-administered with RotarixTM. All
study subjects received 3 doses each of Pediarix®
(DTaP-HepB-IPV), Prevnar® (pneumococcal 7-valent conjugate vaccine), and
ActHIB®. In the co-administration group,
RotarixTM was
administered with the first two routine vaccine doses, while in the separate
administration group, RotarixTM was administered one month after routine vaccine Doses 1 and 2. Antibody
responses to diphtheria, tetanus, pertussis (PRN, FHA, PT), hepatitis B (HBs),
poliovirus (types 1, 2, 3), Hib (PRP), and S. pneumoniae (serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) antigens
were measured one month after Dose 3 of routine vaccinations. Non-inferiority criteria were based on
comparisons of seroprotection rates (diphtheria, tetanus, hep B, Hib, polio)
and GMCs (pertussis, S. pneumoniae) between treatment groups. Non-inferiority
criteria were met for all antigens, indicating that co-administration of
RotarixTM with routine childhood vaccines did not impair the immune
responses to any of these vaccine antigens.
Conclusion
RotarixTM at a potency of 106.5 CCID50 per dose was effective in
preventing RV GE of any grade of severity and in preventing severe RV GE caused
by naturally-occurring RV strains during the first year of life across
heterogeneous geographical populations. Protection against any and severe RV GE
was also demonstrated against circulating G1 and certain non-G1 types that are
similar in distribution in the U.S. Co-administration of RotarixTM
with other routine vaccines in the
2.0
INTRODUCTION
AND BACKGROUND
Rotaviruses are classified according to two protein types: glycoprotein
(G) types and protease-cleaved protein (P) types. Ten G types and 11 P types
have been isolated from humans. These human RVs can further be classified into
two major genetically distinct groups: the group which includes G1, G3, G4, and
G9 strains, and the group which is comprised mainly of G2 strains.
Rotaviruses cause an abrupt onset of fever, abdominal distress, loose and
watery diarrhea and vomiting. Symptoms
usually last 3 to 9 days, and can lead to severe dehydration. Untreated severe
RV GE in infants can be rapidly fatal. Viral shedding can be measured by
enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase-polymerase
chain reaction (RT-PCR), and has been detected for as long as 57 days after
disease onset in immunocompetent hosts.1, 2
2.1
EPIDEMIOLOGY
OF ROTAVIRUS INFECTIONS
Rotavirus (RV) infection is the leading cause of severe acute
gastroenteritis (GE) in infants and young children worldwide. In the
RV disease occurs from winter to spring in temperate climates, and
year-round in tropical and subtropical areas.5, 6, 7 In the U.S.,
disease occurs from November to March.8, 9, 10 In North America and
Europe, most RV infections occur in the first and second years of life, while
severe GE occurs mainly in 3 to 35 month-old children.3, 11, 12 Subsequent
infections usually result in much milder disease. 11
Worldwide, 88.5% of childhood RV diarrhea is caused by G types 1 to 4
associated with P types P[8] and P[4].13, 14, 15 In the 1990’s, G9
type appeared to emerge as the fifth most common type, with mostly G9P[8]
strains circulating in the US and Europe.16, 17, 18, 19 In North
America, Europe and Australia, G1P[8], G2P[4], G3P[8], and G4P[8] represent
over 90% of RV infections.15 In the U.S., the yearly prevalence of
G1, G2, G3, and G4 types have been 70%, 6-15%, 1-8%, and 0-2%, respectively.15,
16, 18, 20 These figures are similar to those of other developed
countries.15 Other uncommon types such as G1P[4] and G2P[8] also
circulate in these countries.15, 17, 19, 21
2.2
REGULATORY
BACKGROUND
The first U.S. licensed RV vaccine was RotaShield®, a tetravalent (G1-4)
rhesus-human reassortant vaccine given in a 3-dose schedule.22 However,
this vaccine was withdrawn from the U.S. market within a year of its
introduction due to the development of an unexpected association with IS.23
The period of highest risk of IS after RotaShield® was determined to be the
first 14 days after the first dose.24 The excess risk of IS from RotaShield®
vaccination that led to withdrawal of the product was 4 cases per 10,000
subjects. However, the consensus estimate of excess risk published in 2001 was lower
at 1 case per 10,000 subjects.
In February 2006, RotaTeq®, a live oral pentavalent recombinant
human-bovine RV vaccine given in a 3-dose schedule, was licensed for routine
use in
RotarixTM
has been investigated under a U.S. Investigational New Drug (IND) application
to CBER beginning in July 2000. Since then, several non-IND studies were
conducted outside of the
The applicant
stated that it took an innovative approach by licensing RotarixTM first
in regions of the world where the medical need was the greatest. RotarixTM
was therefore initially licensed in
2.3
BASIS FOR
LICENSURE
The applicant states that a total of 21 clinical studies evaluating RotarixTM, all randomized, placebo-controlled, and double-blind
in design, have been completed, 18 of which are Phase II and III studies
in the target infant population. Based on an agreement between the applicant
and CBER during a pre-BLA meeting in July 2006, 10 of the completed Phase II
and III studies in the target infant population were submitted in the BLA to
seek licensure for RotarixTM
in the
An additional Phase III study
(Rota-060), conducted in the U.S. and specifically designed to evaluate non-inferiority of
immune responses to routine childhood vaccinations (DTaP, hepatitis B, IPV, Haemophilus influenza type b (Hib), S.
pneumoniae) when co-administered
with RotarixTM, was also submitted to the BLA after a pre-BLA
meeting agreement between the applicant
and CBER. Immunogenicity and extended follow-up safety data were submitted
within 60 days and 5 months, respectively, after the initial BLA submission
RotarixTM
was administered orally as 2-dose series at least 4 weeks apart in infants from
6 weeks of age (5 weeks of age in Rota-014). The applicant chose
a 2-dose regimen for the based on a high proportion of seroconversion and
vaccine take observed after two doses, marginal increase in seropositivity
rates and GMCs after a third dose, and demonstration of VE with two doses.
Vaccine potencies
of 105.3 CCID50,
105.6 CCID50, 106.5 CCID50, 106.6
CCID50, and 106.8 CCID50 were evaluated in the BLA
studies. These studies showed that there was little or no increase in
immunogenicity with a RotarixTM titer of 105.6 CCID50 and above. Based on these
clinical results along with stability testing data, the applicant selected a
potency of at least 106.0 CCID50
at the end of shelf-life for commercial use.
3.0
CLINICAL
OVERVIEW
A total of 6 Phase II and 5 Phase III studies in the target
infant population were submitted in the BLA to seek licensure for RotarixTM in the U.S. Full study
reports and datasets for each study were submitted for FDA review. Table 1 below provides an overview of demographic
and other general characteristics by study.
A total of 75,353 infants received at least one dose of RotarixTM or placebo in the 11
BLA studies. Of these infants, 40,614 infants received at least one dose
of RotarixTM and 34,739
infants received at least one dose of placebo. A total of 78,980 doses of RotarixTM
and 67,349 doses of placebo were
administered.
Among the RotarixTM recipients, 37,214 subjects received vaccine at the potency (≥ 106.0 CCID50 per dose), formulation (lyophilized, buffered), and storage temperature (