1. RotaTeq ® Post Marketing Surveillance and Effectiveness Data Dr Swashraya Shah MSD India 24 Dec 2011

2. RotaTeq ® Post licensure Safety Data: −US −Australia −Indian Data of spontaneous reports till date RotaTeq ® Post licensure Effectiveness Data: −US −Australia −Nicaragua Contents

3. RotaTeq: Post-Marketing Surveillance US Vaccine Safety Datalink (VSD) and Vaccine Adverse Events Report: Feb 06 – Sep 07 Vaccine Safety Datalink: May 06 – May 08 Summary report of meeting of ACIP (Data from 2006- 2010) Australia (July 07 – Dec 08)

4. Large federally funded collaboration Investigates Vaccine AEs at 8 managed care organizations Sites in VSD contribute electronic Data on immunizations, ICD-9 diagnosis codes (inpatient, ED, OPD) and demographics It includes data for about: 8.8 million people annually Annual birth cohort of about 95000. Vaccine AE Reporting System (VAERS) Vaccine Safety Datalink (VSD) National passive surveillance system Managed jointly by FDA and CDC Receives reports of AEs after vaccination from various sources including HCPs, state and local immunization programs, vaccine recipients and manufacturers 1. Haber et al. Postlicensure Monitoring of Intussusception After RotaTeq Vaccination in the United States, February 1, 2006, to September 25, 2007. Pediatrics 2008;121;1206-1212, 2. Belongia E A et al. Real-Time Surveillance to Assess Risk of Intussusception and Other Adverse Events After Pentavalent, Bovine-Derived Rotavirus Vaccine. Pediatr Infect Dis J 2010;29: 1–5)

5. US Feb 06 to Sep 07 – VAERS data 1 Assessed Post RotaTeq ® IS reports using data from VSD and VAERS. Observed versus expected Rate Ratios determined using vaccine dose distribution data and VSD background IS rates. VAERS : Post RotaTeq ® : 1901 AE reports, 160 (8.4%) confirmed IS reports. 47 (29% of total IS) within 1-21 days, 27 (17%) within 1-7 days. (For Rotashield >60% IS cases were within 1-7 days) Expected cases were calculated from the VSD background rate of IS: Observed rate was not elevated above age adjusted background rate of IS within 1-21 day or within 1-7 day. Observed/expected RRs were similar when stratified according to dose or age group. Haber et al. Postlicensure Monitoring of Intussusception After RotaTeq Vaccination in the United States, February 1, 2006, to September 25, 2007. Pediatrics 2008;121;1206-1212 ObservedExpected Within 1-21 d47151 Within 7 d2750

6. US Feb 06 to Sep 07 – VSD data 1 Between May 21, 2006 to Sep 25, 2007, total of 111521 doses of RotaTeq® administered. IS Cases: Data from VSD and VAERS do not indicated that RotaTeq is associated with IS. Observed/expected RRs were similar when stratified according to dose or age group Haber et al. Postlicensure Monitoring of Intussusception After RotaTeq Vaccination in the United States, February 1, 2006, to September 25, 2007. Pediatrics 2008;121;1206-1212 RotaTeq® recipients Non RotaTeq® recipients IS cases3/1115219 / 186722 Relative Risk: 0.84 (95% CI: 0.14 – 3.92)

7. US Surveillance using prospective cohort design May 2006 – May 2008 This study used data from VSD. Participating VSD sites generated weekly data files with immunization data, inpatient and outpatient diagnosis codes (ICD-9 codes) Included the RotaTeq ® Exposed population : children from 4- 48 weeks who received RotaTeq ® between May 06 and May 08. 2,07,621 doses administered (42% were first doses), Largest post licensure study of RotaTeq vaccine safety. Observed frequencies of AEs compared with prelicensure (Background) incidence rate. Cases of IS identified based upon electronic diagnosis codes. IS case Confirmed by medical record review. Belongia E A et al. Real-Time Surveillance to Assess Risk of Intussusception and Other Adverse Events After Pentavalent, Bovine-Derived Rotavirus Vaccine. Pediatr Infect Dis J 2010;29: 1–5)

8. Results:US Surveillance (May 06 – May 08) Total 5 children had ICD - 9 codes for IS. 2 were confirmed of IS by medical record review. Observed incidence (Computerized diagnosis code for IS: 5 and cases expected based on historical rates: 6.75) Only 2 validated cases of IS occurred after more than 2,00,000 doses and neither occurred after first dose. Both cases were diagnosed more than 14 days after vaccination. There was no statistically significant elevated risk following first dose, second dose or third dose of RotaTeq ® By the end of surveillance period, there was no evidence that RotaTeq ® was associated with increased risk for any other prespecified adverse events like meningitis/encephalitis, seizures, myocarditis or gram negative sepsis. Belongia E A et al. Real-Time Surveillance to Assess Risk of Intussusception and Other Adverse Events After Pentavalent, Bovine-Derived Rotavirus Vaccine. Pediatr Infect Dis J 2010;29: 1–5)

9. Updated Data from CDC (Discussed in Oct 27, 2010 Meeting of ACIP) A large post-marketing study of IS following RotaTeq ® which includes over 850,000 total doses. Surveillance conducted for IS using two windows: 30-day and 7-day. At 8 VSD Sites Cohort: –Exposed population : children who received any dose of RotaTeq ® with or without other vaccines from age 4 to 34 weeks. –Concurrent comparison group : received any vaccine besides RotaTeq ® from age 4 to 34 weeks. Data from May 2006 to May 2010. Probably the largest active surveillance study of IS and RotaTeq ® in the US. From Summary Report of ACIP meeting in Oct 2010 accessed on 23 Dec 2011 at http://www.cdc.gov/vaccines/recs/acip/downloads/min-archive/min-oct10.pdf

10. Updated Data from CDC (Discussed in Oct 27, 2010 Meeting of ACIP) IS Cases −31 cases of IS out of 850,000 RotaTeq ® doses. −19 cases In the comparison group, out of 405,000 comparison visits. −Within 7 days: Only 2 cases after first dose (first dose : 3,32,000) While in comparator group there were 4 cases. Summary: –The US post marketing experience in VSD provides no evidence that RotaTeq ® is associated with an increased risk for IS in either the 30-day or 7-day window. From Summary Report of ACIP meeting in Oct 2010 accessed on 23 Dec 2011 at http://www.cdc.gov/vaccines/recs/acip/downloads/min-archive/min-oct10.pdf

11. PMS NIP Australia Safety of rotavirus vaccines, with respect to a possible association with intussusception, was assessed in four states using two concurrent active surveillance mechanisms During the first 18 months following the introduction of rotavirus vaccines into the NIP in Australia Actively sought all cases of confirmed intussusception in infants <24 months of age from 1st July 2007 to 31st December 2008 and determined their rotavirus vaccine status. Buttery J P et al. Intussusception following rotavirus vaccine administration: Post-marketing surveillance in the National Immunization Program in Australia. Vaccine 29 (2011) 3061–3066 The numberof doses administered of either RotaTeq or Rotarix vaccine during the period 1st July 2007 and 30th December 2008. – Light grey – states using Rotarix in the NIP.(only W.Australia & NSW included in analyses) − Dark grey – states using RotaTeq in the National Immunization Program.(only Victoria/S Australia included for analyses).

12. Buttery J P et al. Intussusception following rotavirus vaccine administration: Post-marketing surveillance in the National Immunization Program in Australia. Vaccine 29 (2011) 3061–3066 Within 7 days of receipt of a rotavirus vaccine: Total 10 cases - 5 Rotarix®, - 5 RotaTeq® and 23 occurred within 21 days: 13 Rotarix® and 10 RotaTeq®; IS cases identified in Australian study

13. Results of Australian study Relative risk of IS in infants 1 to < 9 months of age: −1–7 days: ►RotaTeq® RR = 1.15, (95CI: 0.37,2.68) ►Rotarix® RR = 1.58, (95% CI: 0.51,3.69) −1–21 days: ►RotaTeq® RR = 0.77 (95% CI 0.37,1.41) ►Rotarix®RR = 1.37, (95% CI 0.73, 2.34) Is there more risk with particular vaccine: It is not possible to make any comparison of the increased risk following these two vaccinations due the small number of intussusception cases which limits the precision of these estimates. Buttery J P et al. Intussusception following rotavirus vaccine administration: Post-marketing surveillance in the National Immunization Program in Australia. Vaccine 29 (2011) 3061–3066

14. India Spontaneous reports of AEs after RotaTeq ® vaccination Date of receipt of AE report Adverse Event TermSuspect Drug Reporters Causality 24-May-11Diarrhea with blood streaksRotaTeq ® Yes 24-May-11 Abnormal movement of limbs, Voice chocking, Cyanosis, Screaming, Crying RotaTeq ® Yes 16-Aug-11IntussusceptionsRotaTeq ® No 27-Sep-11IntussusceptionsRotaTeq ® No No report of any SAE after receipt of RotaTeq®

15. Different Methods / systems that evaluated Post licensure effectiveness of RotaTeq ®  NREVSS: National Respiratory and Enteric Virus Surveillance System: Is a laboratory-based system that monitors temporal and geographic patterns associated with the detection of respiratory and enteric viruses including rotavirus  New Vaccines Surveillance Network: It evaluates the impact of new vaccines and vaccine policies through a network of 7 sites in the U.S. Conducts population-based inpatient and enhanced outpatient surveillance for vaccine-preventable disease outcomes, applied epidemiologic and health service research, and investigator-initiated studies to achieve the goals of the network.  Hospital Discharge Data from different states and Hospitals

16. Rotavirus Test Results from NREVSS* Includes 2009-2010 season Tate et al Pediatrics 2009; Tate et al PIDJ Jan 2011 NREVSS=National Respiratory and Enteric Viruses Surveillance System Before RotaTeq® Introduction ( 2000 – 2006 Median ) After RotaTeq® Introduction (2007 – 2008 Season) Decreased seasonal peak & delayed occurrence

17. New Vaccine Surveillance Network (2006-2010):Number of Acute Gastroenteritis (AGE) and Rotavirus-confirmed Hospitalizations, Age <3 Yrs Payne D et al PAS, 2009 and unpublished data; Presented by Cortese M. ACIP June 2010 51 % RV+ 52 % RV+ 6 % RV+ 4 % RV+ 26 % RV+ 211 107 101 194 147 9 44 4 168 101 Number of cases 0 50 100 150 200 250 20062007200820092010 Total AGE Rotavirus + 52% RV+ 51% RV+

18. Reduction in AGE Hospitalizations in US after RV Vaccine Introduction  Using 100% hospital discharge data from 18 states, accounting for 49% of the US population, authors calculated acute gastroenteritis hospitalization rates for children aged <5 years by rotavirus season during pre-RV5 rotavirus seasons from 2000 through 2006 with those during the post-RV5 2007 and 2008 seasons. 16% reduction 45% reduction in 2008 season Curns AT, et al. Reduction in Acute Gastroenteritis Hospitalizations among US Children After Introduction of Rotavirus Vaccine: Analysis of Hospital Discharge Data from 18 US States The Journal of Infectious Diseases 2010; 201(11):1617–1624

19. Reduction in AGE Hospitalizations in US after RV Vaccine Introduction Herd Immunity ? Source: Curns AT, et al. Reduction in Acute Gastroenteritis Hospitalizations among US Children After Introduction of Rotavirus Vaccine: Analysis of Hospital Discharge Data from 18 US States The Journal of Infectious Diseases 2010; 201(11):1617–1624 Substantial decreases in AGE Hosp rates noted among age groups that were too young or too old to be vaccinated with RV5.

20. At 2 year period post vaccine introduction (compared to 2 yrs prior) and in age group < 6 yrs: Admissions for RVGE to SA hospitals: reduced by 83% (955 vs 165) Admissions for ACGE to SA hospitals: reduced by 48% (4153 vs 2142) SOUTH AUSTRALIA HOSPITALIZATION DATA Age specific RVGE and ACGE Hospitalization rates per 100000 children: Pre and Post Rotavirus Vaccine Introduction RotaTeq® Introduced in South Australia NIP in July 2007 Clarke M. F. et al. Direct and indirect impact on rotavirus positive and all-cause gastroenteritis hospitalisations in South Australian children following the introduction of rotavirus vaccination. Vaccine 29 (2011) 4663– 4667

21.  2006: Merck-Nicaraguan Ministry of Health RotaTeq partnership implemented. Between 2006 and 2009, 1.3 million RV5 dosages supplied.  A matched case-control study for the effectiveness of RV5 was conducted (Controls were hospital/community controls). Nicaragua: Serotype Specific Effectiveness Data This 3-year demonstration project suggested a significant positive public health impact of RV5 on children at risk for RGE in Nicaragua, Nicaragua was the first GAVI-eligible country to introduce rotavirus vaccine. Mast T. et al. Case-control Study of the Effectiveness of Vaccination With Pentavalent Rotavirus Vaccine in NicaraguaThe Pediatric Infectious Disease Journal Volume 30, Number 11, November 2011

22. Projected Effectiveness of RotaTeq in 6 Asian Countries 1 Background In case it is not always feasible to conduct clinical trials in every country, results from previously conducted studies can help to predict disease reduction in other countries. This analysis used a previously validated mathematical efficacy projection model, which was developed to project the efficacy of a live attenuated rotavirus vaccine in India. The Model was validated by using data from a phase II clinical trial with known rotavirus serotype distribution. 2 1.Khoury et al. Projecting the effectiveness of RotaTeq® against rotavirus-related hospitalizations and deaths in six Asian countries. Human Vaccines 7:5, 506-510 2.Salinas et al.Evaluation of safety,immunogenecity & efficacy of an attenuated rotavirus vaccine,RIX-4414:a randomised placebo control trial in latin american infants.PIDJ 2005;24(9):807-16

23. Projected Effectiveness of RotaTeq® in 6 asian countries Khoury et al. Projecting the effectiveness of RotaTeq® against rotavirus-related hospitalizations and deaths in six Asian countries. Human Vaccines 7:5, 506-510;

24. Projected annual reduction in RGE related deaths Khoury et al. Projecting the effectiveness of RotaTeq® against rotavirus-related hospitalizations and deaths in six Asian countries. Human Vaccines 7:5, 506-510;

25. Indian RV Immunogenicity & Safety Study Serum Anti-rotavirus IgA Responses GMTs of serum anti-rotavirus IgA Time pointsNUnits95% CI Pre dose 11023.81(2.74, 5.29) Post dose 310279.95(55.23, 115.73) % of subjects with ≥3 fold rise = 82.4% (75, 90%) Bhave S. Presented PGHNNC Conference,PGI Chandigarh Oct 2010

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