safety of pentacel l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Safety of Pentacel PowerPoint Presentation
Download Presentation
Safety of Pentacel

Loading in 2 Seconds...

play fullscreen
1 / 44

Safety of Pentacel - PowerPoint PPT Presentation


  • 299 Views
  • Uploaded on

Safety of Pentacel. Karen Farizo, M.D. CBER VRBPAC January 25, 2007. Overview of Presentation. Pivotal Clinical Studies Supportive Post-Marketing Safety Data . Pivotal Studies. Design Overall Safety Database Safety Monitoring Subject Disposition Subject Demographics .

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Safety of Pentacel' - angelo


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
safety of pentacel

Safety of Pentacel

Karen Farizo, M.D.

CBER

VRBPAC

January 25, 2007

overview of presentation
Overview of Presentation
  • Pivotal Clinical Studies
  • Supportive Post-Marketing Safety Data
pivotal studies

Pivotal Studies

Design

Overall Safety Database

Safety Monitoring

Subject Disposition

Subject Demographics

study 494 01
Study 494-01

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

pivotal studies overall pentacel safety database
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.
pivotal studies safety monitoring
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)
pivotal studies completion of safety follow up
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

pivotal studies demographics of pentacel safety population
Pivotal Studies: Demographics of Pentacel Safety Population

n/a indicates not applicable.

East Indian and Native Indian categories applied only to Study 5A9908.

pivotal studies11

Pivotal Studies

Serious Adverse Events

slide12
Pivotal Studies: Percent of Subjects with a Serious Adverse Event within 30 Days following Doses 1-3 of Study Vaccines
slide13
Pivotal Studies: Percent of Subjects with a Serious Adverse Event within 30 Days following Dose 4 of Study Vaccines
slide14
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

slide15
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)

pivotal studies serious adverse events deaths
Pivotal Studies: Serious Adverse Events-- Deaths

*Pentacel N=5980; DAPTACEL N=1454; HCPDT N=1032

pivotal studies serious adverse events encephalopathy
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
pivotal studies use of antipyretics within 3 days post vaccination
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.
pivotal studies seizures within 7 days post vaccination number of subjects
Pivotal Studies: Seizures within 7 days Post-Vaccination, Number (%) of Subjects

*Dose 4: DAPTACEL + ActHIB

pivotal studies febrile seizures within 7 days post vaccination
Pivotal Studies: Febrile Seizures* within 7 Days Post-Vaccination

*includes one possible seizure

**Interval since last dose

pivotal studies afebrile seizures within 7 days post vaccination
Pivotal Studies: Afebrile Seizures within 7 Days Post-Vaccination

*Interval since last dose

pivotal studies23

Pivotal Studies

Hypotonic Hyporesponsive Episodes (HHEs)

pivotal studies hypotonic hyporesponsive episodes definition
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
pivotal studies monitoring for hypotonic hyporesponsive episodes
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.
pivotal studies hypotonic hyporesponsive episodes
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.
pivotal studies27

Pivotal Studies

Solicited Systemic and

Local Adverse Events

controlled pivotal studies routes of temperature measurement
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.
study p3t06 percent of subjects with fever within 3 days post vaccination
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

study 494 01 percent of subjects with fever within 3 days post vaccination
Study 494-01: Percent of Subjects with Fever within 3 Days Post-Vaccination

*Control = HCPDT + POLIOVAX + ActHIB

slide31
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.

pivotal studies medically attended fever
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.
slide33
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

study p3t06 percent of subjects with solicited local events within 3 days post vaccination
Study P3T06: Percent of Subjects with Solicited Local Events within 3 Days Post-Vaccination

*Cries when arm or leg is moved

slide35
Pentacel

Post-Marketing Safety Experience

pentacel post marketing safety experience
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.
slide37
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
slide38
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

slide39
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

slide40
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

immunization monitoring program active impact
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.
impact encephalopathy 1993 2002
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)

impact febrile seizures and hypotonic hyporesponsive episodes
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)

summary pentacel safety database
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.