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Vaccines

OBE BLA Review Memo - MenHibrix

OBE BLA REVIEW

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STN:                                         125363 / 0
PRODUCT:                               MenHibRix® (Hib-MenCY-TT)
                                                   Haemophilus influenzae type b
                                                   Neisseria meningitidis serogroups C and Y-tetanus toxoid (TT) conjugate
 

MANUFACTURER:                    GlaxoSmithKline
SUBMISSION DATE:                 12-AUG-2009
FINAL REVIEW DUE DATE:       07-MAY-2010
ACTION DUE DATE:                  12-JUN-2010

REVIEWER:                              Patricia J. Rohan, MD

 

THRU:                                      David Martin, MD, MPH

                                                  Rickey Wilson, MD, MS, JD


 

PROPOSED USE:                      Hib-MenCY-TT vaccine is proposed to be indicated for active immunization of infants and toddlers 6 weeks through 15 months of age for the prevention of invasive diseases caused by Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y.

DOSE SCHEDULE:                    0.5 ml intramuscular dose at 2, 3, 6 and 12-15 months of age.
                                                      The first dose may be given as early as 6 weeks of age.

MATERIALS REVIEWED:           125363.0000
                                                           Module 1.16       Risk Management Plans
                                                            Module 2.7.4     Summary of Clinical Safety
                                                            Module 5.3.5.1  Active-control-without-placebo
                                                                                     Office visits: HibMenCY 005, 006, 007, 008, 009, 010
                                                            Module 5.3.6      Reports of Postmarketing Experience

BACKGROUND:

Regulatory
The Hib-MenCY-TT vaccine is not currently licensed in any country.

The Haemophilus b capsular polysaccharide (polyribosyl-ribitol-phosphate [PRP]) and MenC component antigens are included in other conjugate vaccines marketed outside the US [Hiberix (Haemophilus influenzae type b conjugate vaccine) for the PRP component and Menitorix (Haemophilus influenzae type b and Neisseria meningitidis serogroup C conjugate vaccine) for the PRP and MenC components].

Clinical
1.   Haemophilus influenzae type B
Prior to introduction of effective vaccines, Haemophilus influenzae type b (Hib) was the leading cause of invasive bacterial disease in US children affecting 0.5% of those 5 years of age and under - two-thirds of pediatric Hib infections in those less than 15 months of age. A large proportion of these children (60%) had meningitis with a mortality rate of 3-6% and permanent neurologic sequelae in 20-30%. Hib accounted for 95% of all cases of invasive H. influenzae disease in this pediatric population. Comparator studies have demonstrated 93-100% Hib vaccine efficacy. (CDC ACIP 2010)

The Advisory Committee on Immunization Practices (ACIP) recommends that all children receive one of the conjugate vaccines licensed for infant use (HbOC or PRP-OMP), beginning routinely at 2 months of age. Administration of the vaccine series may be initiated as early as age 6 weeks. This recommendation was first made in 1991, and while the number of reported cases of invasive Haemophilus influenzae Type b has decreased, over the same period the number of cases of invasive non-B, and non-typeable Haemophilus influenzae have risen. Of note, the latter two types of invasive Haemophilus influenzae represent the majority of invasive Haemophilus influenzae cases. (CDC Active Bacterial Core surveillance or ABC, 1997-2007).

2.   Meningococcal Disease
Following reduction in the incidences of Streptococcus pneumoniae and Haemophilus influenzae type b (HiB) as the result of conjugate vaccines, Neisseria meningitides has emerged as a leading cause of bacterial meningitis in the US, with an estimated annual incidence of 0.5-1.1/100,000 persons (1,400-
2,800 cases). The fatality rate for meningococcal disease is 10%--14% (CDC, unpublished data, 2004). Meningococcal disease also causes substantial morbidity; 11%--19% of survivors have sequelae (e.g., neurologic disability, limb loss, and hearing loss) (DCD, ACIP 2010)

Studies of serogroups A and C vaccines have demonstrated estimated clinical efficacies of >85% among school-aged children and adults. Efficacy has not been evaluated for serogroups Y and W-135 polysaccharides, but these vaccines have demonstrated immunogenicity in adults and children aged >2 years, i.e., production of bactericidal antibodies.

The Advisory Committee on Immunization Practices (ACIP) recommends

  • Routine vaccination of young adolescents (defined in this report as persons aged 11--12 years) with MCV4 at the preadolescent health-care visit (i.e., a visit to a health-care provider at age 11--12 years, at which time ACIP and other professional organizations [e.g., AAP and the American Medical Association] recommend that persons aged 11--12 years receive appropriate vaccinations and other preventive services [106--109]). Introducing a recommendation for MCV4 vaccination among persons aged 11--12 years might strengthen the role of the preadolescent health-care visit and have a positive effect on vaccine coverage during adolescence. For those adolescents who have not previously received MCV4, ACIP recommends vaccination before high school entry (at approximately age 15 years) as an effective strategy to reduce meningococcal disease incidence among adolescents and young adults. By 2008, the goal will be routine vaccination with MCV4 of all adolescents beginning at age 11 years. Other adolescents who wish to decrease their risk for meningococcal disease may elect to receive vaccine.
  • Routine vaccination with meningococcal vaccine also is recommended for college freshmen living in dormitories and for other populations at increased risk (i.e., military recruits, travelers to areas in which meningococcal disease is hyperendemic or epidemic, microbiologists who are routinely exposed to isolates of Neisseria meningitidis, patients with anatomic or functional asplenia, and patients with terminal complement deficiency). Other adolescents, college students, and persons infected with human immunodeficiency virus who wish to decrease their risk for meningococcal disease may elect
    to receive vaccine.

OVERVIEW OF CLINICAL EXPERIENCE WITH Hib-MenCY-TT:
The vaccine, Hib-MenCY-TT, has been evaluated in 6 primary vaccination studies of a 3-dose schedule, at 0, 2 and 6 month (Table 1) and 5 studies of a 4th dose (Table 2). In addition two studies are reported as ongoing, one of which involves a related vaccine, MenACW-135Y-TT in which subjects received a 4th dose of Hib-MenCY-TT (Table 3).

3-dose schedule
7,521 infants received at least one dose of the Hib-MenCY-TT vaccine as part of the 3-dose primary vaccination course starting from 6 weeks of age and a total of 21,943 doses of the Hib- MenCY-TT vaccine have been administered in these studies.

4th dose
7,023 subjects have received Hib-MenCY-TT as a 4th dose in a series; 6,686 subjects had previously received 3 doses of Hib-MenCY-TT, and 337 subjects from study 008 had previously received 3 doses of Hib vaccine and 3 doses of serogroup C conjugate vaccine, Meningitec (licensed in Australia).

Overall
9,148 subjects have received at least one dose of the Hib-MenCY-TT vaccine licensure formulation (7,858 subjects in the Hib-MenCY-TT vaccine clinical development and approximately 1,290 subjects in the ongoing study MenACWYTT- 057).

Safety Database
The total pre-licensure safety database for the Hib-MenCY-TT vaccine includes approximately 9,465 subjects in the target age group who have received at least one dose of any formulation of the Hib- MenCY-TT vaccine.

Non-serious adverse events / serious adverse events leading to study discontinuation:

  • Recorded during the active phase follow-up (Day 0 to Day 30 after last vaccination)
  • Information on discontinuation from the ESFU phase due to AE/SAE was not collected Studies Hib- MenCY-TT-005/006, -007/008, -009/010 and -011/012 and subjects withdrawn from the active phase could participate in the ESFU phase.
  • Data from all subjects enrolled in US studies Hib-MenCY-TT-009 (Center 24660), -010 (Center
    34932), -011 (Center 35785) and -012 (Center 39451) were excluded from all analyses due to repeated GCP violations and protocol non-compliance in spite of intense monitoring and remediation efforts by the sponsor.
    • Certain key data points, such as vaccine accountability, could not be fully reconciled at the site, resulting in exclusion of 261 subjects in study Hib-MenCY-TT-009, 189 subjects in study Hib-MenCY-TT-010, 40 subjects in study Hib- MenCY-TT-011 and 27 subjects in study Hib- MenCY-TT-012.
    • Individual subject data are included separately in the line listing of the respective study reports.
    • Based upon CBER’s recommendation at a teleconference held on March 23, 2009, the sponsor conducted a sensitivity analyses for fever and specific unsolicited AEs by comparing the results obtained including and excluding subjects from this location (Center 24660 in study
      -009 and Center 34932 in study -010) and demonstrated that no bias was detected.

The Hib-MenCY-TT vaccine completed primary vaccination and fourth dose studies, and ongoing studies are summarized, respectively, in Tables 1-3 below.

Table 1: Completed primary vaccination phase studies providing data with the Hib-MenCY-TT can

Study number Study Location Type

Population Age at Dose 1 (Dose Schedule)

Safety Objectives

Study Design / Vaccine Cohorts

Total Vaccinated Cohort

Hib-MenCY-TT-001
Australia (multicenter) Non-pivotal study Immunogenicity Safety/Reactogenicity

Healthy infants
6-12 weeks
(2, 4, 6 months)

Secondary objective: Reactogenicity and safety.

Phase 2, partially DB, RC, primary vaccination

407

 

Group Hib-MenCY 2.5/5/5 + Pediarix + Prevnar

82

 

Group Hib-MenCY 5/10/10 + Pediarix + Prevnar

82

 

Group Hib-MenCY 5/5/5 + Pediarix + Prevnar

80

 

Group Menjugate + ActHIB + Pediarix

81

 

Group ActHIB+ Pediarix + Prevnar

82

Hib-MenCY-TT-003
Belgium, Germany Non-pivotal study Immunogenicity Safety/Reactogenicity

Healthy infants 6-12 weeks
(2, 3, 4 months)

Secondary objective:  Reactogenicity and safety.

Phase 2, partially DB, RC, primary vaccination

388

 

Group Hib-MenCY 2.5/5/5 + Pediarix

78

 

Group Hib-MenCY 5/10/10 + Pediarix

77

 

Group Hib-MenCY 5/5/5 + Pediarix

78

 

Group Hib-MenC 5/5 + Pediarix

78

 

Group Menjugate + Infanrix hexa

77

Hib-MenCY-TT-005
US (multicenter) Pivotal study Immunogenicity, Safety/Reactogenicity

Healthy infants
6-12 weeks
(2, 4, 6 months) Healthy children
3-5 years (1 dose)

Secondary objective: Reactogenicity and safety.

Phase 2, SBRC, primary vaccination

756

 

Group Hib-MenCY + Pediarix + Prevnar

287

 

Group ActHIB + Pediarix + Prevnar

319

 

Group Menomune

150

Hib-MenCY-TT-007
Australia Pivotal study Immunogenicity, Safety/Reactogenicity

Healthy infants
6-13 weeks
(2, 4, 6 months)

Secondary objective: Reactogenicity and safety.

Phase 2, open RC primary vaccination study

1103

 

Group Hib-MenCY + Pediarix + Prevnar

661

 

Group Meningitec + ActHIB + Pediarix + Prevnar

221

 

Group ActHIB + Pediarix + Prevnar

221

Hib-MenCY-TT-009
US, Australia, Mexico
Pivotal study
Lot-to-lot consistency, immunogenicity, Safety/Reactogenicity

Healthy infants
5-16 weeks
(2, 4, 6 months)

Secondary objectives: Reactogenicity and safety;
Incidence of fever >39.5°C w/in 4 days after any vaccine dose.

Phase 3 DB Hib-MenCY-TT lot consistency / SB Hib-MenCY-TT vs. monovalent Hib vaccine, RC primary vaccination

4180

 

Group Hib-MenCY Lot A + Pediarix

1041

 

Group Hib-MenCY Lot B + Pediarix

1046

 

Group Hib-MenCY Lot C + Pediarix

1049

 

Group ActHIB + Pediarix

1044

± Prevnar / influenza vaccine / RotaTeq / Synagis

 

Hib-MenCY-TT-011
US, Mexico Pivotal study Safety

Healthy infants
6-13 weeks
(2, 4, 6 months)

Primary objective: (Hib-MenCY-TT-011 and 009 pooled data) SAEs, ER visits
New onset chronic diseases, e.g. autoimmune disorders, asthma, diabetes, allergies, rash (e.g. hives, ITP, petechiae)

SBRC primary vaccination study

4391

 

Group Hib-MenCY + Pediarix

3278

 

Group ActHIB + Pediarix

1113

± Prevnar / influenza vaccine / RotaTeq / Synagis

 

Total number of subjects exposed to Hib-MenCY group (TVC)

7,522

Hib-MenCY 5/10/10 and 5/5/5 are earlier formulations (Studies 001 and 003); Hib-MenCY 2.5/5/5 (Studies 001 and 003) and Hib-MenCY refer to the licensed formulation.
7,522 subjects in Hib-MenCY TVC include 7,521 subjects who received Hib-MenCY-TT and one subject (study 011) who did not receive Hib-MenCY-TT vaccine. SB = single blinded; DB =double-blinded; R = randomized; C = controlled

STN 1253633/0, Section 1.16, PVP, Table 1

Table 2: Completed fourth dose phase studies providing data with the Hib-MenCY-TT candidate vaccine

Study number
Study Location / Type

Age at Dose 4 (Actual Range)

Safety Objectives

Study Design / Vaccine Cohorts

Total
Cohort

Hib-MenCY-TT-004
Germany
Non-pivotal Extension
Immunogenicity
Safety and Reactogenicity

Healthy toddlers
12 months
(11-18 months)

Secondary objectives:
Reactogenicity and safety.

Phase 2 partially DBC, non-randomized extension of Hib-MenCY-TT-003

221

 

Group Hib-MenCY 2.5/5/5 + Pediarix

47

 

Group Hib-MenCY 5/10/10 + Pediarix

42

 

Group Hib-MenCY 5/5/5 + Pediarix

44

 

Group Hib-MenC 5/5 + Pediarix

44

 

Group Menjugate + Infanrix hexa

44

Hib-MenCY-TT-006
US / Pivotal study
Immunogenicity
Safety and reactogenicity

Healthy toddlers
12 months
(11-16 months)

Secondary objectives:
Reactogenicity and safety.

Phase II, SBC (re-randomized from Hib-MenCY-TT-005)

498

 

Group Hib-MenCY: Hib-MenCY-TT + Prevnar / priming w/ Hib-MenCY-TT + Prevnar + Pediarix

236*

 

Group ActHIB_ActHIB: ActHIB + Prevnar / priming with ActHIB + Prevnar + Pediarix

130

 

Group ActHIB_Hib-MenCY: Hib-MenCY-TT + Prevnar / priming with ActHIB + Prevnar + Pediarix

132

Hib-MenCY-TT-008
Australia Pivotal study Immunogenicity
Safety and reactogenicity

Healthy toddlers
12 months
(11-15 months)

Secondary objectives:
Reactogenicity and safety.

Phase 3, open, RC 4th   dose extension of Hib-MenCY-TT-007

1035

 

Group Hib-MenCY: Hib-MenCY-T, 4th dose + M-M-R II + Varivax
after priming with Hib-MenCY-TT + Pediarix + Prevnar

625

 

Group LicMenC: Hib-MenCY-TT, single dose + M-M-R II + Varivax after priming with Meningitec +
ActHIB + Pediarix + Prevnar

206

 

Group Hib: PedvaxHIB, 4th dose + M-M-R II + Varivax
after priming with ActHIB + Pediarix + Prevnar

204

Hib-MenCY-TT-010
US, Australia, Mexico Pivotal study Immunogenicity,
Safety and reactogenicity

Healthy toddlers
12 months
(11-17 months)

Secondary objectives:
Fever >39.5°C/103.1°F, within
4-days after 4th dose Safety and reactogenicity.

Phase 3, SBRC 4th dose extension of Hib-MenCY-TT-009

3692

 

Group Hib-MenCY: Hib-MenCY-TT
after priming with Hib-MenCY-TT + Pediarix

 

2769

 

Group Hib: PedvaxHIB, 4th dose after priming with ActHIB + Pediarix

923

± hepatitis A vaccine and influenza vaccine; ±4th dose Prevnar, M-M-RII, Varivax

 

Hib-MenCY-TT-012
US, Mexico Pivotal study Safety data

Healthy toddlers
12 months
(11-17 months)

Secondary objective:
SAEs, NOCD*, rash (e.g. hives, ITP, petechiae), ER visits

Phase 3, SBRC 4th dose, extension of Hib-MenCY-TT-011

4020

 

Group Hib-MenCY: Hib-MenCY-TT / priming with Hib-MenCY-TT + Pediarix

3010

 

Group Hib: PedvaxHIB / priming with ActHIB + Pediarix

1010

±4th dose of Prevnar, M-M-RII,  Varivax, hepatitis A and influenza vaccine

 

Total number of subjects in the Hib-MenCY group (TVC)

7,025

Hib-MenCY 5/10/10 and 5/5/5 are earlier formulations (Study 004); Hib-MenCY refers to the licensed formulation.
Study 006: After database lock and completion of analyses, it was discovered that one subject was incorrectly assigned to Hib-MenCY group after having received 3 doses of ActHIB
SB = single blinded; DB =double-blinded; R = randomized; C = controlled

STN 1253633/0, Section 1.16, PVP, Table 2

Table 3: Ongoing studies with the Hib-MenCY-TT candidate vaccine

Study number
Study Location / Type

Population
Age at Enrollment
(Schedule)

Safety Objectives

Study Design / Vaccine Cohorts

Planned enrollment

Hib-MenCY-TT-014
US (multicenter) Observation
Immune Persistence

Healthy children
4 years
(no vaccination)

None

Phase 3, open, controlled extension of study 005 / 006

320*

Group Hib-MenCY (4 doses)

160

Group ActHIB (4 doses)

80

Group ActHIB_Hib-MenCY (ActHIB 3 doses, Hib-MenCY-TT 4th dose

80

MenACWY-TT-057
US (multicenter)
primary phase

Healthy infants
6-12 weeks
(2, 4, 6 months)

Secondary objective:
Safety

Phase 3, RC

1548

Group Hib-MenCY-TT + Pediarix

1290

Group ActHIB + Pediarix
± Prevnar, influenza vaccine, rotavirus vaccine

258

MenACWY-TT-057
US (multicenter)
booster phase

Healthy toddlers
12-15 months (12-
15, 15-18 months)

Secondary objective:
Safety and reactogenicity.

Phase 3, re-randomized, C controlled extension of study 057

1548

Group MenACWY-TT at 12-15 months / Infanrix at 15-18 months

516

Group Hib-MenCY-TT at 12-15 months / Infanrix at 15-18 months

258

Group MenACWY-TT + Infanrix at 15-18 months of age.

516

Group Infanrix at 15-18 months of age.

258

*Planned enrollment in study Hib-MenCY-TT-014 (Year 3 follow-up of study Hib-MenCY-TT-005/006) is more than the number of subjects who participated in study Hib- MenCY-TT-013 (Year 1
follow-up of study Hib-MenCY-TT-005/006) because subjects could participate in each persistence time point independent of other persistence time points.

STN 1253633/0, Section 1.16, PVP, Table 4

Demographics:
The age, race and gender distributions are comparable between the Hib-MenCY and Hib vaccine cohorts for both the primary vaccination series and the fourth dose vaccination studies as shown in Table 4. The relatively large proportion (37-42%) of Hispanic subjects is due to study sites in Mexico.

Table 4: Demographic characteristics of Hib-MenCY and Hib vaccine groups

Characteristics

Parameters or Categories

Hib-MenCY ( N = 7522)

Hib  (N = 2779)

 

 

 

 

Pooled primary vaccination phase studies Hib-MenCY-TT-001, -003, -005, -007, -009, and -011*

 

 

Value or n

%

Value or n

%

Age at first dose (days)

Mean

61.1

-

61.5

-

SD

9.42

-

9.31

-

Median

62.0

-

62.0

-

Minimum

37

-

40

-

Maximum

111

-

116

-

Age at third dose (days)

Mean

185.9

-

186.8

-

SD

14.98

-

13.72

-

Median

185.0

-

186.0

-

Minimum

99

-

133

-

Maximum

322

-

312

-

Unknown

357

-

143

-

Gender

Female

3637

48.4

1361

49.0

Male

3885

51.6

1418

51.0

Race

White / Caucasian

3789

50.4

1496

53.8

African American / Black

332

4.4

139

5.0

 

Hispanic

3068

40.8

1027

37.0

 

Arabic / North African

7

0.1

1

0.0

 

Asian

62

0.8

20

0.7

 

Other

264

3.5

96

3.5

Pooled fourth dose phase studies Hib-MenCY-TT-004, -006, -008, -010, and -012**

Characteristics

Parameters or Categories

Hib-MenCY (N = 6687)

Hib (N = 2267)

 

 

Value or n

%

Value or n

%

Age (months)

Mean

12.1

-

12.1

-

SD

0.45

-

0.47

-

Median

12.0

-

12.0

-

Minimum

11

-

12

-

Maximum

17

-

17

-

Gender

Female

3241

48.5

1108

48.9

Male

3446

51.5

1159

51.1

Race

White / Caucasian

3308

49.5

1155

50.9

African American / Black

266

4.0

87

3.8

Hispanic

2835

42.4

942

41.6

Arabic / North African

5

0.1

1

0.0

Asian

51

0.8

12

0.5

Other

222

3.3

70

3.1

N = total number of subjects in Total Vaccine Cohort (TVC)      n / % = number / percentage of subjects in a given category
Value = value of the considered parameter                               SD = standard deviation

*STN 1253633/0, Section 2.7.4, Table 21                                   **STN 1253633/0, Section 2.7.4, Table 21

Integrated summary of safety (ISS) analysis
An integrated summary of safety (ISS) analysis was performed across the 3-dose and the 4th dose studies of Hib-MenCY- TT vaccine. Groups receiving the Hib-MenCY-TT vaccine or Hib vaccine (control group) were compared by pooling data from studies that included a control group receiving a US-licensed monovalent Hib vaccine (ActHIB or PedvaxHIB).  Note that studies that did not include a US-licensed monovalent Hib vaccine control (Hib-MenCY-TT-003 and -004) and subjects in studies in which a single dose of the Hib-MenCY-TT vaccine was administered at approximately 12 to 15 months of age (Hib-MenCY-TT-006 and -008) after 3 doses of a Hib vaccine (and an Australian-licensed meningococcal serogroup C conjugate vaccine, Meningitec, in study -008) at 2, 4 and 6 months are excluded from the respective analyses.

The safety database includes 9,465 subjects who have received ≥1 dose of any formulation of the Hib-MenCY-TT vaccine.

Solicited AEs
The following symptoms were solicited in all studies except Hib-MenCY-TT-011 and -012:
•      Local solicited events: pain, redness and swelling at each injection site
•      General solicited events: drowsiness, fever, irritability/fussiness and loss of appetite

Additionally, increase in mid-limb circumference was solicited in fourth dose phase studies Hib-MenCY-TT-006 and -010

Solicited general AEs specific to co-administered M-M-RII and Varivax vaccines were solicited in studies Hib- MenCY-TT-
008 and -010 (US Safety and Immunogenicity Cohort) and are described in the section on adverse events of interest, below.

As summarized in Tables 5 and 6, below, statistically significant higher rates (bolded) of several solicited and general AEs were seen in the Hib cohorts in either the primary vaccination series or fourth dose vaccination studies in the Hib cohorts. While no adjustment was made for multiple comparison, it should be noted that there was no solicited AE found to be statistically significantly higher in the Hib-MenCY cohorts.

Table 5: Solicited local AEs reported within the 4-day (Days 0-3) post-vaccination period

 

Symptom

 

Type

 

Hib-MenCY

 

Hib

Relative Risk
(Hib-MenCY over Hib)

 

P-value

 

P-value interact

 

95% CI

N

n

%

N

n

%

RR

LL

UL

 

 

Pooled primary vaccination studies Hib-MenCY-TT-001, -005, -007, and -009*

Pain

All

4113

3034

73.8

1635

1202

73.5

0.95

0.89

1.02

0.1785

0.6742

Grade 2-3

4113

1631

39.7

1635

752

46.0

0.80

0.73

0.88

<0.0001

0.9563

Grade 3

4113

518

12.6

1635

303

18.5

0.62

0.54

0.72

<0.0001

0.0554

Redness

All

4113

2787

67.8

1635

1097

67.1

0.97

0.90

1.04

0.3485

0.7126

>10.0 mm

4113

754

18.3

1635

317

19.4

0.90

0.79

1.03

0.1368

0.9365

>30.0 mm

4113

126

3.1

1635

72

4.4

0.66

0.49

0.90

0.0076

0.1743

Swelling

All

4113

2342

56.9

1635

902

55.2

0.98

0.91

1.06

0.6102

0.9483

>10.0 mm

4113

689

16.8

1635

257

15.7

1.02

0.88

1.18

0.8482

0.7308

>30.0 mm

4113

145

3.5

1635

76

4.6

0.70

0.53

0.94

0.0182

0.1148

Pooled fourth dose vaccination studies Hib-MenCY-TT-006, -008, and -010**

Pain

All

3382

1615

47.8

1159

636

54.9

0.86

0.78

0.94

0.0014

0.1490

Grade 2-3

3382

506

15.0

1159

271

23.4

0.63

0.54

0.73

<0.0001

0.0088

Grade 3

3382

65

1.9

1159

64

5.5

0.34

0.24

0.49

<0.0001

0.2877

Redness

All

3382

1673

49.5

1160

660

56.9

0.86

0.78

0.94

0.0009

0.2654

>10.0 mm

3382

305

9.0

1160

164

14.1

0.63

0.52

0.76

<0.0001

0.0196

>30.0 mm

3382

83

2.5

1160

34

2.9

0.83

0.55

1.27

0.4079

0.4696

Swelling

All

3380

1210

35.8

1159

476

41.1

0.85

0.77

0.95

0.0039

0.0005

>10.0 mm

3380

254

7.5

1159

124

10.7

0.68

0.55

0.85

0.0008

<0.0001

>30.0 mm

3380

66

2.0

1159

35

3.0

0.63

0.41

0.98

0.0384

0.0410

Note: Includes local symptoms at any injection site following the study vaccine as well as co-administered vaccines
N = number of subjects with at least one documented dose; n/% = number/percentage of subjects reporting the symptom at least once
95% CI = 95% confidence interval for relative risk (Exact Stratified Conditional to total number of cases), LL = lower limit, UL = upper limit
P-value: 2-sided Exact Stratified Test conditional to no. of cases; P-value interact: 2-sided Exact Breslow & Day Test for heterogeneity across studies
Grade 2 pain = Cried/protested on touch
Grade 3 pain = Cried when limb was moved/spontaneously painful
Redness/swelling >10.0 mm = grade 2 and grade 3 Redness/swelling > 30.0 mm = grade 3

*STN 1253633/0, Section 2.7.4, Table 26                         ** STN 1253633/0, Section 2.7.4, Table 27

Table 6: Solicited general AEs reported within the 4-day (Days 0-3) post-vaccination period

 

Symptom

 

Type

 

Hib-MenCY

 

Hib

Relative Risk
(Hib-MenCY over Hib)

 

P-value

 

P-value interact

 

95% CI

N

n

%

N

n

%

RR

LL

UL

Pooled primary vaccination studies Hib-MenCY-TT-001, -005, -007, and -009*

Drowsiness

All

4114

3198

77.7

1634

1270

77.7

0.98

0.92

1.05

0.6134

0.8992

Grade 2-3

4114

1194

29.0

1634

555

34.0

0.85

0.77

0.95

0.0026

0.6905

Grade 3

4114

229

5.6

1634

111

6.8

0.78

0.62

0.99

0.0450

0.1051

Irritability

All

4114

3648

88.7

1634

1485

90.9

0.96

0.90

1.02

0.2301

0.8842

Grade 2-3

4114

2105

51.2

1634

944

57.8

0.88

0.81

0.95

0.0010

0.9801

Grade 3

4114

454

11.0

1634

255

15.6

0.70

0.60

0.83

<0.0001

0.3250

Fever

All

4115

1751

42.6

1634

711

43.5

0.96

0.87

1.05

0.3222

0.0995

> 38.5°C

4115

624

15.2

1634

274

16.8

0.87

0.75

1.01

0.0586

0.6673

> 39.0°C

4115

186

4.5

1634

71

4.3

1.00

0.75

1.34

1.0000

0.8726

> 39.5°C

4115

57

1.4

1634

22

1.3

0.92

0.55

1.59

1.0000

0.8726

> 40.0°C

4115

10

0.2

1634

3

0.2

1.10

0.28

6.20

0.8194

0.8080

Loss of appetite

All

4114

2351

57.1

1634

959

58.7

0.95

0.88

1.03

0.2146

0.7646

Grade 2-3

4114

661

16.1

1634

300

18.4

0.86

0.75

1.00

0.0460

0.7527

Grade 3

4114

55

1.3

1634

25

1.5

0.87

0.53

1.48

0.6535

0.5116

Pooled fourth dose vaccination studies Hib-MenCY-TT-006, -008, and -010**

Drowsiness

All

3380

1356

40.1

1157

500

43.2

0.92

0.83

1.02

0.1259

0.7350

Grade 2-3

3380

336

9.9

1157

125

10.8

0.91

0.74

1.13

0.4036

0.2981

Grade 3

3380

50

1.5

1157

14

1.2

1.20

0.65

2.36

0.6536

0.5697

Irritability

All

3380

1957

57.9

1157

716

61.9

0.93

0.85

1.01

0.0992

0.7533

Grade 2-3

3380

702

20.8

1157

285

24.6

0.84

0.73

0.96

0.0139

0.2785

Grade 3

3380

102

3.0

1157

38

3.3

0.92

0.62

1.37

0.7026

0.0220

Fever

All

3381

429

12.7

1158

178

15.4

0.82

0.69

0.98

0.0315

0.2621

> 38.5°C

3381

156

4.6

1158

68

5.9

0.77

0.57

1.04

0.0844

0.2474

> 39.0°C

3381

63

1.9

1158

23

2.0

0.92

0.56

1.55

0.7962

0.3668

> 39.5°C

3381

23

0.7

1158

7

0.6

1.10

0.46

3.03

1.0000

0.7401

> 40.0°C

3380

4

0.1

1158

2

0.2

0.66

0.09

7.25

0.9175

0.3295

Loss of appetite

All

3380

1095

32.4

1157

383

33.1

0.97

0.86

1.09

0.5676

0.1896

Grade 2-3

3380

221

6.5

1157

96

8.3

0.77

0.60

0.99

0.0395

0.0783

Grade 3

3380

43

1.3

1157

16

1.4

0.89

0.49

1.69

0.7856

0.7902

N = number of subjects with at least one documented dose
n/% = number/percentage of subjects reporting the symptom at least once
95% CI = 95% confidence interval for relative risk (Exact Stratified Conditional to total number of cases), LL = lower limit, UL = upper limit
P-value: 2-sided Exact Stratified Test conditional to no. of cases; P-value Interact: 2-sided Exact Breslow & Day Test - heterogeneity across studies
All = all events irrespective of intensity
Incidence of fever is tabulated by 0.5° increments
Fever = rectal or axillary/tympanic temperature ≥38.0°C
Grade 2 = drowsiness interfered with normal activity; temperature >39.0°C to ≤40.0°C; crying more than usual/interfered with normal activity;
eating less than usual/ interfered with normal activity
Grade 3 = drowsiness that prevented normal activity; temperature >40.0°C; crying that could not be comforted/prevented normal activity; not eating at all

*STN 1253633/0, Section 2.7.4, Table 29
** STN 1253633/0, Section 2.7.4, Table 30

Unsolicited Adverse Events Days 0-30 Post-vaccination
Adverse events other than the specified solicited symptoms with onset Day 0-30 post-vaccination as well as solicited AEs with onset outside the 4- or 8-day follow-up period were recorded for studies Hib-MenCY-TT-001, -005, -007, and -009, but not for Hib-MenCY-TT-011 and -012..

While a statistical imbalance was observed in several unsolicited AEs, these analyses were conducted without adjustment for multiplicity. No consistent pattern of AEs is identified. Except for lethargy (higher rate in the Hib vaccine group after
the 4th dose); the imbalances in AEs of all grades were not reflected in the corresponding grade 3 subset for each of these events. Additional grade 3 AEs were reported to have a statistical imbalance included: 1.) Grade 3 upper respiratory
infection after the 4th dose (1.3% of Hib-MenCY and 0.6% of Hib groups with a P-value of 0.0374), none of which were reported as an SAE, while overall upper respiratory infection rates were similar (9.1% in Hib-MenCY group and 8.7% in the Hib group, P-value 0.7437); and 2.) Grade 3 crying across the entire four dose series (0.0% in the Hib-MenCY group vs.
0.3% of subjects in the Hib group, P-value = 0.0311)

Table 7: Unsolicited AEs within 30 days Post-vaccination with statistical imbalance between vaccine groups overall and their corresponding grade 3 events


AE

Grade

Hib-MenCY

Hib

P-value

Primary Vaccination Studies

Bronchitis

All

0.5%

0.1%

0.0461

3

0.1%

0.1%

0.8208

Croup infectious

All

0.8%

1.5%

0.0293

3

0.3%

0.5%

0.1956

Oral candidiasis*

All

0.7%

0.3%

0.0444

3

0.0%

0.0%

1.0000

Rash

All

4.5%

3.1%

0.0412

3

0.1%

0.1%

0.9323

Fourth Dose Vaccination Studies

Injection site nodule

All

0.1%

0.8%

0.0015

 

3

0.0%

0.0%

1.0000

Gastroenteritis rotavirus

All

0.0%

0.2%

0.0308

 

3

0.0%

0.0%

1.0000

Lethargy

All

0.1%

0.6%

0.0008

 

3

0.0%

0.2%

0.0303

Somnolence

All

0.3%

1.0%

0.0133

 

3

0.1%

0.2%

1.0000

Eczema

All

1.1%

0.3%

0.0141

 

3

0.1%

0.0%

1.0000

Across Entire 4-dose Series

Constipation

All

3.3%

2.0%

0.0482

 

3

0.3%

0.3%

1.0000

Insomnia

All

0.7%

1.5%

0.0403

 

3

0.2%

0.3%

0.6416

Rhinitis allergic

All

0.5%

1.2%

0.0427

 

3

0.0%

0.1%

0.4993

Croup infectious

All

1.0%

2.0%

0.0208

 

3

0.4%

0.7%

0.3486

Crying

All

0.2%

0.7%

0.0483

 

3

0.0%

0.3%

0.0311

* Overall and grade 3 candidiasis (including oral candidiasis) showed no statistical imbalance.

STN 1253633/0, Section 2.7.4, pages 146, 177, 199; Tables 61, 62 and 64


 

Additional AEs of Interest

1.   Prespecified AEs of Interest
No statistical imbalances were observed in the rates of reported new onset chronic disease (NOCD), rash and AEs resulting in ER visit across studies. The most frequently reported NOCD was eczema (2.6% of subjects in the Hib-MenCY group and 2.1% of subjects in the Hib group). Asthma was reported in 0.4% of subjects for both treatment groups.

Table 8: New Onset Chronic Disease, rash and AEs resulting in an ER visit Day 0 after Dose 1 through the day preceding administration of Dose 4 (Studies Hib-MenCYTT-005, -007, -009, and -011)


Event

Hib-MenCY
N = 7362

Hib
N = 2697

Relative Risk
(Hib-MenCY over Hib)

 

P-value

 

P-value interact

 

95% CI

 

95% CI

 

95% CI*

n

%

LL

UL

n

%

LL

UL

RR

LL

UL

NOCD

355

4.8

4.3

5.3

118

4.4

3.6

5.2

1.03

0.83

1.28

0.8355

0.6424

Rash

1082

14.7

13.9

15.5

394

14.6

13.3

16

1.02

0.91

1.15

0.7559

0.8613

AEs w/ ER visit

521

7.1

6.5

7.7

186

6.9

6

7.9

1.05

0.89

1.26

0.5727

0.1339

NOCD = new onset chronic disease                                  N = number of subjects with at least one administered dose
n/% = no./percentage of subjects reporting symptom        95% CI = exact 95% confidence interval; LL = lower limit, UL = upper limit
95% CI* = 95% confidence interval for relative risk (Exact Stratified Conditional to total number of cases)
P-value = 2-sided Exact Stratified Test conditional to number of cases              NA = Not Applicable as all events are in one strata
P-value interact = 2-sided Exact Breslow & Day Test for heterogeneity across studies

STN 1253633/0, Section 2.7.4, Table 65

Prespecified AEs of Interest by Country
The reported rates of NOCD, rash and AEs resulting in ER visits were comparable in the US and Australia, and the reported rates were lower in Mexico. The reported rates of SAEs were similar in the three countries. There were no statistical imbalances detected from the Breslow and Day test indicating that the imbalances between Hib-MenCY and Hib groups (as measured by Relative Risks) or the absence thereof did not vary significantly across countries.

2.   Frequent AEs
A meta-analysis of frequently reported AEs (i.e., AE reported in >5% of either the Hib-MenCY or the Hib group) was conducted to unsolicited AEs reported within the 31-day post-vaccination period across studies Hib-MenCY-TT-005/006, -
007/008 and -009/010, to assess for study or country effect. No statistical imbalances detected by the Breslow and Day test in any analysis, except for:

  • Rhinitis within 31 days of any vaccination
    1.9% in the Hib-MenCY group and 1.5% in the Hib group, P-value interact = 0.0463
    This result is due to a statistical imbalance in the rates of rhinitis in Hib-MenCY-TT-007/008 (Australian study), with
    2.9% of subjects in the Hib-MenCY group and 0.5% of subjects in the Hib group with rhinitis (RR = 6.35, P-value =
    0.0480). This result is in contrast to that for the Australian population in HibMenCY-TT-009/010, the observed RR for rhinitis was 0.53. No statistical imbalances were noted in the incidence of rhinitis in the other study populations in the ISS.
  • Cough within 31 days of any vaccination
    6.8% in the Hib-MenCY group and 6.6% in the Hib group, P-value interact = 0.0489
    This result is due to a statistical imbalance in the Australian subjects in Hib-MenCY-TT-009/010, with 6.4% of subjects in the Hib-MenCY group and 13.2% of subjects in the Hib group with cough (RR = 0.48, P-value = 0.0217). No statistical imbalances were noted in the incidence of cough in the other study populations in the ISS.

3.   Medication and Anti-Pyretic Use
Medication use was at the discretion of each study investigator and concomitant medications were recorded for all studies except for Hib-MenCY-TT-001 and -012.  In the latter two studies all medications used for treatment of AEs and SAEs were recorded.  The percentages of subjects who used concomitant medications, antipyretics or prophylactic antipyretics during the 4-day (Days 0-3) post-vaccination period were evaluated and found similar in the Hib-MenCY group and the Hib group after each dose of the primary vaccination course and overall.  A trend of lower usage was seen with subsequent vaccinations.

4.   Prospective Non-inferiority Safety Endpoints
Study 009 safety endpoint comparing the frequency of fever overall for all subjects failed to demonstrate non-inferiority of the Hib-MenCY-TT group to the ActHib group (bolded in Table 9), although comparisons fever after each dose and overall/dose met the statistical definition of non-inferiority. No other endpoints failed to demonstrate non-inferiority as defined.

Table 9: Safety Endpoints in Hib-MenCY-TT Studies

 

Endpoint / Type

Comparison

Results

Hib-MenCY-TT-005

 

Grade 3 solicited and unsolicited AEs Days
0-3  Co-primary objective

Non-inferiority vs. ActHib
LL of 95% CI >-10%

Any symptoms

7.22

General symptoms

4.10

Local symptoms

3.14

Hib-MenCY-TT-009

 

Fever >39.5ºC (>103.1ºF) Secondary objective

Non-inferiority vs. ActHib
LL 95% CI for difference ≥ -
2.4%

Dose 1

-0.34

Dose 2

-0.37

Dose 3

-0.61

Overall/dose

-0.25

Overall/subject

-0.70

Hib-MenCY-TT-10

 

Fever >39.5ºC (>103.1ºF) Co-secondary objective

Non-inferiority vs. PedVaxHib (Both co-administered with MMRII and Varivax)
LL 95% CI ≥ -1.6%

Fever> 39.5ºC (>103.1º F)

-0.66

 

 

 

 

STN 1253633/0, Section 2.7.4, Tables 39, 40, 41

5.   Additional Solicited Symptoms of Interest Related to Concomitant Vaccine Administration (MMRII and Varivax) The following solicited symptoms were evaluated as they are considered of interest for the concomitantly administered vaccines:
•      Signs of meningitis
•      Febrile convulsions
•      Parotid/salivary gland swelling
•      Fever >38°C measured by any method over the 42-day follow-up period
•      Measles/rubella/varicella-like rash

The Hib-MenCY cohort exhibited no increase over the Hib cohort in rates of solicited symptoms specific to co-administered M-M-RII and Varivax in studies Hib-MenCY-TT-008 (all study subjects) and -010 (US Safety and Immunogenicity Cohort only) after the fourth dose.
 

6.   Adverse Events Resulting in Office Visits
Adverse events associated with office visits were evaluated in studies Hib-MenCY-TT-005, -006, -007, -008, -009 and -010 (see Table 10 below). The data were reported in the respective clinical study reports but not evaluated in the ISS analysis. No consistent trend or statistical imbalance was reported in these studies.

Table 10: Physician office visits related to both common* and less common reasons for visit (e.g., illnesses) through ESFU (HibMenCY-TT-005, -006, -007, -008, -009, -010)

 

Hib-MenCY-TT-005

HibMenCY
N = 287

ActHIB
N = 319

 
N%LLULN%LLUL

Physician’s office visit

18163.157.268.719059.65465

Physician’s office visit not related

to common illnesses
5117.813.522.74614.410.818.8

Hib-MenCY-TT-006

HibMenCY
N = 236
ActHIB_ ActHIB
N = 130

ActHIB_HibMenCY
N = 132

N%LLULN%LLULN%LLUL
Physician’s office visit    7531.825.938.13123.816.832.14332.624.741.3

Physician’s office visit not related to common illnesses

135.53.09.286.22.711.8139.85.316.3

Hib-MenCY-TT-007

HibMenCY
N = 661

Meningitec + ActHIB
N = 221

ActHib
N = 221

N%LLULN%LLULN%LLUL
Physician’s office visit  29144.040.247.99040.734.247.58839.833.346.6

Hib-MenCY-TT-008 (booster)

HIb-MenCY (primed w/ Hib-MenCY) N = 625

Hib-MenCY
(primed w/ Meningitec + ActHIB) N = 206

PedvaxHIB (primed w/ ActHIB) N = 204


 
N%LLULN%LLULN%LLUL

Physician’s office visit

22035.231.539.16431.124.837.96330.924.637.7

Hib-MenCY-TT-009

Hib-MenCY N = 3136

Hib
N = 1044

Relative Risk
(Hib-MenCY / Hib)

P- Value

P-value
Interact

N%LLULN%LLULRR95% CI
LLUL
Physician’s office visit133642.640.944.443341.538.544.51.030.921.150.65430.9831

Hib-MenCY-TT-010

Hib-MenCY
N = 2769

Hib
N = 923

Relative Risk (Hib-MenCY / Hib)

P- ValueP-value
Interact
N%LLULN%LLULRR95% CI
LLUL

Physician’s office visit

66824.122.525.820522.219.625.01.080.921.270.34350.0850

At least one symptom = at least one symptom experienced (regardless of the MedDRA Preferred Term)       N = number of subjects with at least one administered dose
n/% = number/percentage of subjects reporting a given symptom at least once                                               95% CI= exact 95% confidence interval; LL = Lower Limit, UL = Upper Limit
*Common illnesses: well-child care, vaccination, injury, or common acute illnesses (e.g., upper respiratory tract infection, otitis media, pharyngitis, gastroenteritis

STN 1253633/0, Section 5.3.5.1.3, Clinical Study Reports 005, 006, 007, 008,009, 010; Tables 46, 39, 29, ,41, 60, 62, respectively

Serious Adverse Events
1.   Primary vaccination studies (Hib-MenCY-TT-005, -007, -009, -011)
No statistically significant imbalances between vaccine cohorts was observed in the reported rates of overall and specific reported SAEs in the primary vaccination studies.
There was one statistical imbalance detected by the Breslow and Day test, an increase in viral infection SAEs in the Hib- MenCY group vs. Hib group in Hib-MenCY-TT-009, but the rates are lower for the Hib-MenCY groups vs. the respective Hib groups in studies MenCY-TT-005, -007, and -011.

2.   Fourth dose studies (Hib-MenCY-TT-006, -008, -010 and -012)
No statistically significant imbalances between vaccine cohorts was observed in the reported rates of overall and specific reported SAEs in studies of a fourth vaccine dose.

There were no statistical imbalances detected by the Breslow and Day test across studies.

3. SAEs of interest

  • ITP
    One case occurred 14 days after the fourth vaccine dose in the Hib-MenCY group in a 12-month old male in study Hib- MenCY-010, and one case of ITP occurred in a 14-month old male in the Hib-MenCY group 58 days after the fourth dose of the vaccine.
  • Henoch-Schonlein Purpura
    One case occurred in the Hib-MenCY group in an 18-month old male, 171 days after the fourth dose of the vaccine.

Deaths
A total of 25 deaths have been reported involving 18 individuals in the Hib-MenCY group including 1 in the earlier formulation, Hib-MenCY-TT (5/5/5), group and 7 individuals in the Hib group and are summarized in Table 10 below.

Nineteen deaths [12 deaths in the Hib-MenCY group (including 1 death in the Hib-MenCY-TT (5/5/5) group), and 7 deaths in the Hib group] were reported during the entire course of the completed primary vaccination phase studies. The onset of the fatal events occurred within the 31-day post-vaccination period for 10 cases.

Two deaths [both in the Hib-MenCY-TT group] have been reported in the completed 4th dose vaccination studies.

Four deaths, all in Hib-MenCY vaccinees, were reported thru February 16, 2009, in the ongoing study, MenACWY-TT-057.

Table 11: Summary of deaths reported in clinical studies with the Hib-MenCY-TT vaccine (TVC)


Study

N total

Deaths

Hib-MenCY

Hib

 

 

 

N

Deaths

N

Deaths

Completed primary vaccination phase studies

Hib-MenCY-TT-001

407

1*

82

1*

82

0

Hib-MenCY-TT-003

388

0

78

0

-

-

Hib-MenCY-TT-005

756

1

287

1

319

0

Hib-MenCY-TT-007

1103

1

661

0

221

1

Hib-MenCY-TT-009

4180

4

3136

3

1044

1

Hib-MenCY-TT-011

4391

12

3278

7

1113

5

Completed fourth dose phase studies

Hib-MenCY-TT-004

222

0

47

0

-

-

Hib-MenCY-TT-006‡

498

1

236

1

130

0

Hib-MenCY-TT-008†

1035

0

625

0

204

0

Hib-MenCY-TT-010

3692

1

2769

1

923

0

Hib-MenCY-TT-012

4020

0

3010

0

1010

0

Ongoing study (data lock point: 16 February 2009)

MenACWY-TT-057 (primary phase) §

~1548

4

~1290

4

~258

0

Note: No deaths reported in ongoing studies Hib-MenCY-TT-002, -013 and -014
Note: The fatal SAE in the Hib group listed in Hib-MenCY-TT-007 began during the ESFU of that study, but the subject died during ESFU in Hib-MenCY-TT-008 after receiving the fourth dose of study vaccine as planned
N = number of subjects in the TVC
* The death was reported in the Hib-MenCY-TT (5/5/5) group
‡ For study Hib-MenCY-TT-006: 132 subjects in the ActHIB_Hib-MenCY group received a single dose of the Hib-MenCY-TT
vaccine at approximately 12-15 months of age after priming with ActHIB
†Study Hib-MenCY-TT-008: 206 subjects were assigned to the LicMenC group in the primary phase, and of these, 205 subjects received a single dose of the Hib-MenCY-TT vaccine 12-15 months after priming with ActHIB and Meningitec
§ SAE data from ongoing studies are considered to be preliminary.

STN 1253633/0, Section 1.16, PVP, Table 16


 

Table 12: Serious adverse events leading to death during the completed primary vaccination phase studies
(Hib-MenCY-TT-001, -003, -005, -007, -009, and -011, all groups)


Group

Subj. No. / Country

Case Id

Age at onset (Week)

Sex

Preferred term

MA
type

Dose

Day of onset

Duration

Outcome

Study Hib-MenCY-TT-001

 

5/5/2005

001-357 / Australia

B0303285A

23

F

Sudden infant death syndrome

ER

1

88

-

Fatal

Study Hib-MenCY-TT-005

 

Hib-MenCY

005-100297 / US

A0544121A

22

F

Sudden infant death syndrome

ER

2

30

1

Fatal

Study Hib-MenCY-TT-007

 

Hib

007-577 / Australia

B0435502A

49

M

Hypertrophic cardiomyopathy

HO

3

160

179

Fatal

Study Hib-MenCY-TT-009

 

Hib-MenCY

009-11906 / Mexico

B0452039A

28

M

Gastroenteritis

HO

3

29

2

Fatal

Hib-MenCY

009-1187 / US

B0470445A

34

M

Child maltreatment syndrome

HO

3

30

49

Fatal

Hib-MenCY

009-7472 / US

B0439262A

16

F

Sudden infant death syndrome

MD

1

43

1

Fatal

Hib

009-11559 / Mexico

B0467393A

37

F

Aspiration bronchial

ER

3

89

1

Fatal

Study Hib-MenCY-TT-011

 

Hib-MenCY

011-4021 / Mexico

B0451077A

7

F

Sudden infant death syndrome

ER

1

10

1

Fatal

Hib-MenCY

011-28 / Mexico

B0445944A

12

F

Hypovolaemic shock

HO

1

14

8

Fatal

Hib-MenCY

011-636 / Mexico

B0460907A

21

M

Bronchiolitis

ER

2

16

11

Fatal

22

 

Dehydration

ER

2

24

3

Fatal

22

 

Gastroenteritis

ER

2

24

3

Fatal

Hib-MenCY

011-4302 / Mexico

B0460908A

13

F

Pneumonia

MD

1

26

2

Fatal

Hib-MenCY

011-1403 / Mexico

B0468848A

11

F

Sudden infant death syndrome

ER

1

37

1

Fatal

Hib-MenCY

011-7729 / US

B0451815A

14

M

Sudden infant death syndrome

MD

1

38

1

Fatal

Hib-MenCY

011-1359 Mexico

B0475988B

44

M

Pneumonia

HO

3

77

9

Fatal

Hib

011-1325 Mexico

B0466435B

19

M

Pneumonia

HO

2

13

30

Fatal

24

 

Cardiac failure congestive

HO

2

42

1

Fatal

Hib

011-4241 Mexico

B0463326A

18

M

Bronchopneumonia

HO

2

16

8

Fatal

Pharyngitis

HO

2

16

8

Fatal

Hib

011-3786 Mexico

B0451071A

10

M

Sudden infant death syndrome

ER

1

22

1

Fatal

Hib

011-3381 Mexico

B0453412A

10

M

Pneumonia

MD

1

24

28

Fatal

Hib

011-3420 Mexico

B0455715A

11

F

Sudden infant death syndrome

MD

1

25

1

Fatal

Sex = Male (M) or Female (F)
Dose = Last dose administered prior to the start of the SAE Day of onset = Number of days since last vaccine dose
MA type (Medical Attention type) = HO: hospitalization; ER: emergency room visit; MD: medical doctor visit; MC = missing confirmed

STN 1253633/0, Section 1.16, PVP, Table 17


 

Table 13: Serious adverse events leading to death during the entire course of the fourth dose studies
(Studies Hib-MenCY-TT-004, -006, -008, -010, and -012, all groups)


Group

Subj. No. / Country

Case Id

Age at onset
(Week)

Sex

Preferred term

MA
type

Dose

Day of onset

Duration

Outcome

Study Hib-MenCY-TT-006

 

Hib-MenCY

006-100113 / US

B0420193A

72

M

Sudden death

ER

4

140

1

Fatal

Study Hib-MenCY-TT-010

 

Hib-MenCY

010-4890 / US

B0468818A

57

F

Multiple injuries

MC

4

29

1

Fatal

Sex = Male (M) or Female (F)                                                                             Dose = Last dose administered prior to the start of the SAE
Day of onset = Number of days since last vaccine dose
MA type (Medical Attention type) = HO: hospitalization; ER: emergency room visit; MD: medical doctor visit, MC: missing confirmed

STN 1253633/0, Section 2.4.7, Summary of Clinical Safety Table 50

Table 14: Serious adverse events in unblinded subjects who died up to 16-FEB-2009 data lock point in ongoing study
(Study MenACWY-TT-057, uncleaned database)


Group

Subj. No. / Country

Case Id

Age at onset
(Week)

Sex

Preferred term

MA
type

Dose

Day of onset

Duration

Outcome

Study Hib-MenCY-TT-057 primary phase vaccination study (US subjects randomization 5:1 to Hib-MenCY or Hib)

 

Hib-MenCY

1912 / US

R0000398A

11

M

Bronchiolitis

HO

1

24

19

Recovered / resolved

R0000398C

12

Dyspnoea

HO

1

31

10

Recovered / resolved

R0000398D

14

Apnoea

HO

1

42

5

Recovered / resolved

R0000398E

12

Respiratory arrest

HO

1

27

3

Recovered / resolved

R0000398F

17

Convulsion

HO

1

65

---

Not recovered / Not resolved

R0000398G

21

Sudden infant death syndrome

ER

1

89

1

Fatal

Hib-MenCY

2603 / US

R0000425A

13

F

Sudden infant death syndrome

ER

1

33

1

Fatal

Hib-MenCY

2709 / US

R0000387A

16

M

Dehydration

HO

1

43

57

Fatal

16

Haemolytic uraemic syndrome

HO

1

43

57

Fatal

16

Septic shock

HO

1

43

57

Fatal

Hib-MenCY

3913 / US

R0000785A*

36

F

Leukaemia

HO

3

57

101

Fatal

NOTE: The SAE data from ongoing studies are considered to be preliminary until final reconciliation is completed after study conclusion.
Sex = Male (M) or Female (F)                     Dose = Last dose administered prior to the start of the SAE                                     Day of onset = Number of days since last vaccine dose
MA type (Medical Attention type) = HO: hospitalization; ER: emergency room visit; MD: medical doctor visit, MC: missing confirmed
* = SAE available in GSK SAE database but not in clinical database. SAEs reported in clinical studies are recorded both in the clinical study database and in the GSK SAE database. Since these preliminary safety data have not undergone a final reconciliation, some SAEs are available only in the GSK SAE database at this time.

STN 1253633/0, Section 2.4.7, Summary of Clinical Safety Table 51

Deaths in Infants
Table 15 displays PTs reported in infants who died, whereas Table 11, above, displays deaths reported in children of all ages in the indicated clinical studies. The infant cohort is a subset of all children enrolled in the clinical studies since older children were also enrolled

Table 15: Frequency of PTs reported in Infants who died during primary Vaccination Studies
(Studies Hib-MenCY-TT-001, -003, -005, -007, -009, and -011)


Preferred Term

Number of Death Cases by Vaccine Cohort

 

Total

Hib-MenCY N = 4113

Hib
N = 1635

Any

23*

11

7

Aspiration bronchial

1

1

0

Bronchiolitis

1

1

0

Bronchopneumonia

1

0

1

Cardiac failure congestive

1

0

1

Childhood maltreatment syndrome

1

1

0

Dehydration

1

1

0

Gastroenteritis

2

2

0

Hypertrophic cardiomyopathy

1

0

1

Hypovolaemic shock

1

1

0

Pharyngitis

1

0

1

Pneumonia

4

2

2

Sudden Infant Death Syndrome

8*

6

2

*Includes one subject who received the non-license formulation Hib-MenCY-TT (5/5/5) NOTE: More than one PT may have been reported for a subject

STN 1253633/0, Section 1.16, PVP, Table 17

Sudden Infant Death Syndrome
The most commonly reported cause of death in the submitted studies was Sudden Infant Death Syndrome (SIDS). This syndrome is defined as sudden death in an infant less than 12 months age and not explained by review of clinical history, investigation of the death scene and autopsy.

A total of 8 cases of SIDS were reported (6 cases in Hib-MenCY recipients and 2 cases in Hib recipients) including 5 females and 3 males; two additional cases of SIDS have occurred in the ongoing study, MenACWY-TT-057.  In the Hib- MenCY cohort, 4 cases are from the US, 3 cases from Mexico and 1 case from Australia; in the Hib cohort 2 cases are from Mexico.

SIDS was reported following Dose 1 in seven cases and Dose 2 in one case and occurred 10-89 days postvaccination
(median 38 days).

Table 16: Sudden Infant Death Cases occurring during completed primary vaccination studies
(Studies Hib-MenCY-TT-001, -003, -005, -007, -009, and -011)


Group

Subj. No. / Country

Case Id

Age at onset (Wk)

Sex

MA type

Dose

Day of onset

Duration

Study Hib-MenCY-TT-001

 

5/5/2005

001-357 / Australia

B0303285A

23

F

ER

1

88

-

Study Hib-MenCY-TT-005

 

Hib-MenCY

005-100297 / US

A0544121A

22

F

ER

2

30

1

Study Hib-MenCY-TT-007 - No SIDS cases

Study Hib-MenCY-TT-009

 

Hib-MenCY

009-7472 / US

B0439262A

16

F

MD

1

43

1

Study Hib-MenCY-TT-011

 

Hib-MenCY

011-4021 / Mexico

B0451077A

7

F

ER

1

10

1

Hib-MenCY

011-1403 / Mexico

B0468848A

11

F

ER

1

37

1

Hib-MenCY

011-7729 / US

B0451815A

14

M

MD

1

38

1

Hib

011-3786 Mexico

B0451071A

10

M

ER

1

22

1

Hib

011-3420 Mexico

B0455715A

11

F

MD

1

25

1

Sex = Male (M) or Female (F)                                                              Dose = Last dose administered prior to the start of the SAE
Day of onset = Number of days since last vaccine dose                   No = no relationship to vaccination as determined by the investigator
MA type (Medical Attention type) = HO: hospitalization; ER: emergency room visit; MD: medical doctor visit

STN 1253633/0, Section 1.16, PVP, Table 17

Pharmacovigilance Plan:
Focused Postmarketing safety surveillance
1.   Serious expected adverse events
At the request of the FDA, GSK proposes to provide monthly periodic reports, consisting of all US serious, expected adverse event reports, for one year following US licensure of HibMenCY-TT vaccine. This will be in addition to expedited reporting of serious unexpected events and filing quarterly periodic safety reports per regulation.

2.   Purpura
In the Menitorix (Haemophilus influenzae type b and Neisseria meningitidis group C conjugate) vaccine UK Risk Management Plan, purpura is considered to be a class effect for meningococcal conjugate vaccines. In addition, the FDA requested that GSK monitor cases of purpura during the Hib-MenCY-TT clinical trials. As part of this PVP, purpura is considered to be an important potential risk per applicable guidances.

GSK Biologicals will follow up reports of purpura with a targeted questionnaire to obtain a more standardized and detailed description of the cases in order to facilitate detection of any patters or potential risk factors. This questionnaire is presented in Appendix 1, Section 1.16 Risk Management Plans. All spontaneous reports of purpura will be discussed in each US Periodic Report/PSUR.

RiskMAP
The sponsor asserts that no specific risks have been identified, and therefore no RiskMAP is required.

Postmarketing Experience with Related Product (Hiberix)
Menitorix [Haemophilus type b and Neisseria meningitides group C conjugate vaccine]

Routine pharmacovigilance:
a.   Safety signal of anaphylactic reaction / anaphylactoid reaction
30-MAR-08 Pharmacovigilance Review: Proposed inclusion in the Core Safety Information (CSI) for Menitorix

b.   Safety signal of febrile convulsion
12-OCT-07 Pharmacovigilance Review: Proposed inclusion in the CSI for Menitorix

Proposed Labeling for Hib-MenCY with Respect to Postmarketing Experience
Based upon postmarketing surveillance through 31-MAY-08 and subsequent data analysis, the sponsor proposes to include the following spontaneously reported adverse events in the Postmarketing Experience section of the HibMenCY US package insert:

  • Rash
  • Convulsion (with or without fever)
  • Hypotonic-hyporesponsive episode
  • Syncope or vasovagal responses to injection
  • Somnolence
  • Apnea
  • Urticaria
  • Allergic reactions (anaphylactic/anaphylactoid reactions)
  • Angioedema
  • Extensive swelling of vaccinated limb
  • Injection site induration

Postmarketing Studies (planned)

  1. Study Hib-MenCY-TT-016
    Immunogenicity, safety and reactogenicity of GSK Biologicals’ Hib-MenCY-TT vaccine compared to Sanofi-Pasteur’s DTPa- IPV/Hib vaccine in healthy infants and toddlers, evaluating the safety and immunogenicity of Havrix and Rotarix concomitantly administered with Hib-MenCY-TT vaccine. When available, a draft protocol will be provided to CBER for review and agreement. GSK expects to initiate this study in 2010, once licensure of Hib-MenCY-TT vaccine has been granted with the study report submitted to CBER in 2013.
  2. Possible post-authorization safety study which is not further described in this submission.

REVIEW COMMENTS:

  1. This reviewer finds no actual or potential safety issues that would require a PMR.
  2. Final determination of the safety profile of the product used in the studies submitted to this BLA is pending final clinical, statistical and product reviews.
  3. Epidemiologic comments on reported cases of deaths including SIDS
    1. The reported rates of all cause death and sudden infant death syndrome following vaccination with HibMnCY- TT as described in this review appear to be comparable to recent background rates in the US (Heron, National Vital Statistics Reports, Deaths: Final Data for 2006 as shown in Tables A and B, below), noting that some of the study data are submitted from non-US study sites and data on background rates for these non-US populations are not readily available.

      Table A: 2006 U.S. infant mortality rates per 1,000 live births

      All infants

      6.69

      Neonatal (0-27 days)

      4.45

      Post-neonatal (28 days – 1 yr)

      2.24

      Males

      7.32

      Females

      6.03

      White*

      5.56

      Black*

      13.29

       *based upon race of mother

       
    2. Cause of death is available only for infants overall, and not for post-neonatal infants, the age group enrolled in the Hib-MenCY-TT studies. It appears that many of the listed causes would have either resulted in death prior to recruitment or likely precluded enrollment.

      Table B: The 10 leading causes of U.S. infant death in 2006*
       

      Rank

      Cause of Death
      (ICD-10, 2004)

      N

      % of total deaths

      Rate*

      ---

      All causes

      28,527

      100.0

      668.8

      1

      Congenital malformation, deformations, and chromosomal abnormalities

      5,819

      20.4

      136.4

      2

      Disorders related to short gestation and low birth weight, no elsewhere classified

      4,841

      17.0

      113.5

      3

      Sudden infant death syndrome

      2,323

      8.1

      54.5

      4

      Newborn affected by maternal complications of pregnancy

      1,683

      5.9

      39.5

      5

      Accidents Unintentional injuries)

      1,147

      4.0

      26.9

      6

      Newborn affected by complications of placenta, cord and membranes

      1,140

      4.0

      26.7

      7

      Respiratory distress of newborn

      825

      2.9

      19.3

      8

      Bacterial sepsis of newborn

      807

      2.8

      18.9

      9

      Neonatal hemorrhage

      618

      2.2

      14.5

      10

      Disease of the circulatory system

      543

      1.9

      12.7

      ---

      All other causes

      8,781

      30.8

      205.9

      *Rates are infant deaths per 100,000 live births
      Heron (2009), National Vital Statistics Reports, Deaths: Final Data for 2006

    3. SIDS—sudden infant death syndrome is more recently considered under the broader term, SUID – sudden unexplained death with includes two additional terms: ASSB—accidental suffocation and strangulation in bed; and death due to unknown causes.  This would be expected to impact current reporting rates and comparison of to historical rates of SIDS.
    4. It should be noted that nearly 3 times as many subjects were exposed to Hib-MenCY as compared to Hib vaccine in the primary vaccination studies and 4th dose studies, so that the proportion of subjects with SIDS in the vaccine cohorts appears to be a reflection of the differential enrollment into the two vaccine cohorts.
    5. There does not appear to be any particular temporal clustering of SIDS cases, taking into account the safety observation periods and sizes of the studies. While SIDS occurs most commonly in infants 2-4 months of age, the multiple dose vaccination schedule and postvaccination safety observation periods might be expected to identify relatively more SIDS cases in older infants. However, 7 of the 8 SIDS cases occurred after Dose 1 administered at 2 months of age, representing the higher incidence SIDS in younger infants.