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 Finland receiving either RotarixTM or placebo. Rota-033 was a Phase III lot-to-lot consistency study of 3 lots conducted in three Latin American countries. Rota-060, a Phase III trial evaluating the immunogenicity of routine childhood vaccines when co-administered with RotarixTM, was conducted in the U.S. 

 

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).

 

Pneumonia deaths – Rota-023

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 Singapore. The applicant stated that these results may be due to a population effect or older age at Dose 1 (median = 13 weeks) when maternal antibodies known to have an impact on RV immune response have already declined. Among the same RotarixTM treatment groups, post-Dose 2 shedding ranged from 4.2% to 18.4% at Day 7, 0% to 16.2% at Day 15, and 0% to 1.2% at Day 30. Shedding at Day 45 post-Dose 2, monitored only in Rota-033, was 0%.  Highest post-Dose 2 shedding rates at Days 7 and 15 were also in subjects from Rota-007.

 

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, South Africa; n = 447) allowed concomitant administration of oral poliovirus vaccine.

 

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 U.S. did not cause interference of the immune response to each of these vaccine antigens. RotarixTM had no increased risk of intussusception. However, increases in pneumonia-related deaths and convulsion-related SAEs were observed in RotarixTM compared to placebo recipients from Dose 1 to Visit 3 in Rota-023, although the difference in pneumonia-related deaths occurring within 31 days post-vaccination was smaller. Rates of bronchitis within 31 days post-vaccination were also generally higher in RotarixTM recipients, most notably in Rota-006.

 

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 U.S., RV infection caused 2.7 million GE episodes, over 400,000 outpatient visits, and up to 70,000 hospitalizations annually between 1993 and 2002 children in children under 5 years of age.3, Mortality data from 1968 to 1991 also indicate that RV caused 60 deaths per year in the U.S. in this same age group.4

 

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 U.S. children. RotaTeq® is indicated for the prevention of RV GE in infants and children caused by the G1, G2, G3 and G4 serotypes contained in the vaccine. The first dose is administered at 6-12 weeks of age, with subsequent doses administered at 4-10 week intervals. The third dose should not be given after 32 weeks of age.

 

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 U.S., including those considered pivotal for efficacy and safety claims, and have been submitted in the BLA.

 

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 Mexico in July 2004. It has subsequently been licensed in 99 other countries in Africa, Australia, Europe, Latin America, the Middle East, and Southeast Asia.

 

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 U.S. Four of the 10 studies (Rota-004, Rota-006, Rota-023, Rota-036) evaluated protective efficacy, with two (Rota-023, Rota-036) considered pivotal to and two (Rota-004, Rota-006) considered supportive of efficacy claims in the BLA. Immunogenicity and safety were also evaluated in all 10 studies, with Rota-023 designed specifically to evaluate the risk of IS following RotarixTM administration compared to placebo.

 

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 (