1. Monitoring Safety of Rotavirus Vaccines David Martin, MD, MPH CBER Office of Biostatistics and Epidemiology, FDA For presentation at the Vaccines and Related Biological Products Advisory Committee May 7, 2010

2. Framework for Vaccine Safety Monitoring Signal* Generation –Clinical trials –Vaccine Adverse Event Reporting System (VAERS) Signal Strengthening and Confirmatory Studies –Clinical trials for pre-specified outcomes (e.g. intussusception) –Vaccine Safety Datalink (VSD) –Controlled Observational Studies * “ A concern about an excess of adverse events compared to what would be expected to be associated with a product’s use.” Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, USDHHS, FDA, CDER, CBER, March 2005

3. Strengths of the Vaccine Safety Monitoring System Clinical trials –Random allocation of treatment –Comparator group VAERS –Rare adverse events can be detected through this national system for passive surveillance of adverse events after vaccination –Heterogeneous population VSD Rapid Cycle Analysis –Near real time monitoring for multiple pre-specified adverse events Controlled observational studies –Large populations with “real world” product use in which inferences can be made about vaccine-adverse event associations

4. Limitations of the Vaccine Safety Monitoring System Clinical trials –Not powered for rare adverse events VAERS –Causal associations cannot usually be determined VSD Rapid Cycle Analysis –Hypothesis generating only Controlled observational studies –Small increased risks of rare adverse events may result from systematic error (bias) rather than a true causal association Long latency effects are difficult to detect

5. RotaTeq ® Licensed in the United States in February 2006 Contraindications –Hypersensitivity to any component of the vaccine –History of Severe Combined Immunodeficiency (SCID) Labeled adverse events from passive surveillance –Intussusception (including death) –Hematochezia –Gastroenteritis with vaccine viral shedding in infants with SCID –Urticaria –Kawasaki disease

6. RotaTeq Clinical Trials N= 71,725 infants in three clinical trials submitted to the FDA to support product safety –36,165 received RotaTeq and 35,560 received a placebo Serious adverse events (SAEs) within the 42-day period after any dose –Overall rates: RotaTeq 2.4% and placebo 2.6% –Deaths: RotaTeq 25 (0.07%), placebo 27 (0.08%) Most common cause of death: Sudden Infant Death Syndrome –RotaTeq 8 (0.02%), placebo 9 (0.03%) –Kawasaki disease (KD): RotaTeq 5 and Placebo 1 RR=4.9, (95% CI: 0.6, 239.1) –Intussusception: N=69,625 Confirmed within 42 days of any dose: RR 1.6, (95% CI: 0.4, 6.4) Confirmed within 1 year of dose #1: RR 0.9, (95% CI: 0.4, 1.9)

7. Post marketing safety activities for RotaTeq Exposure (doses distributed) through March 2010 –United States: 30 million –Global: 37 million Post marketing studies –Completed controlled observational study of ~85,000 RotaTeq recipients sponsored by Merck No statistically significant association with confirmed intussusception or Kawasaki’s Disease* –VSD > 207,000 doses administered between May 2006 and May 2008 No elevation in risk for intussusception, seizures, meningitis/encephalitis, myocarditis, gram (-) sepsis, gastrointestinal bleeding, or Kawasaki disease † VAERS surveillance –Report of secondary transmission ‡ –SCID uncovered by rotavirus vaccine administration New contraindication added to label in December 2009 HRSA advisory committee recommendation for addition of SCID to neonatal screening –No other new safety signals have emerged since licensure *Mast TC, et al US Post-licensure active surveillance safety study of RotaTeq™, Oral Pentavalent Rotavirus Vaccine (RV5). 47th Annual Meeting of the Infectious Disease Society of America, Philadelphia, PA, 10/29/09-11/01/09. Presentation Number: 1161 †Belongia et al. The Pediatric Infectious Disease Journal 2010;29(1):1-5. ‡Payne DC et al., Sibling transmission of vaccine-derived rotavirus (RotaTeq) associated with rotavirus gastroenteritis. Pediatrics. 2010 Feb;125(2):e438-41. Epub 2010 Jan 25.

8. Rotarix ® Licensed in the United States in April 2008 Contraindications –Malformation of the gastrointestinal tract that would predispose the infant to intussusception –Hypersensitivity to any component of the vaccine –History of Severe Combined Immunodeficiency (SCID) Labeled adverse events from passive surveillance –Intussusception (including death) –Hematochezia –Gastroenteritis with vaccine viral shedding in infants with SCID –Idiopathic thrombocytopenic purpura –Kawasaki disease –Maladministration

9. Rotarix Clinical Trials N=71,209 infants in eight clinical trials submitted to the FDA to support product safety –36,755 received Rotarix and 34,454 received a placebo Serious adverse events (SAEs) within the 31-day period following vaccination –Overall rates: Rotarix 1.7% and placebo 1.9% –Deaths: Rotarix 68 (0.19%), placebo 50 (0.15%) Most common cause of death: pneumonia –Rotarix 19 (0.05%), placebo 10 (0.03%) –RR=1.74, (95% CI: 0.76-4.23) –Kawasaki disease (KD): Rotarix 17 and Placebo 9 RR=1.71, (95% CI: 0.71-4.38) –Intussusception: N = 63,225 Confirmed within 31 days of any dose: RR 0.85, (95% CI: 0.30, 2.42) Confirmed within 100 days of dose #1: RR 0.56, (95% CI: 0.25, 1.24)

10. Post marketing safety activities for Rotarix Exposure (doses distributed) through March 2010 –United States: 2.5 million –Global: 68 million Post marketing studies –Two ongoing controlled observational studies sponsored by GSK Outcomes include intussusception, Kawasaki Disease, convulsions, lower respiratory tract infections, and deaths –VSD * rapid cycle analysis with < 5,000 doses administered Outcomes: intussusception, seizures, meningitis/encephalitis, myocarditis, Gram(-) sepsis, gastrointestinal bleeding, Kawasaki disease, & hospitalized pneumonia Analysis of all-cause hospitalization or ED visits (compared with RotaTeq) is underway. VAERS surveillance –SCID uncovered by rotavirus vaccine administration New contraindication added to label in February 2010 HRSA advisory committee recommendation for addition to neonatal screening –No other new safety signals have emerged since licensure –*The VSD Annual meeting, April 7-9, 2010, Seattle, WA

11. Summary -Components of the vaccine safety monitoring system are complementary -Safety signals for Rotarix and RotaTeq are currently being evaluated in controlled observational studies -Two post licensure safety signals: -Increased risk posed by rotavirus vaccines to infants with SCID -Case report of secondary transmission with RotaTeq -Post licensure safety assessment has generated no other safety signals, and multifaceted post marketing monitoring continues

12. Acknowledgements Robert Ball, MD, MPH, ScM Rick Wilson, MD, MS, JD Wei Hua, MD, PhD, MS, MHS Michael Nguyen, MD David Menschik, MD, MPH Rose Tiernan, MD, MPH Jerome Tokars, MD, MPH