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Clinical Review - November 25, 2002 - Pediarix

MEMORANDUM
DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

Date: November 25, 2002
From: Karen M. Farizo, M.D.
Medical Officer
Vaccines Clinical Trials Branch
Division of Vaccines and Related Product Applications
Subject: New Biologics License Application 99-0800 -- Pediarix
Clinical review of interim study report for Protocol 084 [BLA Amendment 35 (STN 103907/0.5034)] and responses to CBER questions from July 30, 2002 telecon [BLA Amendment 39 (STN 103907/0.5042)]
To: BLA 99-0800
STN 103907
Through: Antonia Geber, M.D.
Chief, Vaccines Clinical Trials Branch
Division of Vaccines and Related Products Applications
Cc: Rolf E. Taffs, Ph.D
Theresa Finn, Ph.D.

Date received: Amendment 35-- June 13, 2002; Amendment 39-- August 9, 2002

Candidate Vaccine: Pediarix [Diphtheria and Tetanus Toxoids and Acellular Pertussis, Hepatitis B (Recombinant), Inactivated Poliovirus Vaccine Combined]

Sponsor: GlaxoSmithKline (GSK)

Background: In previous studies submitted to the Pediarix BLA, the incidence of fever tended to be higher in infants who received Pediarix and Haemophilus influenzae type b (Hib) vaccine concomitantly, relative to those who received separate administration of Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine (DTaP), Hepatitis B vaccine, oral poliovirus vaccine, and Hib vaccines. These studies were conducted prior to the approval of Prevnar (Wyeth Lederle's pneumococcal conjugate vaccine) and recommendations for its use in U.S. infants. Previous studies also have shown an increased incidence of fever in infants who received certain DTaP or DTaP-based combination vaccines concomitantly with Prevnar, relative to infants who did not receive concomitant Prevnar. In discussions at the Vaccines and Related Biologics Products Advisory Committee Meeting on Pediarix in March 2001, it was felt that safety data on concomitant administration of Pediarix and Prevnar should be available prior to licensure of Pediarix. It was subsequently agreed that prior to licensure of Pediarix, GSK would initiate a study to evaluate the safety of a three-dose series of Pediarix vs. separate vaccines, administered concomitantly with Hib vaccine and Prevnar (Study 084), and submit an interim study report on safety data following the first dose of study vaccines. A full clinical report will be submitted after completion of the study.

Amendment 35 contains the interim study report for Study 084 and amendment 39 contains responses to CBER questions about the interim study report.

CLINICAL REVIEW

Protocol #: 217744/084 (DTPa-HepB-IPV-084)

Study Title: A phase III, open labeled, randomized, multicenter, clinical study of the safety of a primary series of GlaxoSmithKline Biologicals' (GSK Biologicals') DTPa-HepB-IPV candidate vaccine coadministered with HibTITER and Prevnar to healthy infants at 2, 4, and 6 months of age as compared to the separate administration of Infanrix +Engerix-B + IPOL + HibTITER + Prevnar.

Objectives:

Primary: To evaluate the incidence of grade 2 or grade 3 fever (rectal temperature >38.5° C/>101.3° F) during the 4 days (day 0 - day 3) following a first dose of Pediarix coadministered with HibTITER and Prevnar as compared to that following separate administration of Infanrix, Engerix-B, IPOL, HibTITER and Prevnar.

Secondary: To evaluate the safety of Pediarix coadministered with HibTITER and Prevnar as compared to that following separate administration of Infanrix, Engerix-B, IPOL, HibTITER, and Prevnar.

Design: Open, randomized, multicenter, vaccine safety study. Infants were enrolled at 2 months of age and randomized 2:1 into the following groups:

  • Combination Vaccine Group: Pediarix + HibTITER + Prevnar at 2, 4, 6 months of age
  • Separate Vaccine Group: Infanrix + Engerix-B + IPOL + HibTITER + Prevnar at 2, 4, 6 months of age

Study Population: Nine hundred ninety-nine subjects were to be enrolled (666 in the combination vaccine group and 333 in the separate vaccine group) from 18 U.S. sites.

Inclusion criteria:

  • A male or female infant 2 months (6 - 12 weeks) of age at the time of the first vaccination
  • Free of obvious health problems as established by medical history and clinical examination before entering into the study
  • Written informed consent obtained from the parent or guardian of the subject
  • Born after a normal gestation period (36 to 42 weeks)

Exclusion criteria:

  • Use of any investigational or non-registered drug or vaccine other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period
  • Planned administration/ administration of a vaccine not foreseen by the study protocol within 30 days of the first dose of vaccine(s)
  • Previous vaccination against diphtheria, tetanus, pertussis, hepatitis B, polio, H. influenzae type b, and/or Streptococcus pneumoniae
  • History of diphtheria, tetanus, pertussis, hepatitis B, polio, H. influenzae type b, and/or S. pneumoniae disease
  • Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection
  • History of allergic disease or reactions likely to be exacerbated by any component of any of the vaccines, including streptomycin, neomycin, polymyxin B, thimerosal, 2-phenoxyethanol, and formaldehyde
  • Major congenital defects or serious chronic illness
  • History of any neurologic disorders or seizures
  • Inability to contact a parent/guardian of the subject by telephone
  • Acute illness* at the time of vaccination (warrants deferral of the vaccination pending recovery)

*Acute illness is defined as the presence of a moderate or severe illness with or without fever. All vaccines can be administered to persons with a minor illness such as diarrhea or mild upper respiratory infection with or without low-grade febrile illness, i.e., rectal temperature <38.0°C (<100.4°F), axillary temperature <37.5°C (<99.5°F), tympanic temperature on oral setting <37.5°C (<99.5°F), or tympanic temperature on rectal setting <38.0°C (<100.4°F).

Vaccination schedule:

Table 1. Study 084 Vaccination Schedule

Group Age (months) * Vaccine +
Combined Vaccine Group 2, 4, 6 Pediarix
  2, 4, 6 Prevnar (Wyeth Lederle's pneumococcal conjugate vaccine)
  2, 4, 6 HibTITER (Wyeth Lederle's Hib conjugate vaccine)
Separate Vaccine Group 2, 4, 6 Infanrix (GSK's DTaP vaccine)
  2, 4, 6 Engerix-B (GSK's Hepatitis B vaccine, recombinant)
  2, 4, 6 IPOL (Aventis Pasteur's inactivated poliovirus vaccine)
  2, 4, 6 Prevnar
  2, 4, 6 HibTITER

* Acceptable age at first vaccination is 6-12 weeks (42-90 days). Acceptable interval between first and second doses and second and third doses is 49-83 days.
+ Except for Pediarix, all study vaccines are licensed in the U.S.

Endpoints

Primary

Incidence of grade 2 or grade 3 fever (rectal temperature >38.5°C/>101.3° F) occurring within 4 days (day 0 - day 3) following dose 1.

Secondary

  • Incidence of fever of any intensity (rectal temperature ≥38.0°C/ ≥100.4°F) occurring within 4 days after each vaccine dose
  • Incidence of grade 2 or grade 3 fever (>38.5°C/>101.3° F) occurring within 4 days following dose 2 and dose 3
  • Incidence of grade 3 fever (>39.5°C/>103.1°F) occurring within 4 days after each vaccine dose
  • Incidence of fever >39.0°C (>102.2°F) occurring within 4 days after each vaccine dose
  • Incidence of other solicited general symptoms (any intensity and grade 3) occurring within 4 days after each vaccine dose
  • Incidence of solicited local symptoms (any intensity and grade 3) occurring within 4 days after each vaccine dose
  • Incidence of antipyretic use within 4 days after each vaccine dose
  • Incidence of antibiotic use within 4 days after each vaccine dose
  • Incidence of unsolicited adverse events occurring throughout the entire active phase of the study (including the 31-day follow-up period after the last dose of vaccine)
  • Occurrence of serious adverse events throughout the entire study period including the 182 day follow-up period after dose 3.

Adverse Event Monitoring

Surveillance Period After vaccination, each subject was observed for at least 30 minutes. Solicited adverse events were to be assessed in the evening of the day of vaccination (day 0) and every evening for the following three days (day 1 - day 3). A ll adverse events occurring within the entire active phase of the study [day 0 of the first dose to one month after the last dose (minimum 31 days)] were to be recorded in the subject's electronic case report form. Information on the following events also was collected during the extended safety follow-up phase [from one month through 6 months (182days) after the last dose of vaccine]: onset of chronic illness(es) (diabetes, autoimmune disease, asthma, and allergies), emergency room visits and physician office visits that were not related to well-child care, vaccination, or common acute illnesses such as upper respiratory infection, otitis media, pharyngitis, and gastroenteritis. For each subject, all serious adverse events occurring during the period from the day of the first dose of study vaccine through six months following the last dose of vaccines were to be recorded.

Memory aids Parents/guardians of subjects were given memory aids with information regarding solicited local and general symptoms for the 4-day follow-up period, concomitant medications, and unsolicited adverse events, including serious adverse events. For each solicited symptom, the memory aids included a check box to indicate whether medical advice was sought. Memory aids were to be used by parents/guardians to record information on adverse events and to report this information during telephone calls with study staff. Memory aids were not collected or kept at the study sites.

Telephone contacts

Between days 4 and 6 following each vaccination, study personnel contacted parents/guardians to obtain information on solicited local and general symptoms, the occurrence of unsolicited adverse events including serious adverse events, and administration of concomitant medications during the 4 days (day 0 - day 3) post-vaccination. For each solicited and unsolicited symptom experienced, the subject's parent/guardian was to be asked if they sought medical advice (a visit to or from medical personnel [M.D., D.O., or nurse practitioner]) for any reason.

Between days 31 and 33 following the third vaccination, study personnel contacted parents/guardians to obtain information on the occurrence of unsolicited adverse events, including serious adverse events, and administration of concomitant medications during the period 4-30 days post-vaccination. For each unsolicited symptom experienced, the subject's parent/guardian was asked if they sought medical advice (a visit to or from medical personnel [M.D., D.O., or nurse practitioner]) for any reason.

Six months (182 to 194 days) after the third vaccination, study personnel contacted parents/guardians to obtain information on any serious adverse event that their child may have experienced since the last telephone contact. Information was also collected on the onset of chronic illness(es) and emergency room visits and physician office visits that were not related to well-child care, vaccination, or common acute illnesses that their child may have experienced.

Solicited adverse events

For all subjects, the solicited local symptoms of pain, redness and swelling at the injection site, and the solicited general symptoms of fever, irritability/fussiness, loss of appetite and drowsiness were to be assessed in the evening of the day of vaccination (day 0) and every evening for the following three days (day 1 - day 3). Parents/guardians were given measurement gauges and digital thermometers to assess injection site reactions and body temperature (rectal route preferred). Temperatures taken by the axillary route were converted to the corresponding rectal temperature by adding 1.0°C. Oral temperatures were converted to the corresponding rectal temperature by adding 0.5°C.

Diagnostic studies to evaluate medically attended fever

For each subject for whom medical attention (a visit to or from medical personnel [M.D., D.O., or nurse practitioner]) was sought for fever, a questionnaire was sent to the study site to collect information on diagnostic studies that were performed to evaluate fever.

Statistical considerations The planned sample size (666 subjects in the Pediarix group and 333 subjects in the separate vaccines group) provides 80% power to rule out a doubling of fever >38.5°C, assuming a 4% incidence in the separate vaccines group.

Results-- Dose 1 Interim Analysis

Between December 13, 2001 and April 16, 2002, a total of 1008 subjects were enrolled at 31 study sites, with 673 subjects in the Pediarix group and 335 subjects in the separate vaccines group. Upon availability of the 4-day follow-up for all subjects, the database was locked on May 13, 2002 for the dose 1 interim analysis. At the time of the database lock, 381 subjects had received dose 2 (128 subjects in the separate vaccines group and 253 subjects in the Pediarix group) and 25 subjects had received dose 3 (nine subjects in the separate vaccines group and 16 subjects in the Pediarix group).

Modified Intent to Treat Cohort The cohort analyzed for the interim safety report includes all randomized subjects for whom data are available. Among the 1008 subjects enrolled, two subjects with no safety follow-up were excluded from the analyses.

Study Drop Outs As of the time of the database lock, 13 subjects discontinued the study after receiving dose 1. Safety data following dose 1 were obtained for these 13 subjects and are included in the interim analysis. Reasons for discontinuing the study were withdrawal of consent (6), migration from study area (4), receipt of hepatitis B vaccine at birth (1), and lost insurance (2). No subjects discontinued due to an adverse event.

Demographics Subjects in the separate vaccines group and the Pediarix group were similar with regard to race, age, and gender. Overall (both groups combined), the mean age at enrollment was 8.5 weeks, 50% were male, 69.2% were White, 18.4% were Hispanic, 6.6% were Black, 2.9% were Oriental, and 2.9% were of other racial/ethnic groups.

Solicited General Adverse Events

Table 2. Study 084 Incidence of fever reported within 4 days following dose 1 (Day 0- Day 3) by intensity

Symptom Intensity Separate Vaccine Group
(N =333)
Pediarix Group
(N =667)
n % 95% CI n % 95% CI
LL UL LL UL
Fever* ≥ 38.0°C 66 19.8 15.7 24.5 186 27.9 24.5 31.5
  > 38.5°C# 15 4.5 2.5 7.3 47 7.0 5.2 9.3
  > 39.0°C 1 0.3 0.0 1.7 15 2.2 1.3 3.7
  > 39.5°C 0 0.0 0.0 1.1 3 0.4 0.1 1.3
  M.A. 0 0.0 0.0 1.1 8 1.2 0.5 2.3

Separate Vaccine Group: Infanrix + Engerix-B + IPOL + HibTITER + Prevnar
Pediarix Group: Pediarix + HibTITER + Prevnar
CI = confidence interval; LL = lower limit, UL = upper limit
M.A. = medical advice sought [a visit to or from medical personnel (M.D., D.O., or nurse practitioner)]
* rectal temperature. Axillary temperatures were reported for one subject and were increased by 1°C to derive equivalent rectal temperatures. Three subjects for whom no temperature measurements were recorded and three subjects for whom temperature was measured with tympanic thermometers were excluded from the analysis of fever; none of the six excluded subjects sought medical advice for fever.
# primary endpoint
N.B.: endpoints for which the CI does not include 0 or the p-value is < 0.05 are highlighted in bold
Source: 103907/0.5042 pages 10-11.

Table 3. Study 084 Comparison of solicitedgeneral symptoms between groups, reported within 4 days following dose 1 (Day 0 - Day 3)

Symptoms Intensity Separate
Vaccine
Group
(N=335)
Pediarix
Group
(N=671)
Separate Vaccine
Group minus
Pediarix Group
diff. 95% CI
n % n % LL UL
Fever* ≥ 38.0°C 66 19.8 186 27.9 -8.07 -13.54 -2.60
> 38.5°C# 15 4.5 47 7.0 -2.54 -5.50 0.41
> 39.0°C 1 0.3 15 2.2 -1.95 -3.22 -0.68
> 39.5°C 0 0.0 3 0.4 -0.45 -0.96 0.06
M.A. 0 0.0 8 1.2 -1.20 -2.03 -0.37
Drowsiness Any 181 54.0 383 57.1 -3.05 -9.57 3.47
Grade 3 12 3.6 16 2.4 1.20 -1.10 3.50
Irritability / Fussiness Any 206 61.5 406 60.5 0.99 -5.40 7.38
Grade 3 13 3.9 23 3.4 0.45 -2.03 2.94
Loss of appetite Any 93 27.8 204 30.4 -2.64 -8.57 3.28
Grade 3 2 0.6 5 0.7 -0.15 -1.20 0.90

Separate Vaccine Group: Infanrix + Engerix-B + IPOL + HibTITER + Prevnar
Pediarix Group: Pediarix + HibTITER + Prevnar
diff. = difference between groups in %
CI = confidence interval; LL = lower limit, UL = upper limit
M.A. = medical advice sought [a visit to or from medical personnel (M.D., D.O., or nurse practitioner)]
Grade 3 = Drowsiness that prevents normal activity; Irritability: crying that cannot be comforted/prevents normal activity; Loss of appetite: not eating at all.
* rectal temperature. Axillary temperatures were reported for one subject and were increased by 1°C to derive equivalent rectal temperatures. Three subjects for whom no temperature measurements were recorded and three subjects for whom temperature was measured with tympanic thermometers were excluded from the analysis of fever; none of the six excluded subjects sought medical advice for fever.
# primary endpoint
N.B.: endpoints for which the CI does not include 0 or the p-value is < 0.05 are highlighted in bold
Source: 103907/0.5034, page 57; 103905/0.5042 pages 5-6, 10, and 12.

As demonstrated in Tables 2 and 3, for all categories of fever assessed, there was a trend towards a greater frequency among subjects in the Pediarix Group compared with subjects in the Separate Vaccines Group. The differences were statistically significant for fever ≥ 38.0°C, fever >39.0°C , and for fever associated with a medical visit. Apart from fever, there were no there were no statistically significant differences between groups in the incidence of any solicited general symptom.

Table 4. Study 084 Diagnostic work-up for fever in subjects who sought medical advice via visits to medical personnel within 4 days (day 0-3) following the first dose of Pediarix

Type of visit T max (°F) Day Work-up
Outpatient * 107.6 2 None
Outpatient 101.3 0 CBC
Emergency room 104.3 1 CBC, BC, UC, CXR
Outpatient 101.2 0 None
Emergency room 101.1 3 CBC, BC, UC, CXR, NP
Emergency room 101.4 0 CBC, BC, UC
Outpatient 101.2 0 CBC
Hospitalization 108.0 0 CBC, BC, UC, LP, CXR

* Outpatient visit to or from medical personnel (MD, DO, or nurse practitioner)
T max = Maximum rectal temperature recorded during the 4 day follow-up period (Day 0 - Day 3) post-vaccination
Day = Day on which T max was reported
CBC = Complete blood count
BC = Blood culture
UC = Urine culture
CXR = Chest x-ray
NP = Nasopharyngeal swab
LP = Lumbar puncture
Source: 103905/0.5042 page 7

The results of cultures and chest x-rays included in Table 4 above were negative except for one urine culture reported as 2000 gram positive cocci per ml, one urine culture reported as mixed organisms consistent with contamination, and one chest x-ray reported as possible mild viral pneumonitis.

An additional subject who was hospitalized for fever of 101.1°F seven days following Pediarix, had a complete blood count, blood culture, urine culture, lumbar puncture, and chest x-ray. Blood, cerebrospinal fluid, and urine cultures were negative. The chest x-ray showed minor basilar air trapping, but no focal infiltrates. This subject is not included in Table 4 because the medical attention was sought beyond the first four days following vaccination.

Description of episodes of fever >39.5°C (>/= 103.2°F)

As indicated above in Tables 2-4, fever >39.5°C was reported for 3 subjects in the Pediarix Group. Clinical summaries for these 3 cases are presented below.

On Day 2, a temperature of 42.0°C ( 107.6°F) was reported in a 7-week-old infant. The mother stated that the thermometer had been sitting on a heat duct. The infant was not febrile on any of the other days during which temperature was recorded. On Days 0, 1, and 3, temperatures of 37.6°C, 37.7°C, 37.7°C, respectively, were reported. No local symptoms were reported. Drowsiness (grade 1) was reported on days 0-3. Unsolicited symptoms included cough and nasal congestion. The infant was seen at an outpatient medical visit.

On Day 1, a temperature of 40.2°C (104.3°F) was reported in a 6-week-old infant. Acetaminophen for fever was given on Day 1. The temperature readings on Days 0, 2, and 3 were 36.1°C, 36.7°C, and 36.1°C, respectively. No local symptoms were recorded. General symptoms included grade 2 drowsiness on Day 1 and grade 1 irritability on Day 2. No unsolicited adverse events were reported. The infant was taken to an emergency room.

On Day 1, a temperature of 42.2°C ( 108.0°F) was reported by the mother of a 6-week-old infant. Prior to vaccination, the infant had had diarrhea for 2 days. The infant was taken to a local health clinic, where the temperature was 38°C, and referred to a hospital emergency room. In the emergency room, the infant's temperature was 37.6°C, and the physical exam was unremarkable. The infant was admitted to the hospital for a sepsis work-up. During the 5-day hospitalization, no temperature above 37.7°C was recorded and vital signs were normal. The infant was given acetaminophen orally and ampicillin and garamycin intravenously. Chest x-ray and all cultures (cerebrospinal fluid, blood, urine) were negative. Nevertheless, the discharge diagnosis was clinical sepsis and anemia (hemoglobin 9.3). A follow-up note on the serious adverse event form stated that the "Patient was hospitalized based on maternal history. P Examination, lab results and vital signs documented in the medical record didn't support what mother says."

Duration of fever Among subjects with fever ≥38°C in the Separate Vaccine Group, fever resolved in 1 day in 56 (82.4%) subjects, in 2 days in nine (13.2%) subjects, in 3 days in one (1.5%) subject, and in 4 days in 2 (2.9%) subjects. Among subjects with fever in the Pediarix Group, fever resolved in 1 day in 147 (77.4%) subjects, in 2 days in 35 (18.4%) subjects, in 3 days in 4 (2.1%) subjects, and in 4 days in 4 (2.1%) subjects. All but three fevers that lasted more than 1 day were ≤38.5°C. Fever >38.5°C lasting 2 days was reported for 3 subjects in the Pediarix Group: 39.0°C and 38.6°C; 38.7°C and 38.6°C; and 39.2°C and 38.6°C, for Day 0 and Day 1, respectively. All but one fever resolved within the 4-day period of solicitation (i.e., Days 0-3). In one subject with duration of fever for 4 days, the fever continued beyond day 3 (onset on Day 1 and resolution on Day 4).

Fever in relation to time since vaccination The highest incidence of fever was reported on Day 0 and substantially decreased on Day 1, with few fevers reported beyond Day 1. The frequency of fever ≥38.0°C in the Separate Vaccine Group on Day 0, 1, 2, and 3 was 16.7%, 4.8%, <1%, and <1% respectively. The frequency of fever ≥38.0°C in the Pediarix group on Day 0, 1, 2, and 3 was 21.9%, 9.4%, 1.2%, and <1%, respectively.

Solicited Local Adverse Events

Table 5. Study 084 Comparison of solicited local symptoms between groups, reported within 4 days following dose 1 (Day 0 - Day 3)

Symptoms Vaccine
Injection Site
Intensity Separate
Vaccine
Group
(N=335)
Pediarix
Group
(N=671)
Separate Vaccine Group
minus Pediarix Group
n % n % diff. 95% CI
LL UL
Pain Regardless of site Any 137 40.9 278 41.4 -0.54 -6.99 5.92
Grade 3 13 3.9 19 2.8 1.05 -1.37 3.47
Pediarix or Infanrix Any 107 31.9 242 36.1 -4.13 -10.30 2.05
Grade 3 9 2.7 16 2.4 0.30 -1.78 2.38
Redness Regardless of site Any 105 31.3 214 31.9 -0.55 -6.64 5.54
> 20 mm 6 1.8 6 0.9 0.90 -0.69 2.49
Pediarix or Infanrix Any 61 18.2 167 24.9 -6.68 -11.95 -1.41
> 20 mm 1 0.3 6 0.9 -0.60 -1.52 0.33
Swelling Regardless of site Any 70 20.9 151 22.5 -1.61 -6.99 3.77
> 20 mm 4 1.2 18 2.7 -1.49 -3.18 0.20
Pediarix or Infanrix Any 32 9.6 116 17.3 -7.74 -11.99 -3.48
> 20 mm 2 0.6 13 1.9 -1.34 -2.67 -0.01

Separate Vaccine Group: Infanrix + Engerix-B + IPOL + HibTITER + Prevnar
Pediarix Group: Pediarix + HibTITER + Prevnar
diff. = difference between groups in %
CI = confidence interval; LL = lower limit, UL = upper limit
Grade 3 Pain = cries when limb is moved/spontaneously painful
N.B.: endpoints for which the CI does not include 0 or the p-value is < 0.05 are highlighted in bold
Source: 103907/0.5034, page 66

As shown in Table 5, redness and swelling at the DTaP-based injection site occurred more frequently among subjects in the Pediarix Group than in the Separate Vaccines Group. The comparison between groups for redness or swelling regardless of site (DTaP-based, Engerix-B or IPOL) was not significantly different.

None of the local symptoms led to medical visits. Two subjects, one from each vaccine group, experienced swelling that exceeded 50 mm in diameter. Swelling with a diameter of 55 mm at the Hib injection site was reported for the subject in the Pediarix Group. This subject also had swellings of 50 mm each at the Pediarix and Prevnar injection sites. The subject in the Separate Vaccine Group had swellings of 60 mm reported at the Infanrix injection site and 40 mm at the Prevnar injection site.

Unsolicited adverse events

The percentage of subjects who were reported to experience at least one unsolicited adverse event within four days following the first dose was 12.2% in the Separate Vaccines Group and 13.1% in the Pediarix Group. The most frequently reported unsolicited adverse events were injection site reaction (e.g., knot or bruising at injection site, 3.3%) in the Separate Vaccine Group, and flatulence (2.2%) in the Pediarix group. Grade 3 unsolicited adverse events within four days following the first dose were reported in one subject in the Separate Vaccines Group (bruise at injection site) and in two subjects in the Pediarix Group (flatulence in one subject and sepsis in one subject). The case of sepsis was described above in the section on episodes of fever ≥39.5°C.

Serious Adverse Events

Twelve serious adverse events (4 in the Separate Vaccine Group, 8 in the Pediarix Group) were reported, including 11 events following dose 1 and one event following dose 2, all of which involved hospitalization. Seven of the twelve serious adverse events were bronchiolitis due to Respiratory Syncytial Virus (five in the Pediarix group and two in the Separate Vaccines Group), with onset ranging from 8 to 35 days following vaccination. The remaining five cases included one each of croup and viral meningitis in the Separate Vaccines Group (onset 33 and 66 days post-vaccination, respectively), and one each of clubfoot, fever of undetermined origin, and sepsis in the Pediarix group. The case of sepsis is described above in the section on episodes of fever ≥39.5°C, and is included in Table 4.

The infant diagnosed with fever of undetermined origin was a 2-1/2 month old male, who, eight days following the first dose of study vaccines, was hospitalized with a one-day history of fever as high as 38.4°C, and irritability. No solicited symptoms, including temperature ≥38.0°C, were reported during the initial 4-day follow-up period after vaccination. Relevant test results included white blood cell count 34.5 (units and reference range not provided), normal chest x-ray, and negative urinalysis. The infant was given acetaminophen and one 300 mg dose of Rocephin and was discharged on the same day with results of urine, blood and cerebrospinal fluid cultures pending. The final diagnosis on the discharge note was "Fever, probably viral illness".

Clinical narratives were provided for four additional serious adverse events reported after the database lock. There were three cases of bronchiolitis, one in the Pediarix Group, and two in the Separate Vaccines Group, with onset between 30 and 72 days after the first dose of study vaccine. In addition, one of the subjects with bronchiolitis in the Separate Vaccines Group, also had lingular pneumonia 81 days after vaccination.

Concomitant medications

Table 6. Study 084 Comparison of subjects between groups who received at least one concomitant medication within 4 days following dose 1 (Day 0 to Day 3)

Type Separate Vaccine
Group (N = 335)
Pediarix
Group (N = 671)
Separate Vaccine
Group minus
Pediarix Group
  95% CI   95% CI diff. 95% CI
n % LL UL n % LL UL   LL UL
Any medication 169 50.4 45.0 55.9 374 55.7 51.9 59.5 -5.29 -11.83 1.25
Any antibiotic 3 0.9 0.2 2.6 4 0.6 0.2 1.5 0.30 -0.87 1.49
Any antipyretics† 150 44.8 39.4 50.3 343 51.1 47.3 55.0 -6.34 -12.87 0.19
Prophylactic antipyretics 38 11.3 8.2 15.2 75 11.2 8.9 13.8 0.17 -3.98 4.32
Antipyretics for fever or febrile illnesses 50 14.9 11.3 19.2 130 19.4 16.4 22.6 -4.45 -9.30 0.40

Separate Vaccine Group: Infanrix + Engerix-B + IPOL + HibTITER + Prevnar
Pediarix Group: Pediarix + HibTITER + Prevnar
N = number of subjects vaccinated in each group
n = number of subjects who took the specified concomitant medication in each group
95% CI = exact 95% confidence interval; LL = lower limit, UL = upper limit
diff. = difference between groups in %
† antipyretics also were given for other symptoms, mostly pain and fussiness
Source: 103907/0.5034, page 70

Reviewer's Summary and Conclusions

Study 084 was the first study of Pediarix in which information on medically attended fever was actively and systematically collected. The frequency of fever within four days following the first dose Pediarix administered concurrently with HibTITER and Prevnar was higher than that observed following the first doses of Infanrix, IPOL, Engerix-B, HibTITER and Prevnar administered concurrently, at separate sites. All categories of fever assessed (≥38.0°C, >38.5°C, >39.0°C, >39.5°C, and medically attended fever) tended to occur more frequently in subjects who received Pediarix relative to separately administered vaccines, with statistically significant differences obtained for fever ≥38.0°C, fever >39.0°C, and medically attended fever. For six of the eight infants in the Pediarix group who had a medical visit for fever within 4 days following vaccination, one or more diagnostic studies to evaluate other causes of fever were performed.

The differences observed in the rates of fever between the Pediarix Group and the Separate Vaccines Group in Study 084 were roughly of the same magnitude as those observed in previous studies which examined Pediarix relative to separately administered vaccines, without co-administration of Prevnar.

As shown in Table 7, below, there was a tendency towards a higher frequency of fever >38.5°C within four days following the first dose of Pediarix in Study 084, relative to the Pediarix groups (or Pediarix admixed with Hib) in other studies in which Prevnar was not administered. In the largest safety study submitted to the BLA, study 011, the frequencies of other categories of fever (i.e., ≥38.0°C and >39.5°C) within four days following the first dose of Pediarix were similar to those observed among Pediarix recipients in Study 084. However, comparisons between studies must be interpreted with caution due to potential differences in factors that may influence the rates of fever (e.g., antipyretic use).

Table 7. Percentage of subjects with fever >38.5°C within 4-days following the first dose of study vaccine in subjects who received Pediarix or Pediarix admixed with Hib vaccine in studies submitted to the BLA.

BLA Study Concomitant Vaccines N Percentage [95% CI]
217744-084
( U.S.)
Pediarix + Hib + Prevnar 671 7.0 [5.2, 9.2]
217744-011
( Germany)
Pediarix + Hib 4666 5.8 [5.2, 6.5]
217744-015
( U.S.)
Pediarix + Hib 100 4.0 [1.1, 9.9]
217744-044
(US)
Pediarix + Hib 482 2.9 [1.6, 4.8]
217744-027
( U.S.)
Pediarix admixed with Hib n/a 4.3 [3.2, 5.8]

Reviewer's Recommendations

1. It is my opinion that the Warnings section of the Pediarix package insert should include a statement about the increased risk for fever, particularly medically attended fever, associated with Pediarix relative to separately administered vaccines. This information may be important to physicians and parents in considering the benefits and risks of vaccination with Pediarix vs. separately administered licensed vaccines.

2. A more robust assessment of medically attended fever associated with Pediarix relative to separately administered vaccines, given concurrently with Prevnar and Hib vaccine, should be obtained in a post-marketing safety study. Such a study should be designed to comprehensively ascertain and evaluate potential clinical consequences of fever (e.g., diagnostic procedures to evaluate infectious causes of fever, medical visits, hospitalization, antibiotic use, and febrile seizures). GSK has submitted a draft protocol for a phase 4 study in which febrile seizures within 7 days following vaccination with Pediarix vs. separately administered vaccines is the primary endpoint, and medically attended fever is a secondary endpoint. Reviews of this protocol, with comments for the sponsor, have been included in separate memos.

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