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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

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 products use. Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, USDHHS, FDA, CDER, CBER, March 2005

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

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

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

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)

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 Kawasakis 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.

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

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)

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

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

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