Safety of Pentacel

1. Safety of Pentacel Karen Farizo, M.D. CBER VRBPAC January 25, 2007

2. Overview of Presentation • Pivotal Clinical Studies • Supportive Post-Marketing Safety Data

3. Pivotal Studies Design Overall Safety Database Safety Monitoring Subject Disposition Subject Demographics

4. Study 494-01 *HCPDT = DTaP component of Pentacel (not U.S. licensed)

5. Study P3T06

6. Studies 494-03 and 5A9908

7. Pivotal Studies: Overall Pentacel Safety Database • A total of 5,980 subjects received at least one dose of Pentacel. • 4,198 subjects were from studies of four consecutive doses of Pentacel. • 1,782 subjects were from a study of the fourth dose only. • Overall, 17,021 doses of Pentacel were administered.

8. Pivotal Studies: Safety Monitoring Safety monitoring included: • Observation for 30 minutes at study site • Solicited local reactions and systemic events recorded daily on diary cards Days 0-7 • Serious adverse events monitored through 60 days (3 studies) or 180 days (Study P3T06) following the last dose of study vaccines • Periodic phone calls to inquire about adverse events (Day 2-4, 8, 30, 60 after each dose; also Day 180 post-Dose 4 in Study P3T06)

9. Pivotal Studies: Completion of Safety Follow-up n/a indicates not applicable *participation by randomized group for Studies 494-01 and P3T06 **60 days in Studies 494-01, 494-03 and 5A9908; 180 days in Study P3T06

10. Pivotal Studies: Demographics of Pentacel Safety Population n/a indicates not applicable. East Indian and Native Indian categories applied only to Study 5A9908.

11. Pivotal Studies Serious Adverse Events

12. Pivotal Studies: Percent of Subjects with a Serious Adverse Event within 30 Days following Doses 1-3 of Study Vaccines

13. Pivotal Studies: Percent of Subjects with a Serious Adverse Event within 30 Days following Dose 4 of Study Vaccines

14. Pivotal Studies: Most Frequent* Serious Adverse Events within 30 Days following Doses 1-3, Percent of Subjects *occurring in at least 4 subjects overall **not otherwise specified Control: 494-01 HCPDT, POLIOVAX, ActHIB; P3T06 DAPTACEL, IPOL, ActHIB

15. Pivotal Studies: Most Frequent* Serious Adverse Events within 30 Days following Dose 4, Percent of Subjects *occurring in at least 4 subjects overall **not otherwise specified Control: HCPDT + POLIOVAX + ActHIB (494-01); DAPTACEL + ActHIB (P3T06)

16. Pivotal Studies: Serious Adverse Events-- Deaths *Pentacel N=5980; DAPTACEL N=1454; HCPDT N=1032

17. Pivotal Studies: Serious Adverse Events-- Encephalopathy • Case 1– hypoxic ischemic encephalopathy • secondary to cardiac arrest following surgical repair of congenital heart defects 30 days after the first dose of Pentacel • Case 2– congenital encephalopathy • 7-week old infant developed head lag, loss of visual following, and tremors 8 days after the first dose of Pentacel • Several café au lait spots and subtle left hemiparesis on exam • MRI: Left frontal horn enlargement; left frontal atrophy

18. Pivotal Studies Seizures

19. Pivotal Studies: Use of Antipyretics within 3 Days Post-Vaccination • For Doses 1, 2, and 3, approximately ~40-50% of subjects reported use of an antipyretic within 3 days following Pentacel or Control vaccines. • For Dose 4, approximately 33% of subjects reported use of an antipyretic within 3 days following Pentacel or Control vaccines. • In the controlled studies, use of antipyretics was similar between vaccine groups.

20. Pivotal Studies: Seizures within 7 days Post-Vaccination, Number (%) of Subjects *Dose 4: DAPTACEL + ActHIB

21. Pivotal Studies: Febrile Seizures* within 7 Days Post-Vaccination *includes one possible seizure **Interval since last dose

22. Pivotal Studies: Afebrile Seizures within 7 Days Post-Vaccination *Interval since last dose

23. Pivotal Studies Hypotonic Hyporesponsive Episodes (HHEs)

24. Pivotal Studies: Hypotonic Hyporesponsive Episodes Definition An event of sudden onset: • occurring within 48 hours of vaccination • with duration ranging from 1 minute to 48 hours • involving: 1) limpness or hypotonia, 2) hyporesponsiveness, and 3) pallor or cyanosis or failure to observe or to recall skin coloration • without known cause (e.g., postictal) or urticaria

25. Pivotal Studies: Monitoring for Hypotonic Hyporesponsive Episodes • Studies 494-01, 494-03 and 5A9908: During post-vaccination phone calls, parents were asked about fainting or change in mental status. • Study P3T06: The diary card included specific questions pertaining to symptoms of HHEs.

26. Pivotal Studies: Hypotonic Hyporesponsive Episodes • There were no reports of HHE following: Pentacel (N = 5,980 subjects; 17,021 doses), HCPDT (N = 1,032 subjects; 3,616 doses), or DAPTACEL (N = 1,454 subjects; 4,648 doses). • One subject who received DAPTACEL reported an event that met the criteria for HHE except that it occurred 16 days post-vaccination. • Historically, in the Sweden II Efficacy Trial, the rate of HHE following HCPDT was 14/10,000 subjects or 0.47/1,000 doses. • Historically, in the Sweden I Efficacy Trial, there was one report of HHE among 2,587 subjects (7,703 doses) who received DAPTACEL.

27. Pivotal Studies Solicited Systemic and Local Adverse Events

28. Controlled Pivotal Studies: Routes of Temperature Measurement • Post-doses 1-3 of Pentacel or Control vaccines: • Parents were instructed to measure temperature rectally. • In both studies, ~45% of temperature measurements were axillary and ~50% were rectal. • Post-dose 4 of Pentacel or Control vaccines: • Parents were instructed to measure temperature rectally in one study and axillary in one study. • In both studies, ~60-70% of temperature measurements were axillary and ~25-30% were rectal. • Routes of temperature measurement were similar between the Pentacel and Control groups.

29. Study P3T06: Percent of Subjects with Fever within 3 Days Post-Vaccination *Control = DAPTACEL + IPOL + ActHIB for doses 1-3; DAPTACEL + ActHIB for dose 4

30. Study 494-01: Percent of Subjects with Fever within 3 Days Post-Vaccination *Control = HCPDT + POLIOVAX + ActHIB

31. Study 494-01: Percent of Subjects with Fever within 3 Days following Pentacel, by Route of Measurement N = number of subjects with a recorded temperature by specified route. At each dose, subjects who switched route during the 0-3 day period (~5%) are included in both categories.

32. Pivotal Studies: Medically Attended Fever • Not specifically solicited • Limitations in ability to capture medically attended fever from the database • Outpatient and Emergency Department cases may be missed if not considered a serious adverse event. • Cases in which the reported diagnosis did not include “fever” or “pyrexia” would be missed.

33. Study P3T06: Percent of Subjects with Selected Solicited Systemic Events within 3 Days Post-Vaccination *DAPTACEL + ActHIB for Dose 4 **Disabling, not interested in usual activity

34. Study P3T06: Percent of Subjects with Solicited Local Events within 3 Days Post-Vaccination *Cries when arm or leg is moved

35. Pentacel Post-Marketing Safety Experience

36. Pentacel Post-Marketing Safety Experience • Pentacel was first registered in Canada in 1997 and is currently licensed in 8 countries. • Since 1997-1998, Pentacel (at 2, 4, 6 and 18 months of age) and DTaP-IPV (Sanofi Pasteur Limited) (at 4-6 years of age) have been used exclusively in Canada to prevent pertussis, polio, and invasive Hib disease through early childhood. • Between May 1997 and April 2006, ~13.5 million doses of Pentacel were distributed outside the U.S., 92% of them in Canada. • Annual birth cohort in Canada in 2001-2002 was ~330,000.

37. Post-Marketing Spontaneous Reports of Adverse Events following Pentacel: 5/1/97-4/30/06 (~13.5 million doses distributed) • Sanofi Pasteur received 288 adverse event reports from health care professionals and health authorities, consumers, and literature sources. • The 5 most frequently reported events were: • Injection site reaction • Pyrexia • Crying • Injection site inflammation • Irritability

38. Post-Marketing Reports of SIDS and Other Deaths without Known Cause following Pentacel, 5/1/97-4/30/06 (~13.5 million doses distributed) -- indicates none reported

39. Post-Marketing Reports of Deaths with Identified Cause following Pentacel, 5/1/97-4/30/06 (~13.5 million doses distributed) n/a: data not available -- indicates none reported

40. Post-Marketing Cases of Encephalopathy following Pentacel, 5/1/97-4/30/06 (~13.5 million doses distributed) *Case coded as convulsions **Identified in a post-marketing survey conducted in Canada

41. Immunization Monitoring Program, Active (IMPACT) • IMPACT is a nationwide Canadian hospital-based program that conducts active surveillance for selected post-vaccination adverse events. • Participating hospitals • encompass ~90% of Canada’s tertiary care pediatric beds • serve an immediate population base of 3 million children (~1/2 of Canada’s population <15 yrs of age) • receive referrals from outside immediate catchment areas • All admissions for acute neurological illness are screened for recent immunization.

42. IMPACT: Encephalopathy, 1993-2002 • Encephalopathy or encephalitis within 7 days after pertussis vaccination identified at IMPACT centers: • 3 after whole-cell pertussis • 4 after acellular pertussis (3 Pentacel; 1 DTaP-IPV). • One case had direct evidence of HSV brain infection. Other cases had plausible alternative causes. • Considering estimated doses of pertussis vaccines administered to Canadian children (6 million whole-cell and 7 million acellular) and the size of the IMPACT catchment population, the estimated risk, if any, of encephalopathy or encephalitis attributable to vaccination: • <1 per 3 million doses of whole-cell pertussis vaccine • <1 per 3.5 million doses of acellular pertussis vaccine. (Moore DL et al. Pediatr Infect Dis J 2004;23:568-571)

43. IMPACT: Febrile Seizures and Hypotonic Hyporesponsive Episodes • Active surveillance for seizures and HHEs resulting in hospitalization and HHEs seen in emergency departments • Using Poisson regression models, average monthly admissions for seizures and reports of HHEs compared between 1995-1996 (whole cell DTP period) and 1998-2001 (Pentacel period) • Between the whole cell DTP period and the Pentacel period: • Hospitalizations for febrile seizures within 72 hours after pertussis vaccine decreased 79% • Reports of HHEs within 48 hours after pertussis vaccine decreased 60% • Hospitalizations for febrile seizures within 5-30 days after MMR did not change significantly. (LeSaux N, et al. Pediatrics. 2003;112:e348-353)

44. Summary– Pentacel Safety Database • The safety of Pentacel was evaluated in a total of 5,980 subjects from four pivotal clinical studies. • 4,198 subjects were from studies of four consecutive doses. • 1,782 subjects were from a study of the fourth dose only. • In two studies, Pentacel was compared to separately administered Control vaccines: HCPDT, POLIOVAX and ActHIB in one study, and DAPTACEL, IPOL and ActHIB in the other. • Supportive post-marketing safety data reflect distribution of ~13.5 million doses of Pentacel over a 9-year period, primarily in Canada.