FDA Briefing Document

 

Vaccines & Related Biological Products Advisory Committee Meeting

 

February 20, 2008

 

 

 

 

 

 

 

 

 

Rotarix^TM (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:             Rotarix^TM

 

Product composition (from the Applicant’s proposed label):

 

Rotarix^TM 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 10^6.0 median Cell Culture Infective Dose (CCID₅₀) of live, attenuated HRV. Rotarix^TM, 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. Rotarix^TM contains no preservatives.

 

 

Manufacturer:                         GlaxoSmithKline Biologicals

 

Proposed indication:               Prevention of rotavirus gastroenteritis caused by G1 and non-G1 types

 

Rotarix^TM 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)

                                                ≥ 10^6.0 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 Rotarix^TM, a live, oral, monovalent rotavirus (RV) vaccine indicated for the prevention of RV gastroenteritis (GE) caused by G1 and non-G1 types.  Rotarix^TM 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 ≥ 10^6.2 median Cell Culture Infective Dose (CCID₅₀) per dose of live, attenuated human RV, with an end-of-shelf-life potency of

≥ 10^6.0 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 Rotarix^TM 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 Rotarix^TM, 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 (Rotarix^TM: 9009, placebo: 8558) in Rota-023 and 3874 subjects (Rotarix^TM: 2572, placebo: 1302) in Rota-036. VE for each endpoint was calculated using the following formula: 1 – (attack rate in the Rotarix^TM 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 Rotarix^TM, at 10^6.5 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 Rotarix^TM 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 Rotarix^TM at 10^6.5 CCID₅₀ to 10^6.8 CCID₅₀ per dose (total number of Rotarix^TM subjects at these potencies in the ATP immunogenicity cohorts = 2642), 2 doses of Rotarix^TM 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 Rotarix^TM.

 

Safety

 

Intussusception (IS)

In Rota-023, the primary safety objective was to determine the safety of Rotarix^TM with respect to IS occurring within 31 days (Days 0-30) after each dose. The safety database consisted of the Total Vaccinated Cohort (Rotarix^TM: 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 (Rotarix^TM 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 Rotarix^TM 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 Rotarix^TM at the proposed licensure potency (≥ 10^6.0 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 Rotarix^TM was not observed (Rotarix^TM: 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 Rotarix^TM at the less-than licensure potency (< 10^6.0 CCID₅₀ per dose; n = 3076) (Supplementary ISS analysis) also did not demonstrate a significantly increased risk of IS within 31 days after Rotarix^TM (Rotarix^TM: 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 Rotarix^TM (≥ 10^6.0 CCID₅₀ potency) group, 0.163% (5/3076) in the Rotarix^TM (< 10^6.0 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) (Rotarix^TM: 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 Rotarix^TM 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 Rotarix^TM group than in the placebo group. There were no significant imbalances for any other specific PT except Foreign body trauma (Rotarix^TM: 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 (Rotarix^TM: 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 (Rotarix^TM: 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 Rotarix^TM recipients than placebo recipients. Among subjects who experienced a convulsion-related event within 31 days after any dose, 7 (0.022%) were Rotarix^TM and 9 (0.029%) were placebo recipients. Within 43 days post-vaccination, 12 (0.04%) Rotarix^TM 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 Rotarix^TM 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 (Rotarix^TM group) was reported within 31 days after vaccination. CBER’s analysis showed that 3 cases in the Rotarix^TM 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 (Rotarix^TM: 31, placebo: 7), within 31 days post-vaccination (Rotarix^TM: 2, placebo: 0) and within 43 days post-vaccination (Rotarix^TM: 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 Rotarix^TM 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 Rotarix^TM compared to placebo recipients (1.85% vs. 0.74%, RR=2.39, 95% CI: 1.27, 4.90%). Grade 3 Bronchitis occurred in 6 Rotarix^TM 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%) Rotarix^TM recipients (< 10^6.0 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 Rotarix^TM compared to 0 placebo recipients. In Rota-006, the rate of any Bronchitis in the Rotarix^TM 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 Rotarix^TM group. In the Core ISS analysis, when PTs Bronchitis and Bronchitis acute were combined, 116 (2.3%) Rotarix^TM recipients compared to 45 (1.6%) placebo subjects reported an AE. Grade 3 AE rates were comparable (Rotarix^TM: 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 Rotarix^TM and placebo groups after any dose. The exception was Grade 3 cough/runny nose after any dose in the Core ISS analysis (Rotarix^TM: 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 Rotarix^TM 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 Rotarix^TM treatment groups from studies that administered vaccine at 10^6.5 CCID₅₀ to 10^6.8 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 Rotarix^TM 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 Rotarix^TM at 10^6.5 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 Rotarix^TM vaccinated subjects than samples from wild-type RV GE episodes (14.6% vs. 68.6%)

 

Transmission of Rotarix^TM was not formally evaluated in any of the BLA studies.

 

Co-Administration with Other Childhood Vaccines

 

Concomitant administration of other routine childhood vaccines with Rotarix^TM 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 Rotarix^TM. 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, Rotarix^TM was administered with the first two routine vaccine doses, while in the separate administration group, Rotarix^TM 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 Rotarix^TM with routine childhood vaccines did not impair the immune responses to any of these vaccine antigens.

 

Conclusion

Rotarix^TM at a potency of 10^6.5 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 Rotarix^TM with other routine vaccines in the U.S. did not cause interference of the immune response to each of these vaccine antigens. Rotarix^TM had no increased risk of intussusception. However, increases in pneumonia-related deaths and convulsion-related SAEs were observed in Rotarix^TM 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 Rotarix^TM 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.

 

Rotarix^TM 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 Rotarix^TM first in regions of the world where the medical need was the greatest. Rotarix^TM 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 Rotarix^TM, 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 Rotarix^TM 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 Rotarix^TM 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 Rotarix^TM, 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

 

Rotarix^TM 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 10^5.3 CCID₅₀, 10^5.6 CCID₅₀, 10^6.5 CCID₅₀, 10^6.6 CCID₅₀, and 10^6.8 CCID₅₀   were evaluated in the BLA studies. These studies showed that there was little or no increase in immunogenicity with a Rotarix^TM titer of 10^5.6 CCID₅₀ and above. Based on these clinical results along with stability testing data, the applicant selected a potency of at least 10^6.0 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 Rotarix^TM 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 Rotarix^TM or placebo in the 11 BLA studies. Of these infants, 40,614 infants received at least one dose of Rotarix^TM and 34,739 infants received at least one dose of placebo. A total of 78,980 doses of Rotarix^TM and 67,349 doses of placebo were administered.

 

Among the Rotarix^TM recipients, 37,214 subjects received vaccine at the potency (≥ 10^6.0 CCID₅₀ per dose), formulation (lyophilized, buffered), and storage temperature (2° to 8°C) intended for commercial use in the U.S. A total 72,242 doses were administered.

 

Among the Rotarix^TM recipients, 3076 subjects received vaccine at a potency less than 10^6.0 CCID₅₀ per dose. A total 6098 doses were administered.

 

Table 2 below provides an overview of numbers of subjects in the Total Vaccinated Cohort (i.e. who received at least one dose of Rotarix^TM or placebo) and total number of doses administered by treatment group in each study.

 

Across the studies, 90.5-99.1% of Rotarix^TM recipients and 90.3-100% of placebo recipients received two study doses.

Table 1: Overview of study characteristics of BLA studies

 

Study # (Phase)

Countries

# sites

Start date End date

# planned/ # enrolled

# given  RotarixTM /placebo

Dose potency (CCID50)

Age  at 1st dose/ mean (weeks)

Vaccine interval  (months)

Male: Female ratio

Ethnicity

Co-admin of infant vaccines

Feeding restrictions

Rota-004 (II)

Finland

6

8/21/00 6/26/02

405/ 405

270/135

105.3

6-12/ 8.3

2

214: 191

99% White

No

1 hour  pre-dose

Rota-005 (II)

U.S., Canada

41

12/13/00 8/02/02

500/ 529

421/108

105.6 106.8

6-12/ 8.7

2

260: 269

75% White

Yes

None

Rota-006 (II)

Brazil, Mexico, Venezuela

3

5/25/01 11/08/03

2276/ 2276

1709/567

105.3 105.6 106.6

6-12/ 8.3

2

1197: 1079

73% Mixed; 24% White

Yes, except OPV

None

Rota-007 (II)

Singapore

8

1/04/01 4/15/03

2640/ 2464

1811/653

105.3 105.6 106.6

11-17/ 13.3

1

1226: 1238

93% Oriental

Yes

None

Rota-014 (II)

South Africa

6

11/22/01 10/25/03

450/ 450 (PI - 271; PII- 179)

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

None

Rota-023 (III)

Argentina, Brazil, Chile, Colombia, Dominican Republic, Finland*, Honduras, Mexico, Nicaragua, Panama, Peru**, Venezuela

177*   (136†, 121‡)

8/05/03 10/20/05‡

60,000/ 63,225¶   (20,000/20,170†)   (13,000/15,183‡)

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

None

Rota-033 (III)

Colombia, Mexico, Peru

7

8/08/03 1/29/04

854/ 854

730/124

106.5

6-12/ 8.5

2

439:415

98% Hisp

Yes, except   OPV

None

Rota-036 (III)

Czech Republic, Finland, France, Germany, Italy, Spain

87

9/08/04 8/10/06

3990/ 3994

2646/ 1348

106.5

6-14/ 11.5

1 or 2

2107: 1887

98% White

Yes

None

Rota-039 (III)

Thailand

2

3/27/05 12/30/05

450/ 450

398/52

106.5

6-12/ 8.7

2

235: 215

99% East/ South East Asian

Yes

Yes (controlled)

Rota-048 (II)

Finland

5

8/16/05 11/10/05

250/ 250

200/50

106.5

6-12/ 9.1

1

119: 131

98% White

No

None

Rota-060 (III)

U.S.

44

6/13/2006 2/08/2007

480/ 484

459/0

106.5

6-12/ 8.7

2

256: 228

76% White 13% Black

Yes (for 1 group)

None

 

*Participated in IS Safety study only; **Participated in IS and Year 1 Efficacy studies only; ¶IS Safety study; †Year 1 Efficacy subset; ‡Year 2 Efficacy subset

PI=Part 1; PII=Part II

 (source: Study Reports of Rota-004, Rota-005, Rota-006, Rota-007, Rota-014, Rota-023, Rota-033, Rota-036, Rota-039, Rota-048, Rota-060)

Table 2: Number of Total Vaccinated Cohort (TVC) subjects and doses, BLA studies

 

Study #	Treatment group	# subjects who received at least 1 dose (TVC)	# doses administered
Rota-004	105.3CCID50	270	526
	placebo	135	261
Rota-005	105.6 CCID50	212	415
	106.8 CCID50	209	400
	placebo	108	209
Rota-006 (2-dose Subset)	105.3CCID50	538	1048
	105.6 CCID50	540	1049
	106.6 CCID50	540	1055
	placebo	537	1059
Rota-006 (3-dose Subset)	105.3CCID50	31	93
	105.6 CCID50	30	90
	106.6 CCID50	30	90
	placebo	30	90
Rota-007	105.3CCID50	510	1011
	105.6 CCID50	648	1287
	106.6 CCID50	653	1292
	placebo	653	1295
Rota-014	105.6 CCID50 (Part 1)	91	177
	105.6 CCID50 (Part 1)	90	173
	placebo (Part 1)	90	174
	105.6 CCID50 (Part 2)	57	112
	105.6 CCID50 (Part 2)	59	117
	placebo (Part 2)	60	119
Rota-023	106.5 CCID50	31,673	61,289
	placebo	31,552	61,017
Rota-033	106.5 CCID50 (lot A)	243	463
	106.5 CCID50 (lot B)	241	465
	106.5 CCID50 (lot C)	246	485
	placebo	124	236
Rota-036	106.5 CCID50	2646	5267
	placebo	1348	2686
Rota-039	106.5 CCID50 (buffer)	174	345
	106.5 CCID50 (no buffer)	174	345
	106.5 CCID50 (buffer, stored 7 days at 37°C)	50	98
	placebo (pooled)	52	104
Rota-048	106.5 CCID50 (lyophilized formulation)	100	199
	106.5 CCID50 (liquid formulation)	100	197
	placebo (pooled)	50	99
Rota-060	106.5 CCID50 (co-administered routine vaccines)	249	481
	106.5 CCID50 (separately-administered routine vaccines)	210	411
Total		75,353	146,329

 

(source: Study Reports of Rota-004, Rota-005, Rota-006, Rota-007, Rota-014, Rota-023, Rota-033, Rota-036, Rota-039, Rota-048, Rota-060)

3.1       EFFICACY – PIVOTAL STUDIES

 

Studies Rota-023 and Rota-036 were pivotal Phase III studies that evaluated VE of two doses of Rotarix^TM at 10^6.5 CCID₅₀ per dose. Doses in both studies were administered either 1 or 2 months apart. In Rota-023, 17,867 infants 6-13 weeks of age from 11 Latin American countries were included in the Year 1 According To Protocol (ATP) efficacy cohort (see Table 3). In Rota-036, 3874 infants 6 to 14 weeks of age from 6 European countries were included in the Year 1 ATP efficacy cohort. In both studies, the ATP efficacy cohort was used for the primary efficacy analyses. Criteria for inclusion in the Year 1 ATP efficacy cohort included 1) vaccination with 2 doses of Rotarix^TM or placebo, 2) no RV other than vaccine strain in GE stool samples collected between Dose 1 and 2 week post-Dose 2, and 3) entry into the Year 1 efficacy follow-up period.

 

Table 3: Overview of number of subjects in the ATP efficacy cohort for the Year 1 efficacy follow-up period, BLA pivotal efficacy studies

Study #	Phase	# Total subjects	# RotarixTM 106.5 CCID50	#  Placebo
Rota-023	III	17,867	9009	8558
Rota-036	III	3874	2572	1302

(source: Rota-023 Study Report Year 1, Rota-036 Study Report Year 1)

 

Study endpoints

Primary and selected secondary RV-related efficacy endpoints for the Year 1 efficacy follow-up period in each study are listed in Table 4. In Rota-036, the primary endpoint was the occurrence of any wild-type RV GE during the Year 1 efficacy period (i.e. 1^st efficacy follow-up period). In Rota-023, the primary endpoint was the occurrence of severe wild-type RV GE during the Year 1 efficacy period. Year 1 efficacy period for Rota-023 was defined as the time from 2 weeks post-Dose 2 until 1 year of age. Year 1 efficacy period for Rota-036 was defined as the time from 2 weeks post-Dose 2 until the end of the 1^st RV season. In Rota-036, the RV season covered the beginning of December 2004 to the end of May 2005.

 

Selected secondary Year 1 endpoints for Rota-036 included severe RV GE and any/severe RV GE due to heterologous types (i.e. G1 and non-G1). Selected secondary Year 1 endpoints for Rota-023 included severe wild-type G1 RV GE, and severe non-G1 RV GE, and severe RV GE.

 

Table 4: Overview of primary and selected secondary endpoints for the Year 1 efficacy follow-up period, BLA pivotal efficacy studies

Study #	Primary Efficacy Endpoint	Secondary RV-related Efficacy Endpoints
Rota-023	Severe wild-type RV GE	-    Severe wild-type G1 RV GE -    Severe non-G1 wild-type RV GE, pooled -    Severe non-G1 wild-type RV GE, by individual type -    Severe wild-type RV GE, using Vesikari scale
Rota-036	Any wild-type RV GE	-    Severe wild-type RV GE -    Any & severe wild-type G1 RV GE -    Any & severe non-G1 wild-type RV GE

(source: Rota-023 Study Report Year 1, Rota-036 Study Report Year 1)

VE for each endpoint was calculated using the following formula: 1 – (attack rate in the Rotarix^TM group ÷ attack rate in the placebo group). The attack rate for each group was calculated by dividing the number of subjects who reported at least one endpoint episode (e.g. any wild-type RV GE, severe wild-type RV GE) by the total number of subjects in that group.

 

Case definitions

Definitions for diarrhea (≥ 3 looser than normal stools within a day) and vomiting (≥ 1 episode of forceful emptying of partially digested stomach contents ≥ 1 hour after feeding within a day) were identical in both studies. The definition of GE was diarrhea with or without vomiting. For Rota-036, the primary endpoint definition of wild-type RV GE was an episode of GE in which RV other than vaccine strain is identified in a stool sample collected no later than 7 days after GE symptom onset. In Rota-023, the primary endpoint definition of severe RV GE was an episode of RV GE requiring hospitalization and/or re-hydration therapy (equivalent to WHO plan B or C) in a medical facility. In all studies, including Rota-023 (secondary endpoint), severe RV GE was defined as an episode of RV GE with a Vesikari score ≥ 11 points. The Vesikari 20-point scale, which has been accepted internationally and widely used, measures the following: intensity/frequency and duration of diarrhea and vomiting, degree of fever and dehydration, and type of treatment (see Table 5 below).

 

Table 5: The 20-point Vesikari scale used in the BLA studies

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*
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

*The highest temperature recorded during the episode scored

(source: Rota-036 Study Report Year 1, pg 83)

 

Year 1 RV GE case ascertainment and laboratory diagnosis

In Rota-036, GE case ascertainment was conducted through active weekly follow-up of subjects from 1 week post-Dose 1 until the end of Year 1 (i.e. end of the 1^st RV season). In Rota-23, GE ascertainment was conducted by contacting hospitals and other medical facilities in the study area at least twice a week. Subjects were also contacted or visited at least every 4 days by non-medical study personnel to identify severe cases not identified by medical facility surveillance, such as cases treated in facilities outside the surveillance system.

 

Individual GE diary cards were used in each study to collect daily temperature, stool and emesis data for each GE episode. Parents were also instructed in the collection, labeling, storage, and submission of stool samples for each GE episode. All collected stools were laboratory tested for the presence of RV antigen by ELISA. Stools that tested positive by ELISA were further analyzed for G and P type determination by RT-PCR followed by Reverse hybridization Assay or optional sequencing.

 

Entry criteria

Study subjects were required to be free of obvious health problems as established by pre-enrollment medical history and clinical examination. Both studies included healthy infants of relatively similar age ranges at Dose 1 (Rota-023: 6 to 12/13 weeks; Rota-036: 6 to 14 weeks). In addition, subjects with a birth weight of greater than 2000 grams were included in Rota-036. Both studies excluded infants with histories of gastrointestinal disorders or other serious medical conditions and infants who were immunosuppressed or immunodeficient.

 

Efficacy results – Rota-036 (Applicant analysis)

Results of Year 1 efficacy for pivotal study Rota-036 in the ATP efficacy cohort are summarized in Table 6. The mean (and median) duration of follow-up per treatment group during Year 1 was approximately 6 months. Vaccine efficacy (VE) during Year 1 was 87.1% (95% CI: 79.6%, 92.1%) against any RV GE and 95.8% (95% CI: 89.6%, 98.7%) against severe RV GE.

 

Table 6: Vaccine efficacy results, Rota-036, ATP efficacy cohort, Year 1

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

N= total number of subjects in ATP efficacy cohort, Year 1

n= number of subjects reporting at least one RV GE or severe RV GE caused by circulating wild-type RV

(Source: Study Report Rota-036 Year 1, pg 123)

 

VE against any RV GE and severe RV GE by main G RV serotypes during Year 1 are summarized in Table 7 and Table 8, respectively. All G1, G3, G4, and G9 types were associated with P[8] type. Among the G2 cases, the P type of one case (placebo subject) could not be characterized, while the rest were associated with P[4] type.

 

 

 

 

 

 

Table 7: Vaccine efficacy results, any RV GE, Rota-036, by RV types, 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)

(Source: Study Report Rota-036 Year 1, pg 125)

 

Table 8: Vaccine efficacy results, severe RV GE, Rota-036, by RV types, 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)

(Source: Study Report Rota-036 Year 1, pg 126)

 

During Year 1, VE did not reach statistical significance against any RV GE or severe RV GE caused by G2 type. During Year 2, VE against severe RV GE caused by G2 was 89.9% (95% CI: 9.4, 99.8%). During the combined (Year 1 and Year 2) period, VE was 58.3% (95% CI: 10.1, 81.0%) against any G2 RV GE and 85.5% (95% CI: 24.0, 98.5%) against severe G2 RV GE.

 

When the Total Vaccinated Cohort was used to estimate Year 1 VE from Dose 1, VE against any RV GE was 87.3% (95% CI: 80.3, 92.0%). VE also reached statistical significance against any RV GE caused by wild-type G1 (95.8%; 95% CI: 88.4, 98.9%), G3 (85.4%; 95% CI: 23.6, 98.5%), G4 (89.1%; 95% CI: 60.9, 98.0%), G9 (77.7%; 95% CI: 57.7, 89.0%), and pooled non-G1 (G2, G3, G4, G9) types (80.3%; 95% CI: 67.3, 88.6%).  VE against severe RV GE was 96.0% (95% CI: 90.2, 98.8%). VE reached statistical significance against severe RV GE caused by wild-type G1 (96.5%; 95% CI: 86.1, 99.6%), G3 (100%; 95% CI: 56.7, 100%), G4 (100%; 95% CI: 64.7, 100%), G9 (95.1%; 95% CI: 80.2, 99.4%), and pooled non-G1 (G2, G3, G4, G9) types (95.8%; 95% CI: 86.6, 99.2%). 

 

Efficacy results – Rota-023 (Applicant analysis)

Results of Year 1 efficacy for pivotal study Rota-023 in the ATP efficacy cohort are summarized in Table 9. The mean (and median) duration of follow-up per treatment group during Year 1 was approximately 8 months. VE against severe RV GE during Year 1 was 84.7% (95% CI: 71.7, 92.4%). When using the same case definition for severe RV GE as in Rota-036 (Vesikari score ≥ 11 points), VE was 84.8% (95% CI: 71.1, 92.7%)

 

Table 9: Vaccine efficacy results, Rota-023, ATP efficacy cohort, Year 1

Clinical endpoint	Number of cases (n)		Vaccine efficacy (%)	95% CI
	RotarixTM (N=9009)	Placebo (N=8858)
Severe RV GE	12	77	84.7	71.7, 92.4

N= total number of subjects in ATP efficacy cohort, Year 1

n= number of subjects reporting at least one severe RV GE caused by circulating wild-type RV

(Source: Study Report Rota-023 Year 1, pg 88)

 

VE against severe RV GE by main RV serotypes during Year 1 are summarized in Table 10. All G1, G3, G4, and G9 types were associated with P[8] type, while all G2 types were associated with P[4] type. VE did not reach statistical significance against severe G2 RV GE. VE against G4 type was not evaluated due to limited numbers of subjects in each group. In addition to the RV types noted in Table 10, one severe RV GE episode (placebo subject) was typed as P[6] but unknown G type, while another severe RV GE episode (placebo subject) could not be further characterized by RT-PCR due to insufficient sample quantity.

 

Table 10: Vaccine efficacy results, Rota-023, by RV types, 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)

(Source: Study Report Rota-023 Year 1, pg 90)

 

When the Total Vaccinated Cohort was used to estimate Year 1 VE from Dose 1, VE against severe RV GE was 81.1% (95% CI: 68.5, 89.3%). VE also reached statistical significance against severe RV GE caused by wild-types G1 (86.6%; 95% CI: 68.4, 95.3%), G3 (73.7%; 95% CI: 17.5, 93.7%), G9 (91.0%; 95% CI: 63.6, 99.0%), and pooled non-G1 (G2, G3, G4, G9) types (73.9%; 95% CI: 51.1, 87.0%).

 

 

 

 

 

 

 

 

 

 

 

 

 

3.2       IMMUNOGENICITY

 

In all studies, serum anti-RV IgA response, considered a standard measure of immunity in most field studies and vaccine trials, was measured by ELISA at pre- and post-vaccination time points (including 1-2 months post-Dose 2). Seropositivity was defined as an anti-RV IgA antibody concentration ≥ 20 U/mL (assay cut-off value). Seroconversion was defined as an anti-RV IgA antibody concentration ≥ 20 U/mL in a subject who was seronegative for RV pre-Dose 1. Seroconversion rates and GMC values were obtained at each specified time point. In 7 BLA studies (not including Rota-023, Rota-036, or Rota-060), RV immunogenicity was also measured by vaccine take, which was defined as anti-RV IgA seropositivity in any post-vaccination blood sample or detection of RV antigen by ELISA in any post-vaccination stool sample (including GE stool sample) in a previously RV-uninfected subject. Vaccine take was included as an immunogenicity parameter because in some cases, serum IgA antibodies are not detected post-vaccination despite evidence of RV shedding (i.e. viral replication) in stools several days after vaccination. In all studies, the ATP immunogenicity cohort was used for the primary immunogenicity analyses. Criteria for inclusion in the ATP efficacy cohort included 1) testing negative for serum anti-RV IgA antibodies on the day of Dose 1 2) having no RV other than vaccine strain in GE stool samples collected during the vaccination period and 3) complied with blood sampling schedule.

 

Anti-RV IgA seroconversion rates, take rates, and GMCs for the Rotarix^TM group in 5 BLA studies which used the applicant’s serum IgA ELISA are presented in Table 11. The seroconversion rate and GMC 1 to 2 months post-Dose 2 were higher in Rota-036 than in Rota-023. These differences suggest that immunogenicity of Rotarix^TM among subjects may be higher in certain countries in Europe and Asia (including Singapore, results of which are not shown in Table 11) as compared to Latin American countries, consistent with previous observations using other live oral vaccines.²⁵ In Rota-023, countries with seroconversion rates less than 80% were Argentina, Colombia, Dominican Republic, Panama, Peru, and Venezuela. Countries with low GMCs less than 130 U/mL were Brazil, Colombia, Dominican Republic, Honduras, Panama, Peru, and Venezuela.

 

Table 11: Immunogenicity results, post-Dose 2, ATP immunogenicity cohort

Post-Dose 2 Endpoint (with 95% CI)	Rota-023 106.5 CCID50 (Latin America) N = 393	Rota-036 106.5 CCID50 (Europe) N = 787	Rota-039* 106.5 CCID50 (Thailand) N = 157	Rota-048** 106.5 CCID50 (Finland) N = 86	Rota-060 106.5 CCID50 (US)
					Co-Ad group N = 165	Sep-Ad group N = 121
Seroconversion rate - %
1 month				84 (74-91)
1-2 months	77 (72-81)	87 (84-89)
2 months			85 (78-90)			86 (79-92)
3 months					79 (72-85)
Take rate –%
1 month				84 (75, 91)
2 months			88 (82-93)
GMC – U/mL
1 month				361 (236-550)
1-2 months	103 (86-122)	197 (175-222)
2 months			134 (105-173)			188 (140-254)
3 months					110 (86-141)

*Group receiving Rotarix^TM with buffer and not stored at 37°C; **Group receiving Rotarix^TM in lyophilized formulation

(source: Study Reports of Rota-023, Rota-036, Rota-039, Rota-048, Rota-060)

 

3.3       SAFETY

 

Safety of Rotarix^TM was evaluated in all 11 BLA studies. Table 12 summarizes the categories of safety data collected during each study.

 

Adverse Events

Solicited general AEs were collected from all or a subset of subjects in 9 of the 11 studies (solicited AE data not collected for Rota-023 and Rota-060). AEs consisted of diarrhea, fussiness/irritability, loss of appetite, fever, and vomiting. Cough/runny nose was included as an AE except in Rota-004 and Rota-033. In Rota-033 and Rota-036, AE data was collected from Day 0 to Day 7 post-vaccination, while in the remaining studies, data was collected from Day 0 to Day 14. In all studies, AEs were recorded on diary cards by parents/guardians. For each AE, a standard scale was used for all studies to grade AE intensity.

 

Unsolicited non-serious AEs were collected from all subjects in 10 of the 11 studies (data not collected for Rota-023 except for AEs associated with study drop-out). AEs were coded and reported using the Medical Dictionary for Regulatory Activities (MedDRA) in Rota-023, Rota-033, Rota-036, Rota-039, Rota-048, and Rota-060. AEs were initially coded and reported using the WHO dictionary for adverse reaction terminology in the remaining 5 studies, but were re-coded using MedDRA. In Rota-033, Rota-036, Rota-039, and Rota-048, AE data was collected from Days 0 to 30 post-vaccination, while in the other studies, data was collected from Days 0 to 42.  For each AE, the following standard scale was used for all studies to grade AE intensity:

 

Grade 1 =        Easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities

Grade 2 =        Sufficiently discomforting to interfere with normal everyday activities

Grade 3 =        Prevented normal, everyday activities (In a young child, for example, prevented attendance at a day-care center and caused parents/guardians to seek medical advice)

 

SAEs were collected and reported in all studies throughout the study period and coded using the same methods (MedDRA, WHO dictionary) as for unsolicited AEs. Any SAE was reported to GSK within 24 hours using the SAE Report Form. The following definition of an SAE was applied:

 

-          Any untoward medical occurrence that resulted in death, was life-threatening, resulted in persistent or significant disability/incapacity, required in-patient hospitalization or prolongation of existing hospitalization. In addition, important medical events that may have jeopardized the subject or may have required intervention to prevent one of the other outcomes listed above were considered serious.

 

 

 

 

 

 

 

Table 12: Categories of safety data collected, BLA studies

Study #	ISS analysis group	Solicited general AEs	Solicited AE period (days)	Unsolicited AEs	Unsolicited AE period (days)	SAEs	Unsolicited AE & SAE coding	Weight & Height	Concomitant meds
Rota-004	Supplementary	Yes  (except cough/runny nose)	15	Yes	43	Yes	WHO, MedDRA	First visit	Yes
Rota-005	Core & Supplementary	Yes	15	Yes	43	Yes	WHO, MedDRA	Each visit	Yes
Rota-006*	Core & Supplementary	Yes	15	Yes	43	Yes	WHO, MedDRA	Each visit	Yes
Rota-007	Core & Supplementary	Yes	15	Yes	43	Yes	WHO, MedDRA	Each visit	Yes
Rota-014	Supplementary	Yes	15	Yes	43	Yes	WHO, MedDRA	Each visit	Yes
Rota-023	Core	NC	NA	No§	NA	Yes	MedDRA	First visit	NT
Rota-033	Core	Yes  (except cough/runny nose)	8	Yes	31	Yes	MedDRA	First visit	Yes
Rota-036	Core	Yes  (subset) (also type of medical attention)	8	Yes	31 (also: type of medical attention)	Yes	MedDRA	First visit	Yes
Rota-039†	Core	Yes	15	Yes	31	Yes	MedDRA	First visit	Yes
Rota-048‡	Core	Yes	15	Yes	31	Yes	MedDRA	First visit	Yes
Rota-060	Not included	NC	NA	Yes¶	Throughout study	Yes	MedDRA	First visit	Yes

ISS = Integrated Safety Summary; NC=not collected; NA= not applicable

Core ISS analysis: ≥10^6.0CCID₅₀ potency versus placebo; Supplementary ISS analysis:< 10^6.0CCID₅₀ potency versus placebo

*safety data after 3^rd dose in subset of 121 infants not included in ISS

†safety data not included in ISS for the following study groups: Rotarix^TM without buffer, Rotarix^TM stored at 37°C

‡safety data not included in ISS for the following study group: Rotarix^TM in liquid formulation

¶Specific AEs included new onset of chronic illness(es) that were not congenital anomalies and conditions prompting emergency room visits; also AEs leading to drop-out

§Only AEs leading to drop-out

(source: Study Reports of Rota-004, Rota-005, Rota-006, Rota-007, Rota-014, Rota-023, Rota-033, Rota-036, Rota-039, Rota-048, Rota-060)

Intussusception – Rota-023

A primary objective of Rota-023 was to evaluate the safety of Rotarix^TM with respect to the occurrence of intussusception (IS) within 31 days (Days 0 to 30) after each dose.

The Brighton Collaboration Intussusception Working Group case definition was used for definite IS (Table 13). However, in order to capture all IS events, IS cases were reported irrespective of whether they met the Brighton case definition. A Clinical Events Review Committee (CEC), consisting of physicians acting as consultants who were not study investigators or medical care providers to study subjects, performed blinded objective reviews of all IS cases occurring from Dose 1 to Visit 3. A GSK physician rather than the CEC reviewed IS cases diagnosed after Visit 3 up to Visit 4 using the same case definition for definite IS mentioned above.

 

Table 13: Case definition for “Definite IS,” The Brighton Collaboration Intussusception Working Group

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

(Source: Study Report Rota-023 Visit 1-3, pg 51)

 

In the other BLA studies, parents/guardians were made aware of the symptoms of IS (severe colicky abdominal pain, persistent vomiting, bloody stools, abdominal bloating, high fever) and instructed to inform the investigator and seek medical advice at the nearest hospital. Investigators were also aware of a possible increased risk of IS, and took appropriate diagnostic and therapeutic measures. Cases of IS were diagnosed by radiography.

 

Data analyses: Integrated Safety Summary

Integrated safety summary (ISS) analyses based on TVC safety data from 10 of the 11 clinical studies (Rota-060 not included) were conducted. ISS analyses involved the pooling of subjects from the 10 studies into the following two analysis groups to allow for precise estimation of Rotarix^TM safety:

 

-          Core ISS group: pooled subjects who received Rotarix^TM at the proposed licensure potency of ≥ 10^6.0 CCID₅₀ per dose or placebo.

-          Supplementary ISS group: pooled subjects who received Rotarix^TM at < 10^6.0 CCID₅₀ per dose or placebo.

 

 

Core ISS analysis

A total of 36,755 subjects received 71,320 doses of Rotarix^TM at a potency ≥ 10^6.0 CCID₅₀ per dose. Distribution by individual study is summarized in Table 14.

 

Table 14: Numbers of subjects and doses, Core ISS analysis

Study	Core ISS: RotarixTM vaccine (≥ 106.6 CCID50 per dose) versus placebo
	106.5 CCID50		106.6 CCID50		106.8 CCID50		Placebo
	N	N doses	N	N doses	N	N doses	N	N doses
Rota-005	–	–	_	–	209	400	108	209
Rota-006†	–	–	570	1115	–	–	567	1119
Rota-007	–	–	653	1292	–	–	653	1295
Rota-023	31673	61289	–	–	–	–	31552	61017
Rota-033	730	1413	–	–	–	–	124	236
Rota-036	2646	5267	–	–	–	–	1348	2686
Rota-039	174	345	–	–	–	–	52	104
Rota-048	100	199	–	–	–	–	50	99
Total	36,755 subjects (71,320 doses)						34,454 subjects (66,765 doses)

N = number of subjects receiving at least one dose; N doses = total number of doses administered

†In study Rota-006, 30 subjects in 10^6.6 CCID50 group and 30 subjects in placebo group received a third dose of

Rotarix^TM or placebo. The third dose administered was not counted under N doses in this table and any AEs

reported after the third dose were not included in the ISS.

Placebo group for study Rota-039 includes Placebo group (N=26) and Placebo group without buffer (N=26)

Placebo group for study Rota-048 includes Placebo group (N=25) and Placebo group for the liquid formulation (N=25)

(Source: Summary of Clinical Safety, pg 32)

 

Supplementary ISS analysis

A total of 3076 subjects received 6037 doses of Rotarix^TM at a potency < 10^6.0 CCID₅₀ per dose. Distribution by individual study is summarized in Table 15.

 

Table 15: Numbers of subjects and doses, Supplementary ISS analysis

Study	Supplementary ISS: RotarixTM vaccine (<106.0 CCID50per dose) versus placebo
	105.3 CCID50		105.6 CCID50		Placebo
	N subjects	N doses	N subjects	N doses	N subjects	N doses
Rota-004	270	526	–	–	135	261
Rota-005	–	–	212	415	108	209
Rota-006†	569	1110	570	1109	567	1119
Rota-007	510	1011	648	1287	653	1295
Rota-014	–	–	297	579	150	293
Total	3,076 subjects (6,037 doses)				1,613 subjects (3,177 doses)

N subjects = number of subjects receiving at least one dose; N doses = total number of doses administered

†In study Rota-006, 31 subjects in 10^5.3 CCID50 group, 30 subjects in 10^5.6 CCID50 group and 30 subjects in

placebo group received a third dose of Rotarix^TM or placebo. The third dose administered was not counted under N

doses in this table and the AEs reported after the third dose, were not included in the ISS.

(Source: Summary of Clinical Safety, pg 33)

 

For studies included in both the Core ISS and Supplementary ISS analyses (Rota-005, Rota-006, Rota-007), the same numbers of placebo subjects and doses were used.

 

 

 

 

 

 

ISS analyses: Safety endpoints

The following safety endpoints were included in each ISS analysis:

-          Individual solicited AEs (any intensity and Grade 3) from Days 0-7 post-vaccination.

-          Unsolicited AEs (any intensity and Grade 3) from Days 0-30 post-vaccination.

-          Fatal events from Days 0-30 post-vaccination and during the entire study course.

-          SAEs from Days 0-30 post-vaccination and during the entire study course.

 

The relative risk (RR; percentage in Rotarix^TM / percentage in placebo group) along with the 95% CI were calculated for each safety endpoint based on exact conditional likelihood approach adjusted for the study effect. Multiplicity adjustment was not performed.

 

For both ISS groups, post-Dose 3 safety data from 121 subjects in the 3-dose subset of Rota-006 were excluded. Analysis of solicited AEs included only subjects and doses with a completed solicited AE CRF/eCRF. Subjects not reporting unsolicited AEs were treated as subjects without an unsolicited AE.  Also, analysis of SAEs coded to the MedRA PT Intussusception was based on the onset date and not diagnosis (as in Rota-023), and included cases besides those categorized as “definite IS.”

 

Rota-023, Rota-036: Safety endpoints

The following safety endpoints were included in each study:

-          Fatal events from Days 0-30 post-vaccination and during the entire study course

-          SAEs from Days 0-30 post-vaccination and during the entire study course

 

The following safety endpoints were also included in Rota-036:

-          Individual solicited AEs (any intensity and Grade 3) from Days 0-7 post-vaccination.

-          Unsolicited AEs (any intensity and Grade 3) from Days 0-30 post-vaccination.

 

The risk difference (risk in Rotarix^TM group - risk in placebo group) along with the 95% CI were calculated for each safety endpoint. Multiplicity adjustment was not performed.

 

IS analysis – Rota-023

Rota-023, a non-U.S. IND study, was specifically designed and powered to assess the risk of IS following Rotarix^TM vaccination. Under the original criterion for meeting the primary safety objective, it was required that the upper limit of the 90% CI of the risk difference (Rotarix^TM minus placebo) be less than 2/10,000 subjects. This criterion was based on an overall IS incidence rate of 1/10,000 vaccinees, which in turn was based on a consensus estimate of Rotashield attributable risk. However, based on the number of observed IS cases that occurred within 31 days post-vaccination during Rota-023, the overall incidence rate of definite IS, which was substantiated by data from a separate epidemiological study in which active IS surveillance was conducted (children less than 2 years of age not vaccinated with Rotarix^TM) in the same 11 Latin American countries participating in Rota-023, was revised to 3-5/10,000. This subsequently led to revision of criteria for meeting the following primary safety objective:

 

-          The upper limit of the 95% CI of the risk difference for definite IS should be <6/10,000.

-          There should be no statistically significant increase in the incidence of definite IS  (the lower limit of the 95% of the risk difference should be < 0).

 

Assuming a definite IS incidence rate of 3-5/10,000 in the placebo group and 30,000 subjects in each treatment arm, the study had >86% power to meet its primary objective if the risk difference was truly 0.

 

Independent Data Monitoring Committee

An IDMC consisting of external clinical experts and a biostatistician was established in May 2002 to independently monitor safety aspects of the Rotarix^TM vaccine clinical development. In addition, two other independent committees, a Clinical Events Committee (CEC) and a Safety Review Committee (SRC), reviewed safety data in Rota-023.

 

Safety results – Intussusception, Rota-023 (Applicant analysis)

Thirteen cases of definite IS (Rotarix^TM: 6, placebo: 7) adjudicated by the CEC as definite IS were diagnosed within 31 days (Days 0-30) after any dose; 3 (Rotarix^TM: 1, placebo: 2) were diagnosed after Dose 1 and 10 (Rotarix^TM: 5, placebo: 5) were diagnosed after Dose 2 (see Table 16).  

 

There was no statistically significant difference between Rotarix^TM and placebo groups in the rate (per 10,000) of subjects diagnosed with definite IS during the 31-day risk window after any dose, after Dose 1, or after Dose 2, as demonstrated by the following:

-          the upper limits (UL) of the 95% CI of the risk difference were below 6/10,000.

-          the lower limits (LL) of the 2-sided 95% CI of the risk difference were below 0.

 

RR estimates of definite IS in Rotarix^TM compared to placebo subjects after any dose, Dose 1, or Dose 2 were also not statistically significant.

 

Table 16: Definite IS diagnosed from Days 0 to 30 after study vaccination, Rota-023

	Study group						Risk Difference (RotarixTM – Placebo)			Relative Risk (RR) (RotarixTM / Placebo)
	RotarixTM			Placebo			difference/ 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 = # of subjects in the cohort; n = # with definite IS

(Source: Study Report Rota-023 Visit 1-3, pg 79)

 

The applicant noted that when the original criterion for the primary safety objective was used (i.e. UL of the 90% CI of the risk difference < 2/10,000), the primary objective was still met (UL = 1.71/10,000); the risk difference was -0.32/10,000 with a LL of -2.41.

 

A total of 25 definite IS cases adjudicated by the CEC were diagnosed from Dose 1 until Visit 3 (1 to 2 months post-Dose 2, or 2 to 4 months post-Dose 1) (Rotarix^TM: 9, placebo: 16). There was no statistically significant difference between Rotarix^TM and placebo groups in the rate of subjects diagnosed with definite IS during this interval (risk difference =

-2.23/10,000, 95% CI: -5.70, 0.94/10,000; RR = 0.56, 95% CI: 0.25, 1.24).

 

Safety results – Intussusception, Rota-023 (FDA analysis)

One definite IS case had an onset on Day 29 but was diagnostically confirmed on Day 31. When FDA analyzed the risk of definite IS within Days 0-30 based on onset date rather than diagnosis date, there were 7 out of 31,673 Rotarix^TM cases compared to 7 out of 31,552 placebo cases. The risk difference was -8.48/10⁷ with a 95% CI of -2.63 to 2.61/10,000. The 90% CI of the risk difference was -2.12 to 2.12/10,000. Of note, none of the definite IS cases in either treatment group had an onset from Days 1 to 14 post-Dose 1. Numbers and rates of IS post-vaccination by onset interval after any study dose (Rotarix^TM or placebo) are presented in Table 17.

 

Table 17: Numbers and rates of definite IS by onset interval after any dose, Rota-023

Onset interval (days)	RotarixTM IS	RotarixTM subjects	Incidence (per 10,000)	Placebo  IS	Placebo subjects	Incidence (per 10,000)	Risk Difference (per 10,000)	95% CI Difference  (per 10,000)
1 to 7	2	31,673	0.63	1	31,552	0.32	0.31	-1.21, 2.02
8 to 14	0	31,673	0	1	31,552	0.32	-0.32	-1.80, 0.90
15 to 21	3	31,673	0.95	2	31,552	0.63	0.31	-1.46, 2.22
22 to 30	2	31673	0.63	3	31,552	0.95	-0.32	-2.23, 1.45
1 to 14	2	31,673	0.63	2	31,552	0.63	-0.002	-1.74, 1.73
1 to 21	5	31,673	1.58	4	31,552	1.27	0.31	-1.90, 2.58
1 to 30	7	31,673	2.21	7	31,552	2.22	-0.01	-2.63, 2.61

(Source of # of IS cases and # of subjects in each group: Study Report Rota-023 Visit 1-3)

 

Safety results – Intussusception, ISS analyses (Applicant analysis)

In the Core ISS analysis, 9 out of 36,755 (0.024%) Rotarix^TM recipients compared to 7 out of 34,454 placebo subjects (0.020%) had onset of PT Intussusception within 31 days after any study dose. The relative risk was not statistically significant (RR=1.23, 95% CI: 0.41, 3.90).  In addition to the 7 cases of definite IS previously mentioned in Rota-023, two other IS cases were reported (Rota-023: onset on Day 22 post-Dose 2 of Rotarix^TM; Rota-036: onset on Day 8 post-Dose 2 of Rotarix^TM). Rates of PT Intussusception throughout the study periods were similar in both groups (Rotarix^TM: 16 [0.04%]; placebo: 22 [0.06%]; RR=0.69, 95% CI: 0.34, 1.37).

 

In the Supplementary ISS analysis, a significant increase in risk of PT Intussusception within 31 days after Rotarix^TM vaccination was also not observed (Rotarix^TM: 1 [0.033%], placebo: 0 [0%]; LL 95% CI: 0.01). The lone IS case occurred in Rota-007 on Day 8 post-Dose 1 (10^5.6 CCID₅₀ group). Throughout the entire study periods, IS was reported in 2 (0.07%) Rotarix^TM recipients and 1 (0.06%) placebo recipient (RR=1.08, 95% CI: 0.06, 63.94).

 

Safety results – Intussusception, all BLA studies (FDA analysis)

The rates of PT Intussusception post-vaccination by onset intervals using data from all BLA studies at all Rotarix^TM potencies are presented in Table 18. Only data pertaining to the lyophilized formulation with buffer was used for the Rotarix^TM group calculations. Date of illness onset was used instead of date of diagnosis, including IS cases for Rota-023.

 

 

 

 

 

 

Table 18: Numbers and rates of IS by onset interval after any dose, all BLA studies

Onset interval (days)	RotarixTM IS	RotarixTM subjects	Incidence (per 10,000)	Placebo  IS	Placebo subjects	Incidence (per 10,000)
1 to 7	3	40315	0.74	1	34739	0.29
8 to 14	1	40315	0.25	1	34739	0.29
15 to 21	3	40315	0.74	2	34739	0.58
22 to 30	3	40315	0.74	3	34739	0.86
1 to 14	4	40315	0.99	2	34739	0.58
1 to 21	7	40315	1.74	4	34739	1.15
1 to 30	10	40315	2.48	7	34739	2.02

(Source of # of IS cases and # of subjects in each group: Study Reports Rota-023 Visit 1-3, Rota-007, Rota-036)

 

Safety results – deaths, ISS analyses (Applicant analysis)

A total of 128 post-vaccination deaths were reported from the 10 studies in the ISS. In addition, no deaths were reported from Rota-060. Distribution of deaths by individual study is presented in Table 19.

 

Table 19: Distribution of deaths by BLA study

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	31673	62	-	-	31552	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	36755	68	3076	5	34739	55

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

(Source: Summary of Clinical Safety, pg 50)

 

In the Core ISS analysis, 53 deaths (Rotarix^TM: 33, placebo: 20) were reported from Days 0-30 post-vaccination. The RR was 1.64 (95% CI: 0.92, 3.02). For each MedDRA PT, the relative risk estimate was not statistically significant (95% CIs of RR did not include 1.0). Notable imbalances between groups were also not observed for any PT. Among the PTs, the largest number of deaths was coded under PT Pneumonia (Rotarix^TM: 7, placebo: 5; RR=1.39, 95% CI: 0.38, 5.57).

 

In the Core ISS analysis, 118 deaths (Rotarix^TM: 68, placebo: 50) were reported throughout the course of the studies. The RR was 1.31 (95% CI: 0.89, 1.93). For each MedDRA PT, the relative risk estimate was not statistically significant, and notable imbalances between groups were also not observed. Among the PTs, the largest number of deaths was PT Pneumonia (Rotarix^TM: 19, placebo: 10; RR=1.74, 95% CI: 0.76, 4.23).

 

In the Supplementary analyses, imbalances between groups were not observed for deaths within 31 days post-vaccination (Rotarix^TM: 3, placebo: 4), deaths throughout the course of the studies (Rotarix^TM: 5, placebo: 6), and any MedDRA PT for both intervals.

 

 

 

Safety results – deaths, Rota-023 (Applicant analysis)

A total of 111 post-vaccination deaths were reported during Rota-023 (Rotarix^TM: 62 [0.20%], placebo: 49 [0.16%]). Of these deaths, 99 (Rotarix^TM: 56, placebo: 43; p=0.198) occurred up to September 10, 2004 (approximately 1.5 months after the last Visit 3) (Table 20).

 

Table 20: Number of deaths occurring within different time intervals, Rota-023

Time window	RotarixTM					Placebo						Risk Difference (RotarixTM minus Placebo)				P-value
				95% CI*						95% CI*				95% CI**
	n	N	Per 10000	LL	UL		n	N	Per 10000	LL	UL		Per 10000	LL	UL
All up to 9/10/04	56#	31673	17.68	13.36	22.95		43	31552	13.63	9.86	18.35		4.05	-2.15	10.4	0.198
Post Dose 1
Within 31 days	22#	31673	6.95	4.35	10.51		11	31552	3.49	1.74	6.24		3.46	-0.11	7.39	0.057
Post Dose 2
Within 31	2	29616	0.68	0.08	2.44		5	29465	1.70	0.55	3.96		-1.02	-3.37	0.95	0.254

N = number of subjects in the considered cohort; n = number of subjects who died within the specified time window

Per 10 000 = number of subjects per 10 000 with death date within the specified time window

#For 1 HRV subject the onset of the primary CoD was before vaccination (Dose 1).

(Source: Study Report Rota-023 Visit 1-3, pg 287)

 

Among the 99 deaths, PT Pneumonia was reported significantly more in the Rotarix^TM group than the placebo group (14 vs. 5, risk difference = 2.84/10,000, p=0.04). Of these 19 PT Pneumonia deaths, 7 (Rotarix^TM: 5, placebo: 2) had symptom onset within 31 days following study dose. Because the etiologic pathogen was not recovered in all pneumonia-related deaths, the sponsor conducted an ad-hoc analysis by pooling PTs Pneumonia, Bronchopneumonia, and Pneumonia cytomegalovirus. When pooled, the number of deaths due to pneumonia disease was not significantly different between groups (Rotarix^TM: 16 [0.51%], placebo: 6 [0.019%]; risk difference = 3.15/10,000, p=0.054). Of the pooled pneumonia deaths with symptom onset occurring within 31 days after vaccination/placebo, 7 (0.022%) were in Rotarix^TM and 3 (0.010%) in placebo recipients. A temporal association was not clearly established when analyzing pneumonia onset by week for each group (Rotarix^TM /placebo) (week 1: 2/2, week 2: 2/0, week 3: 2/0, week 4: 1/1).

 

Safety results – deaths, Rota-023 (FDA analysis)

FDA obtained exact p-values of 0.0345 and 0.0354 using two methodologies for the difference in pneumonia-related PTs between treatment groups (Rotarix^TM: 16 [0.51%], placebo: 6 [0.019%]). Also, of the pooled pneumonia deaths with symptom onset occurring within 43 days after vaccination/placebo, 8 were in Rotarix^TM and 3 in placebo recipients.

 

Safety results – SAEs, ISS (Applicant analysis)

In the Core ISS analysis, 1286 subjects (Rotarix^TM: 627 [1.71%], placebo: 659 [1.91%]) reported at least 1 SAE from Days 0-30 post-vaccination. The RR was 0.90 (95% CI: 0.81, 1.01). Compared to placebo recipients, Rotarix^TM recipients reported significantly less PTs Diarrhoea (RR=0.35, 95% CI: 0.14, 0.78), Gastroenteritis (RR=0.62, 95% CI: 0.45, 0.84), and Dehydration (RR=0.43, 95% CI: 0.17, 0.97). Rates of SAEs were similar or the same between groups for PTs Pneumonia (Rotarix^TM: 0.33%, placebo: 0.35%) and Convulsions (Rotarix^TM: 0.02%, placebo: 0.02%).

 

In the Core ISS analysis, 4519 subjects (Rotarix^TM: 2219 [6.04%], placebo: 2300 [6.68%]) reported at least 1 SAE throughout the entire study period. The RR was 0.89 (95% CI: 0.84, 0.94). Compared to placebo recipients, Rotarix^TM recipients reported significantly less PTs Diarrhoea, Ileus, Gastroenteritis, Gastroenteritis rotavirus and Dehydration. Reports of PT Foreign body trauma were significantly higher in the Rotarix^TM group compared to the placebo group (11 vs. 1; RR= 9.11, 95% CI: 1.31, 394.8). However, all cases involved occurred between 48 to 483 days post-dose, and were assessed as not related to vaccination. Rates of SAEs under the PT Pneumonia (Rotarix^TM: 1.23%, placebo: 1.28%) and PT Convulsions (Rotarix^TM: 0.09%, placebo: 0.06%) were similar or the same between groups.

 

In the Supplementary analyses, rates of subjects that reported at least 1 SAE within 31 days post-vaccination and throughout the course of the studies were not significantly different between groups. Relative risks for each PT in either study interval were also not statistically significant. Within 31 days post-vaccination, rates of PTs Bronchitis (Rotarix^TM: 0.23%, placebo: 0%) and Pneumonia (Rotarix^TM: 0.20%, placebo: 0.12%) were higher in the Rotarix^TM group. Throughout the course of the studies, rates of PTs Bronchitis (Rotarix^TM: 0.72%, placebo: 0.50%) and Pneumonia (Rotarix^TM: 1.89%, placebo: 1.55%) were also higher in the Rotarix^TM group.

 

Safety results – SAEs, Rota-023 (Applicant analysis)

In Rota-023, significantly less Rotarix^TM than placebo recipients reported at least 1 SAE from Dose 1 to Visit 3 (928 [2.93%] vs. 1047 [3.32%]). During this interval, PTs Diarrhea, Vomiting, Gastroenteritis and Dehydration were also reported significantly less in the Rotarix^TM than the placebo group. Reporting of PT Urticaria was significantly higher in the Rotarix^TM compared to placebo group (5 vs. 0 subjects). Four of the 5 subjects developed urticaria between 15 and 82 days after Dose 1; 1 subject developed urticaria after intake of an unspecified medication, while 2 developed urticaria within 4 and 16 days after receiving DTPw vaccination. Moreover, these 4 subjects did not develop urticaria after receiving Dose 2. The remaining fifth subject had onset 4 days after Dose 2. All 5 were judged as not being related to vaccination, and the applicant concluded that the observed imbalance was likely a chance finding and not clinical relevant. No cases of anaphylaxix or drug hypersensitivity were reported in Rotarix^TM subjects.

 

From Dose 1 to Visit 3, PT Convulsions was also reported significantly more in the Rotarix^TM compared to the control group (16 [0.051%] vs. 6 [0.019%]; p = 0.034). After convulsion-related PT terms Convulsions, Epilepsy, Grand mal convulsion, Status epilepticus, and Tonic convulsion were combined, no statistical difference between groups was found (Rotarix^TM: 20, placebo: 12; p=0.219). Among subjects who experienced a convulsion-related episode within 31 days after any dose, 7 (0.022%) were Rotarix^TM and 9 (0.029%) were placebo recipients. Ten cases occurred after Dose 1 (Rotarix^TM: 5, placebo:  5), while 6 subjects had onset after Dose 2 (Rotarix^TM: 2, placebo: 4). Among the subjects with onsets beyond 31 days after any dose until Visit 3, 14 (0.044%) were in Rotarix^TM and 3 (0.01%) were placebo recipients.

 

Analyses of pooled pneumonia-related PTs showed that there were no significant differences between groups in the number of subjects hospitalized for pneumonia-related SAEs from Dose 1 to Visit 3 (Rotarix^TM: 277, placebo: 273; p=0.90). Significant differences when stratified by dose (post-Dose 1 vs. post-Dose 2) and timing of hospitalization (within 31 days vs. beyond 31 days after each dose) were also not observed.

 

In addition, there were no significant differences in the number of pooled pneumonia SAEs from all pneumonia-containing PTs (within SOC Infections and infestations) between groups for the following intervals: Dose 1 to Visit 3 (Rotarix^TM: 280, placebo: 277), within 31 days post-Dose 1 (Rotarix^TM: 100, placebo: 96), within 31 days post-Dose 2 (Rotarix^TM: 49, placebo: 57), beyond 31 days post-Dose 1 (Rotarix^TM: 88, placebo: 83), and beyond 31 days post-Dose 2 (Rotarix^TM: 43, placebo: 41).

 

Safety results – SAEs, Rota-036 (Applicant analysis)

In Rota-036, 290 (11.0%%) of Rotarix^TM and 176 (13.1%) of placebo subjects reported at least 1 SAE from Dose 1 to Visit 7 (end of second RV season). PTs Gastroenteritis and Gastroenteritis rotavirus were reported significantly less in the Rotarix^TM than placebo group.

 

From Dose 1 to Visit 7, PT Pneumonia was reported significantly more in the Rotarix^TM group compared to the placebo group (24 vs. 4, p=0.029). Of the 28 cases, 19 (Rotarix^TM:  17, placebo: 2) were reported after Visit 5 (end of first RV season). Only one case was reported within 31 days after vaccination (Rotarix^TM group, 29 days post-Dose 2).

 

Safety results – SAEs, Rota-023 and Rota-036 (FDA analysis)

In Rota-023, FDA calculated rates of convulsion-related SAEs within the first 43 days after vaccination in each group. A noticeable imbalance was not observed (Rotarix^TM: 12 [0.04%], placebo: 9 [0.03%]).

 

In Rota-023, FDA calculated rates of non-fatal SAE pneumonia and SAE bronchitis in each group. After PTs Pneumonia, Bronchopneumonia, Pneumonia cytomegalovirus, and Pneumonia viral were combined, imbalances were not observed within 31 days post-vaccination (Rotarix^TM: 148 [0.48%], placebo: 154 [0.49%]) or within 43 days post-vaccination (Rotarix^TM: 193 [0.61%], placebo: 194 [0.61%]). After PTs Bronchitis and Bronchitis acute were combined, imbalances were not observed within 31 days post-vaccination (Rotarix^TM: 24 [0.08%], placebo: 24 [0.08%]) or within 43 days post-vaccination (Rotarix^TM: 34 [0.11%], placebo: 30 [0.10%]).

 

In Rota-036, FDA calculated rates of convulsion-related SAEs in each group. After PTs Convulsion, Epilepsy, Infantile spasms, Myoclonus, and Partial seizures were combined, an imbalance between groups was not observed within 31 or 43 days post-vaccination (Rotarix^TM: 1 [0.04%], placebo: 1 [0.07%]).

 

In Rota-036, FDA noted that among the 28 cases of PT Pneumonia, 3 (Rotarix^TM: 3, placebo: 0) occurred within 43 days post-vaccination. When the reviewer combined pneumonia-related PTs (Pneumonia, Bronchopneumonia, Lobar pneumonia, Pneumonia viral), an imbalance was still seen from Dose 1 to Visit 7 (Rotarix^TM: 31, placebo: 7), within 31 days post-vaccination (Rotarix^TM: 2, placebo: 0) and within 43 days post-vaccination (Rotarix^TM: 5, placebo: 0).

 

In Rota-036, FDA calculated rates of SAE bronchitis in each group. After PTs Bronchitis and Bronchitis acute were combined, an unfavorable imbalance in the Rotarix^TM group was not observed within 31 days post-vaccination (Rotarix^TM: 1 [0.04%], placebo: 2 [0.15%]) or within 43 days post-vaccination (Rotarix^TM: 4 [0.15%], placebo: 3 [0.22%]).

 

Safety results – Solicited AEs, ISS (Applicant analysis)

A total of 3286 Rotarix^TM recipients and 2015 placebo recipients had a completed solicited AE Case Report Form. Compliance was high (>98%) in each group for subjects who returned AE diary cards after each dose.

 

In the Core ISS analysis, rates of each AE symptom, regardless of intensity, from Days 0 to 7 after any dose are presented in Table 21. Rates were similar between groups. In both groups, fussiness/irritability was the most reported, followed by cough/runny nose, fever, and loss of appetite. In general, rates were comparable after each dose (data not presented).

 

Table 21: Solicited AEs, any intensity, after any dose, Core ISS

Solicited symptom (any intensity)	Dose	Group	N	n	%	95% CI		RR (RotarixTM over Placebo)
									95% CI
						LL	UL	RR