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

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

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

4. 4 Study 494-01 Country /Dates Pentacel and Control Vaccines Schedule Concomitant Vaccines Pentacel N Control N U.S./ 12/1999- 4/2002 Pentacel: 2, 4, 6, 15 m HCPDT* + POLIOVAX + ActHIB: 2, 4, 6, 15 m Prevnar: 2, 4, 6 m (~80%) RECOMBIVAX HB: 2, 6 m 25061032 *HCPDT = DTaP component of Pentacel (not U.S. licensed)

5. 5 Study P3T06 Country /Dates Pentacel and Control Vaccines Schedule Concomitant Vaccines Pentacel N Control N U.S./ 5/2001- 1/2004 Pentacel: 2, 4, 6, 15-16 m DAPTACEL + ActHIB: 2, 4, 6, 15-16 m; IPOL: 2, 4, 6 m Prevnar: 2, 4, 6 m RECOMBIVAX HB: 2, 6 m 485Doses 1-3: 1454 Dose 4: 418

6. 6 Studies 494-03 and 5A9908 Study/ Country/ Dates Pentacel Schedule Concomitant Vaccines Pentacel N 494-03/ U.S./ 7/2000- 12/2002 2, 4, 6, 15-16 m Prevnar: 2, 4, 6 m RECOMBIVAX HB: 2, 4, 6 m or 2, 6 m. Prevnar, MMR II, VARIVAX: with 4th dose of Pentacel or staggered 1207 5A9908/ Canada/ 8/2000- 10/2001 15, 16, 17 or 18 m none1782

7. 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. 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. 9 Pivotal Studies: Completion of Safety Follow-up 494-01 494-03P3T065A9908 PentacelControlPentacel ControlPentacel Participation* (N)25061032120748414551782 60 day follow- up post-dose 3 (%) 9085 88 93 n/a 60 or 180 day follow-up post-dose 4** (%)7568798684>99 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. 10 Pivotal Studies: Demographics of Pentacel Safety Population Studies 494-01, 494-03, P3T06 N = 4198 Study 5A9908 N = 1782 Mean age at 1 st dose (mo.)2.1n/a % Male49.848.3 Race/Ethnicity % Caucasian Black Hispanic Asian East Indian Native Indian Other 61.1 9.8 15.0 4.3 n/a 9.7 86.0 1.9 0.8 4.3 2.0 0.5 4.5 n/a indicates not applicable. East Indian and Native Indian categories applied only to Study 5A9908.

11. 11 Pivotal Studies Serious Adverse Events

12. 12 Pivotal Studies: Percent of Subjects with a Serious Adverse Event within 30 Days following Doses 1-3 of Study Vaccines 494-01494-03P3T06 HCPDT + POLIOVAX + ActHIB N=1032 Pentacel N=2506 Pentacel N=1207 DAPTACEL + IPOL + ActHIB N=1455 Pentacel N=484 1.10.92.13.43.9

13. 13 Pivotal Studies: Percent of Subjects with a Serious Adverse Event within 30 Days following Dose 4 of Study Vaccines 494-01494-03P3T065A9908 HCPDT + POLIOVAX + ActHIB N=739 Pentacel N=1862 Pentacel N=958 DAPTACEL + ActHIB N=418 Pentacel N=431 Pentacel N=1782 0.3 0.81.01.21.1

14. 14 Pivotal Studies: Most Frequent* Serious Adverse Events within 30 Days following Doses 1-3, Percent of Subjects 494-01494-03P3T06 Control N=1032 Pentacel N=2506 Pentacel N=1207 Control N=1455 Pentacel N=484 Bronchiolitis0.6 0.2 0.71.90.8 Dehydration0.00.10.20.10.6 Pneumonia**0.00.10.20.10.4 Gastroenteritis**0.0<0.10.10.20.4 Otitis media**0.00.10.20.0 Bronchospasm**0.1 0.0 Gastroenteritis rotavirus0.00.1 0.00.2 GE reflux0.0<0.10.20.10.0 Otitis media chronic**0.0 0.10.4 *occurring in at least 4 subjects overall **not otherwise specified Control: 494-01 HCPDT, POLIOVAX, ActHIB; P3T06 DAPTACEL, IPOL, ActHIB

15. 15 Pivotal Studies: Most Frequent* Serious Adverse Events within 30 Days following Dose 4, Percent of Subjects 494-01494-03P3T065A9908 Control N=739 Pentacel N=1862 Pentacel N=958 Control N=418 Pentacel N=431 Pentacel N=1782 Dehydration0.0 0.10.50.00.2 Gastro- enteritis**0.0 0.2 Asthma**0.00.10.0 0.20.1 Pneumonia**0.00.10.0 0.2 * occurring in at least 4 subjects overall ** not otherwise specified Control: HCPDT + POLIOVAX + ActHIB (494-01); DAPTACEL + ActHIB (P3T06)

16. 16 Pivotal Studies: Serious Adverse Events-- Deaths Vaccine Group* Age (mo.) at death Last dose Days since last dose Cause of death Pentacel1548 Asphyxia due to suffocation Pentacel2123Head trauma Pentacel4152SIDS Pentacel153256Neuroblastoma DAPTACEL + IPOL + ActHIB 133222Aspiration; metastatic ependymoma * Pentacel N=5980; DAPTACEL N=1454; HCPDT N=1032

17. 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. 18 Pivotal Studies Seizures

19. 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. 20 Pivotal Studies: Seizures within 7 days Post-Vaccination, Number (%) of Subjects HCPDT + POLIOVAX + ActHIB Doses 1-3: N=1032 Dose 4: N=739 DAPTACEL + IPOL + ActHIB * Doses 1-3: N=1455 Dose 4: N=418 Pooled Pentacel Doses 1-3: N=4197 Dose 4: N=5033 Febrile Doses 1-3 Dose 4 0 (0.0) 2 (0.3) 0 (0.0) 2 (<0.1) Afebrile Doses 1-3 Dose 4 1 (0.1) 0 (0.0) 1 (0.1) 0 (0.0) 1 (<0.1) 0 (0.0) Possible Doses 1-3 Dose 4 0 (0.0) 1 (<0.1) 0 (0.0) * Dose 4: DAPTACEL + ActHIB

21. 21 Pivotal Studies: Febrile Seizures* within 7 Days Post-Vaccination Study group Age (mo.) Last Dose Interval (days)** Additional Clinical Information HCPDT1546URI; recovered w/o sequelae HCPDT1747Viral illness; recovered w/o sequelae Pentacel1542Pharyngitis; recovered w/o sequelae Pentacel1744URI; recovered w/o sequelae Pentacel630Possible seizure; fever noted same day; recovered w/o sequelae *includes one possible seizure **Interval since last dose

22. 22 Pivotal Studies: Afebrile Seizures within 7 Days Post-Vaccination Study group Age (mo.) Last Dose Interval * (days) Additional Clinical Information HCPDT420Migraine variant seizure activity Unspecified head injury 26 d earlier 2 siblings with acute hemiparesis associated with unilateral seizure Follow-up 2.5 yrs after discontinuation from the study indicated continued seizures Pentacel216Recovered w/o sequelae Completed study w/o further seizures DAPTACEL11015 sec of twitching and staring; 5 sec of apnea Recovered w/o sequelae * Interval since last dose

23. 23 Pivotal Studies Hypotonic Hyporesponsive Episodes (HHEs)

24. 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. 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. 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. 27 Pivotal Studies Solicited Systemic and Local Adverse Events

28. 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. 29 Study P3T06: Percent of Subjects with Fever within 3 Days Post-Vaccination Dose 1Dose 2Dose 3Dose 4 Pentacel (N=389-466) ≥38.0°C >38.5°C >39.5°C 5.8 1.3 0.4 10.9 2.4 0.0 16.3 4.4 0.7 13.4 5.1 0.3 Control* (Doses 1-3: N=1301- 1390; Dose 4: N=379) ≥38.0°C >38.5°C >39.5°C 9.3 1.6 0.1 16.1 4.3 0.4 15.8 5.1 0.3 8.7 3.2 0.8 *Control = DAPTACEL + IPOL + ActHIB for doses 1-3; DAPTACEL + ActHIB for dose 4

30. 30 Study 494-01: Percent of Subjects with Fever within 3 Days Post-Vaccination Dose 1Dose 2Dose 3Dose 4 Pentacel (N=1630-2296) ≥38.0°C >38.5°C >39.5°C 8.1 1.5 0.3 14.3 3.5 0.2 19.3 6.1 0.8 10.7 2.6 0.7 Control* (N=634-920) ≥38.0°C >38.5°C >39.5°C 13.8 2.3 0.1 15.7 4.9 0.6 20.6 4.6 0.7 13.1 3.9 0.5 *Control = HCPDT + POLIOVAX + ActHIB

31. 31 Study 494-01: Percent of Subjects with Fever within 3 Days following Pentacel, by Route of Measurement Dose 1Dose 2Dose 3Dose 4 RectalN=1241N=1184N=1119N=451 >38.0°C >38.5°C >39.5°C 11.6 1.6 0.3 20.8 4.5 0.2 25.7 8.2 0.9 23.1 3.8 0.7 AxillaryN=1156N=980N=891N=1193 >38.0°C >38.5°C >39.5°C 3.6 1.2 0.3 5.7 1.9 0.3 9.5 3.1 0.6 5.9 2.1 0.7 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. 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. 33 Study P3T06: Percent of Subjects with Selected Solicited Systemic Events within 3 Days Post- Vaccination Pentacel N=398-467 DAPTACEL+ IPOL * + ActHIB Doses 1-3: N=1312-1406 Dose 4: N=381 Dose 1 2 341 2 34 Less Active Any Severe ** 45.8 2.1 32.7 0.7 32.5 0.2 24.1 2.5 51.1 1.2 37.4 1.4 33.2 0.6 24.1 0.3 Inconsolable Crying Any >3 hours 59.3 1.9 49.8 0.9 47.3 1.1 35.9 2.3 58.5 2.2 51.4 3.4 47.9 1.4 36.2 1.8 Fussiness Any >3 hours 76.9 4.3 71.2 4.0 68.0 5.0 53.5 5.3 75.8 5.6 70.7 5.5 67.1 4.3 53.8 4.5 *DAPTACEL + ActHIB for Dose 4 **Disabling, not interested in usual activity

34. 34 Study P3T06: Percent of Subjects with Solicited Local Events within 3 Days Post-Vaccination Pentacel Injection Site N=392-467 DAPTACEL Injection Site Doses 1-3: N=1311-1404 Dose 4: N= 378-380 Dose 12341234 Redness >5 mm >25 mm >50 mm 7.1 2.8 0.6 8.4 1.8 0.2 8.7 1.8 0.0 17.3 9.2 2.3 6.2 1.0 0.4 7.1 0.6 0.1 9.6 1.9 0.0 16.4 7.9 2.4 Swelling >5 mm >25 mm >50 mm 7.5 3.0 0.9 7.3 2.0 0.0 5.0 1.6 0.0 9.7 3.8 0.8 4.0 1.6 0.4 4.0 0.7 0.1 6.5 1.1 0.1 10.3 4.0 1.3 Tenderness Any Severe* 47.5 5.4 39.2 1.6 42.7 1.4 56.1 3.3 48.8 4.1 38.2 2.3 40.9 1.7 51.1 2.4 *Cries when arm or leg is moved

35. 35 Pentacel Post-Marketing Safety Experience

36. 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. 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. 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) Age at Death Interval Since Vx Co-administered Vaccines Reporting Term 2 m1 d--SIDS 2 m2 d--SIDS 2 m7 dPrevnarSIDS 2 m8 dPrevnarSIDS 2 m13 d--SIDS 4 m24 hrMeningococcal CSudden death 2 m8 d--Sudden death 36 m11 dHepatitis B, MMR, Meningococcal Sudden death 19 m25 d--Death -- indicates none reported

39. 39 Post-Marketing Reports of Deaths with Identified Cause following Pentacel, 5/1/97-4/30/06 (~13.5 million doses distributed) Age at Death Interval Since Vx Co-administered vaccines Events/ Cause of Death 2 m9 hr--Group B Streptococcal sepsis (reported as ongoing since birth) 2 m3 d--Unspecified congenital anomaly; cardiac myopathy 5 m3 m--Hib meningitis/pneumonia (post-Dose 1) 3 m30 d--Hib meningitis (post-Dose 1) 20 mn/a--Convulsions n/a: data not available -- indicates none reported

40. 40 Post-Marketing Cases of Encephalopathy following Pentacel, 5/1/97-4/30/06 (~13.5 million doses distributed) Age Days Since VxClinical Information 18 m1Fever, cough, coryza, status epilepticus Cerebral edema on CT; Influenza A from NP aspirate 4 m5Fever, vomiting, bloody diarrhea, ↑ liver enzymes, status epilepticus, coma* Cerebral edema, laminar necrosis, cortical bleeding CSF nl; no organism identified (respiratory/stool/CSF) 2 m7Fever, abnormal crying, cough, apnea, seizures Cranial CT and CSF normal Influenza A from NP aspirate 18 m10Atypical Kawasaki syndrome with acute encephalopathy** Also received MMR 4 m24Convulsions, infantile spasms, hepatosplenomegaly, pneumonia, developmental delay *Case coded as convulsions **Identified in a post-marketing survey conducted in Canada

41. 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. 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. 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. 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.