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

1. Vaccines and Related Biological Drug Products Advisory Committee MeetingFebruary 20, 2008 Rotarix™ (rotavirus vaccine, live, oral) GlaxoSmithKline Biologicals Paul Kitsutani, MD, MPH (Steven Rosenthal, MD, MPH) CBER/FDA

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

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

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

5. Question 1 • Are the available data presented adequate to support the efficacy of Rotarix™ in preventing rotavirus gastroenteritis caused by serotypes G1, G2, G3, G4, and G9, when the first dose of vaccine is administered beginning 6 weeks of age, followed by a second dose separated by at least 4 weeks? • If not, what additional information should be provided?

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

7. Question 3 • Are there additional issues that should be addressed in post-marketing studies beyond the applicant’s proposed U.S. post-licensure safety study

8. Presentation Overview - Rotarix™ • Clinical overview • Efficacy – Pivotal Studies • Safety – Serious Adverse Events • Co-administration of Rotarix™ with routine childhood vaccines • Post-marketing commitments • Questions for the Advisory Committee

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

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

12. Efficacy – Pivotal Studies

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

14. Efficacy – Pivotal Studies Year 1 ATP efficacy cohort

15. Pivotal Efficacy Studies - Demographics Year 1 ATP efficacy cohort

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

17. Pivotal Efficacy Studies – Exclusion Criteria • History of chronic GI disease or other serious medical condition • Immunocompromised condition, including HIV • >14 days on immunosuppressive drugs

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

19. Pivotal Efficacy Studies – Other Characteristics • Co-administration of infant vaccines allowed in Rota-036 • DTaP-Hib-HepB-IPV: Czech Republic, Finland, Germany, Italy, Spain • DTaP-Hib-HepB-IPV (Dose 1, 3), DTaP-Hib-IPV: France • Meningococcal group C conjugate: Spain • Prevnar®: France, Germany

20. Pivotal Efficacy Study – Rota-023 • Primary efficacy objective • Determine if 2 doses of Rotarix™ can prevent severe wild-type RV GE during Year 1 efficacy period (2 weeks post-Dose 2 to 1 year of age) • Secondary efficacy objectives: • Determine Year 1 efficacy of Rotarix™ against • Severe G1 wild-type RV GE • Severe non-G1 wild-type RV GE, pooled • Severe non-G1 wild-type RV GE, by individual type • Severe RV GE (Vesikari scale case definition)

21. Pivotal Efficacy Study – Rota-036 • Primary efficacy objective: • Determine efficacy of 2 doses of Rotarix™ given with childhood vaccines against any wild-type RV GE during Year 1 efficacy period (2 weeks post-Dose 2 until end of 1st RV season) • Secondary efficacy objectives: • Determine Year 1 efficacy of Rotarix™ against • Severe wild-type RV GE • Any/severe G1 wild-type RV GE • Any/severe non-G1 wild-type RV GE • Hospitalization for RV GE • Any medical attention for RV GE

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

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

24. Vesikari Scale

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

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

27. Pivotal Efficacy Studies – Vaccine Efficacy Calculation Vaccine Efficacy = 1 – Relative Risk = 1 – (ARV/ARU) ARV = attack rate in Rotarix™ group = # subjects with at least one episode of RV GE endpoint ÷ total # subjects in Rotarix™ group ARU = attack rate in placebo group = # subjects with at least one episode of RV GE endpoint ÷ total # subjects in placebo group

28. Efficacy Results – Rota-036 ATP efficacy cohort, Year 1 N= total number of subjects in ATP efficacy cohort, Year 1 n= number of subjects reporting at least one clinical endpoint event caused by circulating wild-type RV

29. Efficacy Results – Rota-036 VE against any RV GE, ATP efficacy cohort, Year 1

30. Efficacy Results – Rota-036 VE against severe RV GE, ATP efficacy cohort, Year 1

31. Efficacy Results – Rota-036 ATP efficacy cohort, Year 1

32. Efficacy Results – Rota-023 ATP efficacy cohort, Year 1

33. Efficacy Results – Rota-023 VE against severe RV GE (main definition), ATP efficacy cohort, Year 1

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

35. Safety – Intussusception Study (Rota-023)

36. Intussusception (IS) Study – Rota-023 • Primary safety objective: • Determine the safety of Rotarix™ with respect to intussusception (IS) within 31 days (Days 0 to 30) after each dose • Primary safety endpoint: • Occurrence of definite IS within 31 days after each dose • The Brighton Collaboration IS Working Group case definition for IS used

37. IS Study – Rota-023 • The Brighton Collaboration IS Working Group case definition for “Definite IS”

38. IS Study – Rota-023 • To capture all IS events, IS cases reported irrespective of whether they met the Brighton case definition • Clinical Events Review Committee (CEC) performed blinded objective reviews of all IS cases occurring from Dose 1 to Visit 3* • CEC consisted of physicians acting as consultants who were not study investigators or medical care providers to study subjects *Visit 3 = 1-2 months post-Dose 2 or 2-4 months post-Dose 1

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

40. IS Study – Rota-023 • 9 months after study initiation, blinded overall IS incidence rate 31 days post-vaccination was 2-4/10,000 • Exceeded anticipated rate of 0.3/10,000 in placebo group • UL of 90% CI exceeded 2/10,000 • Background incidence rate of 5/10,000 calculated from concurrent, prospective, multi-center epidemiologic study in the same countries

41. Intussusception Study – Rota-023 • Criteria for meeting primary safety objective revised • UL of 95% CI of risk difference for definite IS < 6/10,000 (limit based on IS incidence of 3-5/10,000 in placebo group and 30,000 subjects in each group) • LL of 95% CI of the risk difference < 0 • Study had >86% power to meet primary objective if the risk difference was truly 0

42. IS Study Results– Rota-023 Definite IS diagnosed 31 days (Days 0 to 30) post-vaccination N = # subjects in the cohort; n = # subjects with definite IS

43. IS Study Results– Rota-023 • Applicant noted that when original criterion for primary safety objective used (UL of 90% CI of risk difference < 2/10,000), objective still met • UL = 1.71/10,000 • 25 definite IS cases diagnosed from Dose 1 until Visit 3 • Rotarix™ = 9, placebo = 16 • Risk difference = -2.23/10,000 (95% CI: -5.70, 0.94) • RR = 0.56 (95% CI: 0.25, 1.24)

44. IS Study Results– Rota-023 (FDA analysis) • One definite IS case had onset on Day 29 but diagnosed on Day 31 • Analysis of IS risk within 31 days after any dose based on onset date rather than diagnosis date • Rotarix™ = 7, placebo = 7 • Risk difference = -0.008/10,000 (95% CI: -2.63, 2.61) • RR = 0.996 (95% CI: 0.36, 2.72)

45. IS Study Results– Rota-023(FDA analysis) Definite IS by onset interval after each dose

46. IS Study Results– Rota-023(FDA analysis) Definite IS by onset interval after each dose

47. IS Study Results– Rota-023 (FDA analysis) • Criteria to meet the primary safety objective was revised during the conduct of the study • Such change while the trial is ongoing could potentially compromise the integrity of the study • Because FDA did not discuss this change with applicant (study was not performed under US IND), more detailed information has been requested to ensure that proper procedure was followed

48. Safety – Serious Adverse Events (SAEs)

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

50. Safety – ISS Analyses • Core ISS analysis group • 36,755 Rotarix™ subjects (71,320 doses) • 34,454 placebo subjects (66,765 doses) • 8 studies • Supplementary ISS analysis group • 3076 Rotarix™ subjects (6037 doses) • 1613 placebo subjects (3177 doses) • 5 studies • For studies included in both ISS analysis groups, the same numbers of placebo subjects used