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

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

2506 1032

*HCPDT = DTaP component of Pentacel (not U.S. licensed)

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

485 Doses 1-3: 1454

Dose 4: 418

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, MMRII, VARIVAX:

with 4th dose of Pentacel or staggered

1207

5A9908/Canada/8/2000-10/2001

15, 16, 17 or 18 m

none 1782

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

494-01 494-03 P3T06 5A9908

Pentacel Control Pentacel Pentacel Control Pentacel

Participation* (N) 2506 1032 1207 484 1455 1782

60 day follow-up post-dose 3 (%) 90 85 88 93 93 n/a

60 or 180 day follow-up post-dose 4** (%)

75 68 79 86 84 >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

Pivotal Studies: Demographics of Pentacel Safety Population

Studies 494-01, 494-03, P3T06

N = 4198

Study 5A9908

N = 1782

Mean age at 1st dose (mo.) 2.1 n/a

% Male 49.8 48.3

Race/Ethnicity % Caucasian Black Hispanic Asian East Indian Native Indian Other

61.1 9.8

15.0 4.3 n/an/a9.7

86.01.90.84.32.00.54.5

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

494-01 494-03 P3T06

HCPDT + POLIOVAX + ActHIBN=1032

PentacelN=2506

PentacelN=1207

DAPTACEL + IPOL + ActHIBN=1455

PentacelN=484

1.1 0.9 2.1 3.4 3.9

13

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

494-01 494-03 P3T06 5A9908

HCPDT + POLIOVAX + ActHIBN=739

PentacelN=1862

PentacelN=958

DAPTACEL + ActHIB

N=418PentacelN=431

PentacelN=1782

0.3 0.3 0.8 1.0 1.2 1.1

14

Pivotal Studies: Most Frequent* Serious Adverse Events within 30 Days following Doses 1-3, Percent of Subjects

494-01 494-03 P3T06

ControlN=1032

PentacelN=2506

PentacelN=1207

ControlN=1455

PentacelN=484

Bronchiolitis 0.6 0.2 0.7 1.9 0.8

Dehydration 0.0 0.1 0.2 0.1 0.6

Pneumonia** 0.0 0.1 0.2 0.1 0.4

Gastroenteritis** 0.0 <0.1 0.1 0.2 0.4

Otitis media** 0.0 0.1 0.2 0.0 0.0

Bronchospasm** 0.1 0.1 0.1 0.0 0.0

Gastroenteritis rotavirus 0.0 0.1 0.1 0.0 0.2

GE reflux 0.0 <0.1 0.2 0.1 0.0

Otitis media chronic** 0.0 0.0 0.0 0.1 0.4*occurring in at least 4 subjects overall**not otherwise specifiedControl: 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

494-01 494-03 P3T06 5A9908

ControlN=739

PentacelN=1862

PentacelN=958

ControlN=418

PentacelN=431

PentacelN=1782

Dehydration 0.0 0.0 0.1 0.5 0.0 0.2

Gastro-enteritis** 0.0 0.0 0.0 0.2 0.2 0.2

Asthma** 0.0 0.1 0.0 0.0 0.2 0.1

Pneumonia** 0.0 0.1 0.0 0.0 0.0 0.2

*occurring in at least 4 subjects overall**not otherwise specifiedControl: HCPDT + POLIOVAX + ActHIB (494-01); DAPTACEL + ActHIB (P3T06)

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Pivotal Studies: Serious Adverse Events-- Deaths

Vaccine Group*

Age (mo.) at death

Last dose

Days since

last doseCause of death

Pentacel 15 4 8 Asphyxia due to suffocation

Pentacel 2 1 23 Head trauma

Pentacel 4 1 52 SIDS

Pentacel 15 3 256 Neuroblastoma

DAPTACEL + IPOL + ActHIB

13 3 222 Aspiration; metastatic ependymoma

*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

HCPDT + POLIOVAX +

ActHIBDoses 1-3: N=1032

Dose 4: N=739

DAPTACEL + IPOL + ActHIB*

Doses 1-3: N=1455

Dose 4: N=418

Pooled PentacelDoses 1-3:

N=4197Dose 4: N=5033

Febrile Doses 1-3 Dose 4

0 (0.0) 2 (0.3)

0 (0.0)0 (0.0)

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)0 (0.0)

0 (0.0)0 (0.0)

1 (<0.1) 0 (0.0)

*Dose 4: DAPTACEL + ActHIB

21

Pivotal Studies: Febrile Seizures* within 7 Days Post-Vaccination

Study group

Age

(mo.)

Last Dose

Interval (days)** Additional Clinical Information

HCPDT 15 4 6 URI; recovered w/o sequelae

HCPDT 17 4 7 Viral illness; recovered w/o sequelae

Pentacel 15 4 2 Pharyngitis; recovered w/o sequelae

Pentacel 17 4 4 URI; recovered w/o sequelae

Pentacel 6 3 0 Possible seizure; fever noted same day; recovered w/o sequelae

*includes one possible seizure **Interval since last dose

22

Pivotal Studies: Afebrile Seizures within 7 Days Post-Vaccination

Study group

Age

(mo.)

Last Dose

Interval*

(days) Additional Clinical Information

HCPDT 4 2 0 •Migraine 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

Pentacel 2 1 6 •Recovered w/o sequelae

•Completed study w/o further seizures

DAPTACEL 1 1 0 •15 sec of twitching and staring; 5 sec of apnea

•Recovered w/o sequelae*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

Dose 1 Dose 2 Dose 3 Dose 4

Pentacel (N=389-466) ≥38.0°C >38.5°C >39.5°C

5.81.30.4

10.92.40.0

16.34.40.7

13.45.10.3

Control* (Doses 1-3: N=1301-1390; Dose 4: N=379) ≥38.0°C >38.5°C >39.5°C

9.31.60.1

16.14.30.4

15.85.10.3

8.73.20.8

*Control = DAPTACEL + IPOL + ActHIB for doses 1-3; DAPTACEL + ActHIB for dose 4

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Study 494-01: Percent of Subjects with Fever within 3 Days Post-Vaccination

Dose 1 Dose 2 Dose 3 Dose 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

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Study 494-01: Percent of Subjects with Fever within 3 Days following Pentacel, by Route of Measurement

Dose 1 Dose 2 Dose 3 Dose 4

Rectal N=1241 N=1184 N=1119 N=451

>38.0°C>38.5°C>39.5°C

11.61.60.3

20.84.50.2

25.78.20.9

23.13.80.7

Axillary N=1156 N=980 N=891 N=1193

>38.0°C>38.5°C>39.5°C

3.61.20.3

5.71.90.3

9.53.10.6

5.92.10.7

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.

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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

PentacelN=398-467

DAPTACEL+ IPOL* + ActHIBDoses 1-3: N=1312-1406

Dose 4: N=381

Dose 1 2 3 4 1 2 3 4

Less ActiveAny Severe**

45.82.1

32.70.7

32.50.2

24.12.5

51.11.2

37.41.4

33.20.6

24.10.3

Inconsolable Crying Any >3 hours

59.31.9

49.80.9

47.31.1

35.92.3

58.52.2

51.43.4

47.91.4

36.21.8

Fussiness Any >3 hours

76.94.3

71.24.0

68.05.0

53.55.3

75.85.6

70.75.5

67.14.3

53.84.5

*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

Pentacel Injection Site N=392-467

DAPTACEL Injection SiteDoses 1-3: N=1311-1404

Dose 4: N= 378-380

Dose 1 2 3 4 1 2 3 4

Redness>5 mm >25 mm>50 mm

7.12.80.6

8.41.80.2

8.71.80.0

17.39.22.3

6.2 1.00.4

7.10.60.1

9.6 1.90.0

16.47.92.4

Swelling >5 mm >25 mm>50 mm

7.53.00.9

7.32.00.0

5.01.60.0

9.73.80.8

4.01.60.4

4.00.70.1

6.51.10.1

10.34.01.3

TendernessAny Severe*

47.55.4

39.21.6

42.71.4

56.13.3

48.84.1

38.22.3

40.91.7

51.12.4

*Cries when arm or leg is moved

35

PentacelPost-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)

Ageat Death

Interval Since Vx

Co-administeredVaccines

Reporting Term

2 m 1 d -- SIDS

2 m 2 d -- SIDS

2 m 7 d Prevnar SIDS

2 m 8 d Prevnar SIDS

2 m 13 d -- SIDS

4 m 24 hr Meningococcal C Sudden death

2 m 8 d -- Sudden death

36 m 11 d Hepatitis B, MMR, Meningococcal

Sudden death

19 m 25 d -- Death-- 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)

Ageat Death

Interval Since Vx

Co-administeredvaccines

Events/Cause of Death

2 m 9 hr -- Group B Streptococcal sepsis (reported as ongoing since birth)

2 m 3 d -- Unspecified congenital anomaly; cardiac myopathy

5 m 3 m -- Hib meningitis/pneumonia(post-Dose 1)

3 m 30 d -- Hib meningitis (post-Dose 1)

20 m n/a -- Convulsionsn/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)

AgeDays

Since Vx Clinical Information

18 m 1 •Fever, cough, coryza, status epilepticus •Cerebral edema on CT; Influenza A from NP aspirate

4 m 5 •Fever, vomiting, bloody diarrhea, ↑ liver enzymes, status epilepticus, coma*•Cerebral edema, laminar necrosis, cortical bleeding•CSF nl; no organism identified (respiratory/stool/CSF)

2 m 7 •Fever, abnormal crying, cough, apnea, seizures•Cranial CT and CSF normal•Influenza A from NP aspirate

18 m 10 •Atypical Kawasaki syndrome with acute encephalopathy**•Also received MMR

4 m 24 •Convulsions, infantile spasms, hepatosplenomegaly, pneumonia, developmental delay

*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.