1. A 1 GlaxoSmithKline’s Human Rotavirus Vaccine ROTARIX ® Vaccines and Related Biological Products Advisory Committee February 20, 2008

2. A 2 GlaxoSmithKline Presentation Clare Kahn, Ph.D Vice President North America, Regulatory Affairs Introduction Leonard Friedland, M.D. Executive Director - Clinical R&D North America, Vaccines Clinical Development Plan Clinical Trial Results Thomas Verstraeten, M.D. Director Head Worldwide Safety, Vaccines Post-marketing Safety Data Pharmacovigilance Plan Clare Kahn, Ph.DConclusion

3. A 3 Proposed Names Proprietary Name Rotavirus Vaccine, Live, Oral Trade Name Rotarix ®

4. A 4 Human RV Vaccine - Rotarix Lyophilized vaccine + liquid diluent (CaCO 3 ) –1 mL per dose –Each dose: ≥10 6 CCID 50 of live, attenuated HRV strain Orally administered 2 doses –1 st dose beginning at 6 weeks of age –2 nd dose at ≥4 weeks after first dose; completed by 24 weeks of age

5. A 5 Proposed Indication ROTARIX is indicated for the prevention of rotavirus gastroenteritis 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.

6. A 6 Risk by 5 th Birthday Annual Burden 1 : 5 1 : 1 1 : 205 1 : 50 610,000 2.4 million 24 million 114 million Estimated Global Prevalence of Rotavirus Disease Deaths Hospitalizations Outpatient Visits RV Episodes Glass RI, et al. Lancet 2006;368:323-332

7. A 7 Estimated US Prevalence of Rotavirus Disease 1 : 7 4 : 5 20-60 55,000-70,000 1 : 100,000 1 : 80 600,000 2.7 million Deaths Hospitalizations Outpatient Visits RV Episodes Risk by 5 th Birthday Annual Burden Glass RI, et al. Lancet 2006;368:323-332

8. A 8 Distribution of Rotavirus Strains by Region between 1973 and 2003 Latin America (n=2,950) North America (n=2,892) Europe (n=17,475) n= number of RV infections analyzed Santos et al. Rev Med Virol 2005;15:29-56

9. A 9 Rotavirus Virion Figure adapted from Cunliffe et al, Lancet 2002;359:640–642 11 segments of dsRNA encased by 3 protein capsids VP6 common to all RV strains Outer capsid proteins VP7 (G protein) and VP4 (P protein) induce neutralizing antibodies involved in disease protection Human RV classified into 10 G (VP7) and 11 P (VP4) types 5 G-P combinations constitute 90% of worldwide strains: G1P[8], G2P[4], G3P[8], G4P[8], G9P[8] P[4] and P[8] share cross-reactive epitopes

10. A 10 33 passages in cell culture Limiting dilution cloning in Vero cells and further passage in tissue culture Initial Safety and Efficacy studies 1 Live-Attenuated Human Rotavirus Vaccine (RIX4414 - Rotarix ® ) Human rotavirus strain circulating in Cincinnati in 1989 Human RV Vaccine - Rotarix 1 Bernstein et al, Lancet, 1999; 354:287-290 G1P[8]

11. A 11 Basis for Vaccination with Human Strain Natural RV infection attenuates severity of subsequent infections, regardless of serotype 1-3 1 Velazquez et al, N Eng J Med 1996 335 1022–1028 2 Bernstein DI, et al. JID. 1991; 164(2); 277-83 3 Velazquez et al, J Infect Dis 2000 182 1602–1609 Two Previous RV infectionsOne Previous RV infection

12. A 12 Development of live attenuated rotavirus vaccines derived from animal hosts began in 1970s RotaShield ®: rhesus-human reassortant vaccine licensed in the US in 1998 –Withdrawn in 1999 due to causal link with intussusception RotaTeq ® : human-bovine reassortant vaccine licensed in 2006 Rotarix ® : live attenuated human RV vaccine Large scale placebo-controlled safety trials required to refute intussusception related to vaccination Rotavirus Vaccines - History

13. A 13 Global Strategy for Rotarix Vaccine Development Following RotaShield withdrawal in 1999: Need for very large studies to assess risk of possible vaccine-induced intussusception (60,000 subjects) WHO recommendation to manufacturers to extend their development programs to countries with high medical need Majority of deaths resulting from RV gastroenteritis occur in South East Asia, Africa and Latin America Other considerations: - Availability of sound epidemiology data on RV disease and intussusceptions rates - a healthcare infrastructure to conduct very large trials

14. A 14 Rotarix BLA Development Finland Mexico Honduras Nicaragua Panama Brazil Venezuela Colombia Peru Chile Argentina Phase III – Study 023 Dominican Rep. Other BLA Studies Canada USA South Africa Thailand Singapore Phase III – Study 036 France Germany Spain Czech Rep Italy

15. A 15 Global Clinical Development Non US clinical studies were pivotal for US licensure as all complied with the following criteria defined by FDA for acceptance of foreign clinical data (21 CFR §312.120, § 314.106; ICH E5) Circulating serotypes and IS background rates are similar to the US Objectivity of pivotal endpoints –Identification of IS –Case definition for RV GE –Use of internationally accepted and widely used scoring system for severity of GE Study design and conduct in compliance with GCPs

16. A 16 Registration Status for Rotarix Argentina Aruba Bolivia Brazil Chile Colombia Costa Rica Curacao Dom Republic Ecuador El Salvador Guatemala Honduras Jamaica Mexico Nicaragua Panama Paraguay Peru Suriname Trinidad Venezuela AngolaBeninBurkina FasoCameroon CongoDRC EgyptGabon GuineaIvory Coast Kenya Madagascar Malawi Mali Mauritania Mauritius MozambiqueNamibia Niger Nigeria RCA SenegalSouth Africa Togo Bangladesh Hong Kong Macau Malaysia Myanmar Philippines Singapore Sri Lanka Taiwan Thailand Vietnam Bahrain Israel Jordan Kuwait Morocco Oman Pakistan Qatar Saudi Turkey UAE Yemen EU Canada Norway Iceland Kazakhstan Switzerland Australia New Zealand WHO prequalification – Feb 2007 12 million doses distributed

17. A 17 GlaxoSmithKline Presentation Clare Kahn, Ph.D. Vice President North America Regulatory Affairs Introduction Leonard Friedland, M.D. Executive Director - Clinical R&D North America, Vaccines Clinical Development Plan Clinical Trial Results Thomas Verstraeten, M.D. Director Head, Worldwide Safety, Vaccines Post-marketing Safety Data Pharmacovigilance Plan Clare Kahn, Ph.D.Conclusion

18. A 18 Phase III Immuno, Safety Study 039 Thailand n=174 n=52 Immuno US coad vaccines, Safety Study 060 US n=459 Efficacy, Safety (IS), Immuno Study 023 Latin America, Finland n=31673 n=31552 Lot consistency, Safety, Immuno Study 033 Latin America n=730 n=124 Efficacy, Safety, Immuno Study 036 Europe n=2646 n=1348 Phase II Study 004 Finland n=270 n=135 Study 006 Latin America n = 1139 n=570 n=567 Study 007 Singapore n = 1158 n=653 n=653 Safety, Immuno Study 005 US, Canada n=212 n=209 n=108 Immuno OPV Coad, Safety Study 014 S. Africa n=297 n=150 Immuno, Safety Study 048 Finland n=100 n=50 Efficacy, Safety, Immuno Summary of Clinical Studies in BLA Rotarix <10 6.0 CCID 50 n = 3076 Rotarix >10 6.0 CCID 50 n = 37214 Placebo n =34739 Total Exposure = 75029 subjects Phase II Study 004 Finland n=270 n=135 Study 006 Latin America n = 1139 n=570 n=567 Study 007 Singapore n = 1158 n=653 n=653 Safety, Immuno Study 005 US, Canada n=212 n=209 n=108 Immuno OPV Coad, Safety Study 014 S. Africa n=297 n=150 Immuno, Safety Study 048 Finland n=100 n=50 Efficacy, Safety, Immuno Phase III Immuno, Safety Study 039 Thailand n=174 n=52 Immuno US coad vaccines, Safety Study 060 US n=459 Efficacy, Safety (IS), Immuno Study 023 Latin America, Finland n=31673 n=31552 Lot consistency, Safety, Immuno Study 033 Latin America n=730 n=124 Efficacy, Safety, Immuno Study 036 Europe n=2646 n=1348 Rotarix <10 6.0 CCID 50 n = 3076 Rotarix >10 6.0 CCID 50 n = 37214 Placebo n =34739 Total Exposure = 75029 subjects

19. A 19 Rotarix Clinical Development Pivotal & Supportive Studies Randomized, blinded, prospective, placebo-controlled (10 of 11 studies) Healthy infants, range 5 to 17 weeks at 1 st dose (ph III 6 to 14 weeks); 2 nd dose 1-2 months later Efficacy evaluated through 2 years/RV seasons after vaccination Safety evaluated in all studies (study 023 powered for IS assessment) Immunogenicity typically evaluated one month after 2 nd dose Coadministration of routine infants vaccines: allowed in 9 of 11 studies

20. A 20 Clinical Trial Data to be Presented Efficacy Phase III Latin America Phase III Europe Immunogenicity Seroconversion and Vaccine Take Coadministration with US licensed Vaccines Fecal Antigen and Live Virus Shedding Safety Intussusception Integrated Summary of Safety: SAEs Events of Clinical Interest Integrated Summary of Safety: Reactogenicity Reactogenicity: Europe, US & Canada

21. A 21 Clinical Trial Data to be Presented Efficacy Phase III Latin America Phase III Europe Immunogenicity Seroconversion and Vaccine Take Coadministration with US licensed Vaccines Fecal Antigen and Live Virus Shedding Safety Intussusception Integrated Summary of Safety: SAEs Events of Clinical Interest Integrated Summary of Safety: Reactogenicity Reactogenicity: Europe, US & Canada

22. A 22 Dominican Republic 4056 (6.4%) Mexico 13245 (20.9%) Brazil 3218 (5.1%) Nicaragua 4057 (6.4%) Honduras 4195 (6.6%) Panama 4061 (6.4%) Chile 3458 (5.5%) Argentina 4671 (7.4%) Venezuela 4250 (6.7%) Colombia 3910 (6.2%) Peru 12044 (19.0%) Finland 2060 (3.3%) Study 023: Phase III Study in Latina & Finland Study 023: Phase III Study in Latina & Finland 18 sites in 12 countries ~63,000 infants LA: efficacy & safety Finland: safety only

23. A 23 N=63,225 infants age 6-13 weeks randomized (1:1) month 0 Placebo N=31,552 Rotarix N=31,673 1 st Dose2 nd Dose Month 1-2 Month 2-4 Safety surveillance (N=63,225) Month 9-10 1 yr Efficacy analysis (ATP N=17,867) Routine immunizations were co-administered according to local regulations Study 023: Phase III Safety & Efficacy Study in Latin America and Finland Month 21-22 2 yr Efficacy analysis (ATP N=14,237) Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354:11-22

24. A 24 Efficacy Latin America (Study 023) Primary Efficacy Objective To determine if 2 doses of Rotarix can prevent severe RV GE caused by circulating RV strains starting from 2 weeks after dose 2 until 1 year of age Secondary Efficacy Objectives Efficacy against G1 and non-G1 serotypes Efficacy using Vesikari severity scale Efficacy through 2 years of age

25. A 25 Efficacy Latin America (Study 023) RV GE Case Definition “Severe GE”: diarrhea (≥3 loose stools in 24 hrs) with or without vomiting that required hospitalization and/or re-hydration therapy in a medical facility [Clinical Case Definition] RV detection by ELISA Type determination by RT-PCR followed by reverse hybridization assay (or optional sequencing as needed) –Discrimination between G1 vaccine virus and wild-type G1 RV

26. A 26 Efficacy Endpoints Severe RV GE during 1st year efficacy period –Clinical Case Definition –Vesikari scale: based on intensity and duration of diarrhea, vomiting, fever, dehydration and type of treatment; score ≥11 = “severe” Efficacy against RV hospitalizations, all-cause severe GE Type-specific efficacy Second year efficacy Efficacy Latin America (Study 023)

27. A 27 From 2 weeks post-dose 2 until 12 months of age (ATP cohort) 85% [72;92] 85% [71;93] 85% [70;94] 40% [28;50] 12V:77P11V:71P9V:59P183V:300P Efficacy Latin America (Study 023) randomization 1:1

28. A 28 From 2 weeks post-dose 2 until 24 months of age (ATP cohort) 81% [71;87] 82% [73;89] 83% [73;90] 39% [30;47] 32V: 161P 22V: 127P 28V: 154P 342V: 551P 85% [72;92] 85% [72;93] 85% [70;94] 40% [28;50] randomization 1:1 Efficacy Latin America (Study 023) From 2 weeks post-dose 2 until 12 months of age (ATP cohort)

29. A 29 From 2 weeks post-dose 2 until 24 months of age (ATP cohort) *Not statistically significant 82% [65;92] 79% [25;96] 87% [73;94] 39%* [-112;84] 62% [4;87] 10V:55P 3V:14P + 7V:18P 9V:66P 5V:8P + one episode was P[6] Type-specific Efficacy Latin America (Study 023) - severe RV GE randomization 1:1

30. A 30 Study 036: Phase III Study in Europe 124 Sites in 6 EU Countries ~4000 Infants Spain 7.5% Germany 7% France 3.7% Italy 0.6% Finland 74% Czech Republic 7.5%

31. A 31 Study 036: Phase III Safety & Efficacy Study in Europe Month 0 Placebo N=1,348 Co-administered with DTaP-HepB-IPV/Hib (all), PCV7 (subset), MenC (subset) Rotarix N=2,646 1 st dose2 nd dose Months 1–2 Months 7-9 Season 1 Efficacy analysis (ATP N=3,874) Months 19-21 Season 2 Efficacy analysis (ATP N=3,848) N=3,994 infants age 6-14 wks randomized (2:1) Vesikari T et al. Lancet 2007;370:1757-63

32. A 32 Primary Efficacy Objective To determine if 2 doses of Rotarix can prevent any RV GE caused by circulating RV strains starting from 2 weeks after dose 2 until end of the first RV season post-vaccination Secondary Efficacy Objectives Efficacy against severe RV GE Efficacy against G1 and non-G1 serotypes Efficacy against RV hospitalizations Efficacy against medically-attended RV GE Efficacy through 2 RV seasons post-vaccination Efficacy Europe (Study 036)

33. A 33 Efficacy Europe (Study 036) RV GE Case Definition GE: diarrhea (≥3 loose stools in 24 hrs) with or without vomiting Severity assigned using Vesikari scale; score ≥11 = “severe” RV detection by ELISA Type determination by RT-PCR followed by reverse hybridization assay (or optional sequencing as needed) –Discrimination between G1 vaccine virus and wild-type G1 RV

34. A 34 Efficacy Europe (Study 036) Efficacy Endpoints Any and Severe RV GE during 1st RV season Efficacy against RV hospitalizations, medically-attended RV, all-cause GE hospitalizations Type-specific efficacy Second RV season efficacy Efficacy from dose 1 to dose 2

35. A 35 From 2 weeks post-dose 2 until end of the 1 st RV season (ATP cohort) 87% [80;92] 75% [46;89] 92% [84;96] 100% [82;100] 96% [90;99] Efficacy Europe (Study 036) 24V:94P 5V:60P 0V:12P10V:62P11V:22P randomization 2:1

36. A 36 79% [73;84] 72% [53;83] 84% [77;89] 96% [84;100] 90% [85;94] 85V: 204P 24V: 127P 2V: 25P 41V: 128P 27V: 48P From 2 weeks post-dose 2 until end of the 1st RV season (ATP cohort) From 2 weeks post-dose 2 until end of the 2 nd RV season (ATP cohort) 87% [80;92] 96% [90;99] 100% [82;100] 92% [84;96] 75% [46;89 ] randomization 2:1 Efficacy Europe (Study 036)

37. A 37 100% [-23;100] 90% [9;100] From Dose 1 up to before Dose 2 (Total Vaccinated Cohort) Efficacy Europe (Study 036) 1V:5P 0V:3P TVC = all subjects who received at least one dose regardless of protocol adherence randomization 2:1

38. A 38 From 2 weeks post-dose 2 until end of the 2 nd RV season (ATP cohort) 96% [90;99] 86% [24;99] 85% [72;93] 95% [68;100] 94% [53;100] 4V:57P 1V:8P1V:11P13V:44P + * P genotype not typable for one episode, + P[8] genotype not detected for one episode 2V:7P* Type-specific Efficacy Europe (Study 036) - Severe RV GE randomization 2:1

39. A 39 Summary of Efficacy Rotarix prevents: –Severe RV GE disease (96% EUR; 85% LA) –Any RV GE disease (87% EUR) –RV GE hospitalizations (100% EUR: 85% LA) –Medically attended RV GE (92% EUR) –RV GE as early as dose 1 (90% EUR) Rotarix prevents RV GE caused by G1, G2, G3, G4 and G9 strains Rotarix efficacy persists through 2 years/seasons after vaccination

40. A 40 Clinical Trial Data to be Presented Efficacy Phase III Latin America Phase III Europe Immunogenicity Seroconversion and Vaccine Take Coadministration with US licensed Vaccines Fecal Antigen and Live Virus Shedding Safety Intussusception Integrated Summary of Safety: SAEs Events of Clinical Interest Integrated Summary of Safety: Reactogenicity Reactogenicity: Europe, US & Canada

41. A 41 Immunogenicity – Seroconversion Serum anti-Rotavirus IgA Response Seroconversion = ≥20 U/mL in subjects RV negative prior to 1 st dose Seroconversion after dose 2 in phase III pivotal efficacy studies: –study 036 (Europe): 681/787 = 87% –study 023 (Latin America): 302/393 = 77% Efficacy against severe RV GE paralleled, but always higher compared to antibody response

42. A 42 Immunogenicity – “Vaccine Take” Vaccine take: Seroconversion and/or RV stool antigen detection in subjects RV negative prior to 1 st dose (≥10 6 CCID 50 ) StudyN testedVaccine Take (%) 005 (US-CA)15088 006 (Latin America)10676 007 (Singapore)4698 033 (Latin America)2673 039 (Thailand)16788 048 (Finland)9489

43. A 43 Immunogenicity – Coadministered Vaccines US Study 060 Randomized 1:1, controlled, open label 1º Objective: Non-inferiority immunogenicity Rotarix + coads vs. coads alone N=484 (1:1) Month of Age 2345 67 Co-Ad group Rotarix Pediarix Prevnar ActHIB Rotarix Pediarix Prevnar ActHIB Pediarix Prevnar ActHIB Blood Sample Serology Testing Sep-Ad group Pediarix Prevnar ActHIB RotarixPediarix Prevnar ActHIB RotarixPediarix Prevnar ActHIB Blood Sample Serology Testing

44. A 44 Pre-specified non-inferiority criteria met for all 17 coadministered antigens: anti-PRP, anti-HBsAg, anti-poliovirus 1, 2 & 3, anti-D and anti-T: LL of 95% CI for the treatment difference in seroprotection rate  -10% anti-PT, anti-FHA and anti-PRN: LL of 95% CI for the GMC ratios  0.67 S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F & 23F: LL of 95% CI for the GMC ratios  0.5 Immunogenicity – Coadministered Vaccines US Study 060

45. A 45 Viral Shedding RV antigen excretion is a feature of natural RV infection Following vaccination antigen excretion is expected; indication of vaccine activity Methodology –Stool RV antigen detected by ELISA –Stool live attenuated RV detected by cell culture

46. A 46 Fecal Antigen* Shedding Study Rota-033 + Columbia, Mexico, Peru Dose 1 (n=24-26) Dose 2 (n=23-26) * ELISA positive + Dose Conc ≥10 6.5 CCID 50 n = number of subjects with available results

47. A 47 Live Virus Shedding in Vaccinees Day 7 post-dose 1 Study # ELISA pos / N tested [N 1] # cell culture pos / N tested [N 2] * % of Vaccinees with live RV detected in stool [N1 x N2] 039 (Thailand) 90/162 (55.6%) 6/13 (46.2%) 25.6 % (95% CI 10 - 41) 048 (Finland) 49/84 (58.3%) 15/33 (45.5) 26.5 % (95% CI 16 - 38) * all ELISA positive samples with remaining stool cultured for live virus

48. A 48 Immunogenicity Summary Rotarix is immunogenic Rotarix does not negatively impact the immune response to the antigens present in: – Pediarix (DTaP-HepB-IPV), Prevnar (7 valent pneumococcal) and ActHIB (PRP) Live virus shedding: ~26% of subjects at 7 days after first dose in two clinical trials

49. A 49 Clinical Trial Data to be Presented Efficacy Phase III Latin America Phase III Europe Immunogenicity Seroconversion and Vaccine Take Coadministration with US licensed Vaccines Fecal Antigen and Live Virus Shedding Safety Intussusception Integrated Summary of Safety: SAEs Events of Clinical Interest Integrated Summary of Safety: Reactogenicity Reactogenicity: Europe, US & Canada

50. A 50 N=63,225 infants age 6-13 weeks randomized (1:1) month 0 Placebo N=31,552 Rotarix N=31,673 1 st Dose2 nd Dose Month 1-2 Month 2-4 Safety surveillance (N=63,225) Month 9-10 1 yr Efficacy analysis (ATP N=17,867) Routine immunizations were co-administered according to local regulations Study 023: Phase III Safety & Efficacy Study in Latin America and Finland Month 21-22 2 yr Efficacy analysis (ATP N=14,237) Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354:11-22

51. A 51 Intussusception (IS) Safety Objective Study 023: Latin America and Finland Primary Safety Endpoint: Risk of IS within 31 days (day 0-30) after each vaccine dose –Definite IS according to Brighton Collaboration Active Surveillance for IS by independent, complementary methods –Hospital surveillance system –Info query at each study visit. Parent’s contacted who missed a follow-up visit. Review of all potential IS cases –Blinded expert Clinical Event Committee –Safety monitoring by IDMC with authority to unblind

52. A 52 Intussusception Safety Objective Study 023: Latin America and Finland Primary Safety Objective Met if, within 31 Days of Vaccination: UL of the 2-sided 95% CI of the Risk Difference (Rotarix minus Placebo): below 6 per 10,000 No stat. sig. increase in IS incidence: LL of the 2-sided 95% CI of the Risk Difference: below 0 Secondary safety endpoint: Occurrence of SAEs during safety surveillance period

53. A 53 Study 023 Intussusception Results Dose 1 through end of safety surveillance (median 100 days) 27 Investigator-Diagnosed Intussusception Cases 13 cases within 31 days of a dose 12 cases >31 days of a dose and end safety surveillance 1V:0P6V:7P3V:9P 26 positively-adjudicated “Definite” cases 0 negatively- adjudicated cases 1 adjudicated “Probable” case 1V:0P 1 case after safety surveillance completed

54. A 54 Placebo group Rotarix group within 31 days 67 Relative Risk = 0.85 (0.30 ; 2.42) Risk Difference = -0.32 (-2.91 ; 2.18) 9 16 within median 100 days Cases of IS Safety cohort N=31,673Safety cohort N=31,552 Relative Risk = 0.56 (0.25 ; 1.24) Risk Difference = -2.23 (-5.7 ; 0.94) Study 023: No Increased Risk of Intussusception Compared to Placebo

55. A 55 Study 023: No Clustering of IS Cases within 7 or 14 Day Window Post-vaccination Day Range Dose 1Dose 2Any Dose RotarixPlaceboRotarixPlaceboRotarixPlacebo N = 31,673N = 31,552N = 29,616N = 29,465N = 31,673N = 31,552 0-7002020 8-14000202 15-21112132 22-30011213 Total (0-30)125567 RR= 0.5 (0.07;3.8) RD= -0.32 (-2.03;1.2) RR= 0.99 (0.31;3.21) RD= -0.01 (-2.48;2.45) RR= 0.85 (0.3;2.42) RD= -0.32 (-2.91;2.18)

56. A 56 Study 023: No Evidence for Increased Risk of Intussusception Primary Safety Hypothesis Satisfied Pre-specified statistical criteria met UL of the 2-sided 95% CI of the RD: < 6 per 10,000 after any dose LL of the 2-sided 95% CI of the RD: < 0 after any dose Within 31 days any dose RR = 0.85 (95% CI 0.3 ; 2.42) RD = - 0.32 per 10,000 (95% CI -2.91; 2.18) No evidence of clustering of IS cases within 7 or 14 days after any dose among Rotarix recipients

57. A 57 IS cases reported to occur within 31 days after vaccination in all studies 10 Rotarix, 7 Placebo: RR=1.3 (95% CI 0.44 – 4.06) IS cases reported to occur any time after vaccination in all placebo controlled studies 18 Rotarix*, 22 Placebo: RR=0.72 (95% CI 0.36 – 1.41) Intussusception: All BLA studies *one additional case in study 060, not included in total as not placebo controlled

58. A 58 Integrated Summary of Safety (ISS) Based on all RD, placebo-controlled clinical trials in the BLA “Core” ISS compares Rotarix licensure potency to placebo 8 clinical trials: US, CA, Latin America, Asia, EU Solicited AEs day 0-7 post each vaccination –fever, fussiness/irritability, loss of appetite, vomiting, diarrhea, cough/runny nose Unsolicited AEs day 0-30 post each vaccination SAEs (including IS and fatalities) day 0-30 post each vaccination Imbalance defined as exact 95% CI for RR across studies excludes “1”

59. A 59 Core ISS: Most Frequently Reported SAEs Within 31 Days of Any Dose Adverse Event (MedDRA PT) Rotarix N=36,755 Placebo N=34,454 Relative Risk (95% CI) n (%) At least one SAE627 (1.71%)659 (1.91%)0.90 (0.81 – 1.01) Bronchiolitis127 (0.35%)137 (0.40%)0.88 (0.68 – 1.13) Pneumonia122 (0.33%)122 (0.35%)0.99 (0.76 – 1.28) Gastroenteritis72 (0.20%)111 (0.32%)0.62 (0.45 – 0.84) § § 95% CI for RR excludes 1 Relative Risk adjusted for study effect

60. A 60 Core ISS: SAEs with Imbalance Within 31 Days of Any Dose Adverse Event (MedDRA PT) Rotarix N=36,755 Placebo N=34,454 Relative Risk (95% CI) n (%) Gastroenteritis72 (0.20%)111 (0.32%)0.62 (0.45 – 0.84) § Diarrhea9 (0.02%)25 (0.07%)0.35 (0.14 – 0.78) § Dehydration9 (0.02%)21 (0.06%)0.43 (0.17 – 0.97) § § 95% CI for RR excludes 1 Relative Risk adjusted for study effect

61. A 61 Events of Clinical Interest Clinical EventReason for Interest Hematochezia Reports with RotaShield RotaTeq US Package Insert Kawasaki disease RotaTeq US Package Insert Convulsion RotaTeq US Package Insert Imbalance in single study (Rota-023) Pneumonia deaths Imbalance in single study (Rota-023) Pneumonia Imbalance in single study (Rota-036) Bronchitis Imbalance in single study (Rota-006)

62. A 62 Events of Clinical Interest: Core ISS Within 31 Days of Any Dose Adverse Event (MedDRA PT) Rotarix N=36,755 Placebo N=34,454 Relative Risk (95% CI) n (%) Hematochezia SAE00- Kawasaki disease00- Convulsion SAE9 (0.02%)7 (0.02%)1.18 (0.39 – 3.76) Pneumonia deaths7 (0.02%)5 (0.01%)1.39 (0.38 – 5.57) Pneumonia SAE122 (0.33%)122 (0.35%)0.99 (0.76 – 1.28) Bronchitis SAE21 (0.06%)24 (0.07%)0.85 (0.45 – 1. 59) Relative Risk adjusted for study effect

63. A 63 Kawasaki Disease 27 reports in clinical trials –22 in one large (N=10,700) ongoing phase III DB, 1:1 study in Asia 13 following Rotarix, 9 following placebo; RR = 1.4 (CI 0.6 - 3.4 ) No temporal evidence of an association: –2 reports in Rotarix and 1 report in placebo within 31 days after vaccination (none in the 11 studies in support of licensure in the BLA) –Median time to onset: 152 days after last dose of study vaccine (range: 3 to 578 days) No fatal cases No cases considered to be related to study vaccine

64. A 64 Safety Analysis Study 023 Multiple comparisons made between groups for exploratory purposes to evaluate potential imbalances within –24 different MedDRA system organ classes (SOCs) –265 different MedDRA preferred terms (PT’s) Asymptotic p-values used as an aid to highlight potential imbalances worth further clinical assessment –no statistical adjustment for multiple testing was made Findings have to be interpreted based on overall clinical assessment

65. A 65 SAE imbalances in favor of Rotarix – study 023 within safety surveillance period Diarrhea: Rotarix 15 (0.05%) placebo 37 (0.12%) p=0.002* Vomiting: Rotarix 3 (0.01%) placebo 12 (0.04%) p=0.020* * Exploratory analysis, not corrected for multiplicity Gastroenteritis: Rotarix 132 (0.42%) placebo 226 (0.72%) p=0.000* Dehydration: Rotarix 20 (0.06%) placebo 46 (0.15%) p=0.001*

66. A 66 SAE imbalances in favor of placebo – study 023 within safety surveillance period Urticaria: Rotarix 5 (0.02%) placebo 0 p=0.026* Convulsion: Rotarix 16 (0.05%) placebo 6 (0.02%) p=0.034* * Exploratory analysis, not corrected for multiplicity Pneumonia death: Rotarix 14 (0.04%) placebo 5 (0.02%) p=0.040*

67. A 67 Convulsion SAEs Study Rota-023 PT “convulsion” –Within whole surveillance period Rotarix 16 (0.05%), placebo 6 (0.02%); p=0.034* –Within 31 days post-vaccination Rotarix 7 (0.02%), placebo 5 (0.02%); p=0.568* Pooled convulsion-related PTs + –Within whole surveillance period Rotarix 20 (0.06%), placebo 12 (0.04%); p=0.219* –Within 31 days post-vaccination Rotarix 7 (0.02%), placebo 9 (0.03%); p=0.798* * exploratory analysis, not corrected for multiplicity + convulsion-related PT = convulsion, epilepsy, grand mal convulsion, status epilepticus, tonic convulsion

68. A 68 Convulsion SAEs – Overall Assessment Many subjects in Rotarix and placebo groups had pre-existing or concurrent medical conditions* that could have accounted for the convulsion No temporal association within 31 days after vaccination No imbalance with pooled convulsion-related SAEs No imbalance in phase III study Rota-036 No imbalance in core ISS Currently available data do not suggest a causal relationship between Rotarix and convulsion * neonatal hypoxia, family history of epilepsy, previous convulsion episodes, hypocalcemia and hyponatremia,, chronic malnutrition, seizure after metoclopramide

69. A 69 Pneumonia Deaths Study Rota-023: Not designed to study the effect of vaccination on fatalities. Study not controlled for factors associated with higher post- neonatal fatality rate –prematurity, age of mother, exposure to smoking, nutritional deficiencies Within whole surveillance period: pooled pneumonia-related * Rotarix 16 (0.05%), placebo 6 (0.02%); p=0.054 + * pneumonia-related PT = pneumonia, bronchopneumonia, pneumonia CMV + exploratory analysis, exact p-value, not corrected for multiplicity

70. A 70 Clinical Case Review Study Rota-023: Pneumonia-related deaths in Rotarix Group There were no unique or distinguishing clinical characteristics, or common CXR findings Symptom onset of 16 cases –7 between day 0-30; no temporal clustering –9 beyond day 30 (range day 31-199) 5 of the 16 had pre-existing conditions, risk factors and/or other alternative diagnoses* * clinical diagnosis pertussis; CMV in lung tissue on autopsy, mother HIV positive; clinical diagnosis pneumonia, exposed to HIV positive mother with bacterial meningitis; Down syndrome and congenital heart disease; Ependymoma and CSF fistula with nosocomial adenovirus pneumonia

71. A 71 Pneumonia-related* Hospitalizations Whole Surveillance Period – Study Rota-023 Rotarix (N=29616-31673) Placebo (N=29465-31552) TimingnPer 10000n Overall follow-up period27787.4627386.52 Post-dose 1 Any time18558.4117756.10 Within 31 days9931.269429.79 Post-dose 2 Any time9231.069632.58 Within 31 days4916.555619.01 * all pneumonia-containing PTs within SOC infections and infestations

72. A 72 IDMC Assessment of Safety Analysis, Nov 2004 General Rotarix vaccinees lower rates of overall hospitalization, and SAEs with diarrhea and dehydration, than placebo recipients. Hospitalization rates for respiratory diseases and for all infectious causes (excluding diarrheal disease) comparable in the two groups Fatalities Finding could be due to chance; multiple analyses of safety data could have resulted in spurious finding No known biological explanation for this observation; natural rotavirus infection not an established cause of mortality from non-diarrheal causes Current trials should be continued Further post-licensure evaluation warranted

73. A 73 Causality assessment of pneumonia- related deaths in Study 023 Consistency –finding isolated to 1 study –not confirmed by analysis of pneumonia SAEs in Study 023 Strength of association –of marginal statistical significance –exploratory analyses, not adjusted for multiplicity Specificity –lower RTIs common in study population –multiple etiologies/pathogens Temporal relationship –only 7/16 (44%) occurred 0-30 days after immunization –no temporal clustering within 0-30 days Biological plausibility –no established link between RV and lower RTIs

74. A 74 Pneumonia Deaths - Overall Assessment Currently available data do not suggest a causal relationship between Rotarix and pneumonia deaths Further assessment planned in PM setting

75. A 75 Core ISS: Reactogenicity Solicited Symptoms: Any Intensity within 8 days post-vaccination Percent of infants RotarixPlaceboDose 1 Dose 2  38 o C Runny NoseFussiness

76. A 76 Core ISS: Reactogenicity Solicited Symptoms: Grade 3 Intensity within 8 days post-vaccination Percent of infants  39.5 o C RotarixPlaceboDose 1 Dose 2 Runny Nose Fussiness Grade 3 cough/runny nose: prevented normal activity Grade 3 diarrhea: > 6 looser than normal stools per day Grade 3 vomiting: >3 episodes per day Grade 3 fussiness/irritability: crying unable to be comforted/prevented normal activity Grade 3 loss of appetite: not eating at all

77. A 77 /Fussiness Reactogenicity - Study 036: Europe Solicited Symptoms within 8 Days of Any Dose Coadministered: DTaP-HepB-IPV/Hib (all); PCV7 (subset), MenC (subset)

78. A 78 /Fussiness Reactogenicity - Study 005: US & Canada Solicited Symptoms within 15 Days of Any Dose Coadministered: DTaP, IPV, Hib, PCV7, (HepB) Rotarix* *≥10 6 CCID 50 group

79. A 79 Summary of Safety Rotarix is well tolerated No increased risk of intussusception among infants vaccinated with Rotarix compared to placebo Fewer SAEs associated with GE disease in Rotarix group compared to placebo PM studies planned to monitor acute lower respiratory tract infection hospitalizations and convulsions No increased reactogenicity following co-administration with routine pediatric vaccines The overall safety profile of Rotarix is similar to placebo

80. A 80 GlaxoSmithKline Presentation Clare Kahn, Ph.D Vice President North America, Regulatory Affairs Introduction Leonard Friedland, M.D. Executive Director - Clinical R&D North America, Vaccines Clinical Development Plan Clinical Trial Results Thomas Verstraeten, M.D. Director Head, Worldwide Safety, Vaccines Post-marketing Safety Data Pharmacovigilance Plan Clare Kahn, Ph.DConclusion

81. A 81 Post-Marketing Experience and Pharmacovigilance Plan: Overview Summary of spontaneous reports up to 11 July 2007 –Intussusception Global Pharmacovigilance Plan for Rotarix: –Intussusception –Effectiveness/impact –Other topics of interest

82. A 82 PM Experience as of July 2007 Doses Distributed: 12.3 million –Latin America: 11.5 (8.7 million to Brazil) –Europe: 0.4 million –Rest of the World: 0.4 million 802 Adverse Event reports –reporting rate 6.5 /100,000 doses distributed* –Including 323 Serious Adverse Event reports Distribution of the reports by dose –Dose 1 = 43%Dose 2 = 22% Unknown dose = 35% * RotaTeq: 20.2/100,000 doses distributed by June 2007 (Dr Haber, ACIP June 07)

83. A 83 PM Experience: Most Frequently Reported Events Number of Reports Reported Frequency per 100 000 doses Diarrhea2522.05 Vomiting1741.41 Intussusception1331.08

84. A 84 PM Experience: Fatal Events One fatality in Venezuela related to ITP with symptoms within hours after vaccination One fatality in Mexico related to a rotavirus Infection 9 months after vaccination (not vaccinated according to pediatrician) One fatality in Kenya related to a Gastroenteritis caused by adenovirus, starting same day as vaccination 4 unconfirmed reports of fatalities related to IS in Brazil, 3 with unknown time to onset, 1 with symptoms 6 days after vaccination

85. A 85 PM Experience: Intussusception Male48 (62%) Median TTO (range)15 days (0-244) Median age (range)5 months (2-13) Fatal0 Dose number: 1 2 Unknown 36 (45%) 25 (32%) 18 (23%) * Confirmed refers to the manufacturer’s assessment of the diagnostic certainty according to Brighton Collaboration criteria (Bines et al, Vaccine 2004), not to the relationship to vaccination RotaTeq: 1.9/100,000 doses distributed by June 2007 (P. Haber, ACIP June 07) 79 confirmed cases (out of 131 total spontaneous reports up to the DLP of July 2007) Reporting rate = 0.64/100,000 doses distributed* Characteristics of the 79 confirmed cases:

86. A 86 PM Experience: Intussusception Observed Within 30 days Expected Within 30 days Observed Within 7 days Expected Within 7 days global EU Observed versus expected analyses:

87. A 87 PM Experience: Intussusception Observed Within 30 days Expected Within 30 days Observed Within 7 days Expected Within 7 days global5849640116 EU Observed versus expected analyses:

88. A 88 PM Experience: Intussusception Observed Within 30 days Expected Within 30 days Observed Within 7 days Expected Within 7 days global5849640116 EU81945 Observed versus expected analyses:

89. A 89 PM Experience: Intussusception Observed versus expected analyses: Sensitivity analysis: 75% of cases reported and 75% of doses distributed Observed within 30 days Expected Within 30 days Observed Within 7 days Expected within 7 days global773865390 EU11146 *4 * ratio is 1.7 (95% confidence intervals : 0.5 – 4.2)

90. A 90 PM experience: Events of Interest Clinical Event Number of cases reported Reporting rate per 100,000 doses distributed Hematochezia° 570.48 Kawasaki disease 0NA Convulsion 50.04 Pneumonia deaths 0NA Pneumonia 40.03 Bronchitis 5*0.04 ° excluding IS and allergic colitis, including bloody diarrhea, * 3 cases of bronchiolitis, 2 cases of bronchospasm

91. A 91 Post-licensure Pharmacovigilance Plans Clinical Trials Post-licensure observational studies Enhanced pharmacovigilance

92. A 92 Post-licensure Clinical Studies Dominican RepublicTransmission of HRV between twins South Africa Safety and immunogenicity of HRV in HIV positive infants Europe Safety and immunogenicity of HRV in preterm infants

93. A 93 Post-licensure Observational Studies: US cohort Outcomes of interest: Intussusception, Kawasaki disease, hospitalizations for acute lower respiratory tract infections and convulsions. Powered to detect a RR of IS of 2.5 or greater with 80% probability Design and study setting under discussion with FDA and CDC All deaths will be reported to FDA and CDC

94. A 94 Post-licensure Observational Studies: IS in Mexico Study setting: Instituto Mexicano de la Seguridad Social 40 million individuals  birth cohort of 575,000 UMV in IMSS system started 2006 Will have > 80% power to exclude a RI of IS under 1 year of age of 2.6 within 30 days following dose 1 of Rotarix (i.e. upper limit of 95% CI of RI < 2.6) Additional outcomes of interest: pneumonia related deaths and hospitalizations. Study start: December 2007, duration: 2-4 years

95. A 95 Additional Post-licensure Observational Studies Intussusception: Surveillance in Germany and the UK Vaccine effectiveness: case-control studies in Panama, Belgium and Singapore Vaccine strain surveillance: Europe rotavirus surveillance network

96. A 96 Enhanced Pharmacovigilance Worldwide network for spontaneous reporting Enhanced follow-up of all intussusception cases Enhanced reporting to the FDA and CDC Systematic observed/expected analyses

97. A 97 Rotarix Post Marketing Experience and Pharmacovigilance Plans: Conclusions Currently available information from spontaneous reporting system does not suggest any increased risk for IS following Rotarix, nor any new safety signal related to other events A comprehensive pharmacovigilance plan has been put in place to further monitor the safety and effectiveness/impact of Rotarix

98. A 98 GlaxoSmithKline Presentation Clare Kahn, Ph.D Vice President North America, Regulatory Affairs Introduction Leonard Friedland, M.D. Executive Director - Clinical R&D North America, Vaccines Clinical Development Plan Clinical Trial Results Thomas Verstraeten, M.D. Director Head, Worldwide Safety, Vaccines Post-marketing Safety Data Pharmacovigilance Plan Clare Kahn, Ph.D Conclusion

99. A 99 Concluding Remarks: Efficacy Rotarix, an attenuated human rotavirus vaccine, administered as a 2-dose oral vaccine starting at 6 weeks of age induces protective immunity against RV GE: –Severe RV GE disease (96% EUR; 85% LA) –Any RV GE disease (87% EUR) –RV GE hospitalizations (100% EUR: 85% LA) –Medically attended RV GE (92% EUR)

100. A 100 Concluding Remarks: Efficacy RV GE caused by G1 and non-G1 serotypes (including G2, G3, G4 and G9) Severe GE disease regardless of etiology (75% EUR; 40% LA) Efficacy evident from post dose 1 Persistent through at least 2 years of life Rotarix can be concomitantly administered with US licensed pediatric vaccines

101. A 101 Concluding Remarks: Safety Rotarix is supported by extensive safety experience: Clinical trials in > 75,000 (> 40,000 Rotarix; > 34,000 placebo) Rotarix was well tolerated; no increased reactogenicity profile following coadministration with routine pediatric vaccines No signal of a safety concern wrt IS according to pre-specified criteria Active monitoring of AEs of special interest in PM Plans

102. A 102 Concluding Remarks: Safety Post Marketing Safety: Rotarix is licensed in > 100 countries (2004-present); > 12 MM doses distributed GSK is utilizing the WW availability of Rotarix to study all outcomes of interest: No pattern or frequency of reporting to suggest any increased risk of IS No new safety signal related to any other events detected

103. A 103 Concluding Remarks: Post Marketing Plans Extensive Global PM Activities including clinical trials, observational studies and enhanced pharmacovigilance: IS and other potential safety outcomes Vaccine effectiveness Vaccine transmission Use in immunocompromised and preterm infants

104. A 104 Rotarix Risk/Benefit Rotavirus is a significant cause of childhood morbidity in the US –600,000 clinic or emergency room visits/year –55,000 to 70,000 hospitalizations/year Vaccination represents an important preventative strategy to control morbidity and mortality caused by RV GE Rotarix confers significant protection against RV GE caused by G1 and non-G1 serotypes, with an acceptable safety/reactogenicity profile comparable to placebo Risk-benefit ratio for Rotarix is overall favorable for the intended population

105. A 105 Vaccines and Related Biological Products Advisory Committee February 20, 2008 GlaxoSmithKline ROTARIX ROTARIX ®