Vaccines and Related Biological Products Advisory Committee

 

Meeting Date:  November 5, 1999

 

 

 

 

 

 

 

 

 

 

FDA Briefing Document for

 

 

Wyeth-Lederle Vaccine and Pediatrics

Seven Valent Pneumococcal Conjugate Vaccine

 

 

 

 

 

 

 

Clinical Section

 

R. Douglas Pratt, M.D., M.P.H.

 

 

 

Table of Contents

 

 

Overview........................................................................................................................... 3

 

Draft Question #1:  Efficacy......................................................................................... 6

 

Draft Question #2:  Safety.......................................................................................... 18

 

Draft Question #3:  Concurrent Immunizations................................................... 35

 

Draft Question #4:  Catch-up Schedule.................................................................. 41

 

Attachment A:  Selected Case Narratives.............................................................. 46

 

Attachment B:  Supporting Studies........................................................................ 49

 

Attachment C:  Otitis Media Analysis Preliminary Review Comments........... 67

 

Attachment D:  Pneumonia Analysis Preliminary Review Comments........... 75

 

 

 

Overview

 

Wyeth-Lederle Vaccines and Pediatrics submitted a Product License Application (PLA) to FDA/CBER on June 1, 1999, for Prenevar^TM, a 7-valent, polysaccharide-protein conjugate vaccine for prevention of disease caused by Streptococcus pneumoniae.  FDA/CBER granted priority review status to the application, and committed to an expedited review, based on the severity of disease for which the vaccine would be indicated, i.e.,“invasive pneumococcal disease (meningitis and bacteremia)”, and preliminary results indicating substantial evidence of efficacy.  Preliminary efficacy data were presented to the committee at the November 19,1998 advisory committee meeting.

 

Regulatory approval was requested to market Prevenar for active immunization of infants and children beginning as early as 6 weeks of age for three indications:

-       To help protect against invasive diseases caused by Streptococcus pneumoniae due to the capsular serotypes included in the vaccine (4, 6B, 9V, 14, 18C, 19F, 23F)

-       Reduction in the incidence of ear tube placement associated with frequent otitis media

-       Reduction in the incidence of clinical pneumonia with abnormal chest x-ray  

 

At the VRBPAC meeting of November 5, 1999, FDA/CBER will primarily address, and seek advice from the committee about, the safety and efficacy data intended to support an indication for prevention of invasive pneumococcal disease. 

 

FDA/CBER has determined that indications for reduction in ear tube placement and clinical pneumonia will not be given priority review status.  FDA/CBER will review data submitted to support the latter two indications within the standard review periods of 10 months, and data submitted to support these indications may be presented at a future VRBPAC meeting.  Preliminary review comments based on Wyeth-Lederle’s analysis of pneumonia and otitis media endpoints are attached to this document as an addendum.

 

A brief chronology of some key elements in the clinical development and review of Prevenar is presented below:

 

Chronology of Clinical Development

 

IND 5832 filed (7-valent)                                                         November 1994

NCKP efficacy study initiated                                                      October 1995

Safety, OM, pneumonia data of efficacy trial locked                 April 30, 1999

Primary analysis of efficacy study                                               August 20, 1998

Otitis media analysis plan finalized                                            November 1998

Pneumonia analysis plan finalized                                              March 3, 1999

Efficacy trial unblinded, case ascertainment ends                April 20, 1999

Manufacturing-bridging study complete                                     May 17, 1999

PLA Submitted                                                                              June 1, 1999

FDA/CBER accepts PLA as complete                                      July 13, 1999

Advisory committee                                                                     November 5, 1999

 

The clinical section of the application contains study reports for 8 studies and supporting data from 3 additional clinical studies.  An integrated clinical summary is also provided. 

 

In the tables and summaries that follow, 7-valent pneumococcal conjugate vaccine is referred to as 7VPnC, meningococcal group C conjugate vaccine is  referred to as MnCC.

 

Clinical Studies in the Product License Application

Study Number	Population	Schedule (Months)	Control	Regulatory Objective/ Other Information
D92-P5	Infants	2, 4, 6	No 5VPnC	Saccharide model and dose selection
	Toddlers	15-18	None	PNU-IMUNE®23 Boost
D118-P2	Adults	18-60 yr	PNU-IMUNE®23	Safety, immunogenicity in adults
D118-P3	Infants	2, 4, 6, 12-15	MnCC	Safety and Immunogenicity Support MnCC as control for phase 2 and 3
D118-P7	Infants	2, 4, 6, 12-15	MnCC	Pilot for Efficacy Study; Safety and Immun. Compatibility with Hep B
D118-P8	Infants	2, 4, 6, 12-15	MnCC	Efficacy: invasive disease, AOM, pneumonia; Large safety data base for adverse events; Safety when given with DTP or DTaP
D118-P9	Toddlers	15-24	7VPnC	2 Lots of 7VPnC;
D118-P12	Infants	2, 4, 6	No vaccine	Pilot Lot Consistency; Safety and reactogenicity given with DTaP; Catch-up data; Compatibility with HbOC, DTaP;
	Infants	7, 9	None
	Toddlers	15-18	None
D118-P15	Infants	2, 4, 6, 12-15	MnCC	Ongoing efficacy study among Navajo and Apache;  Only catch-up immunogenicity data provided
	Toddlers	Various	MnCC
D118-P16	Infants	2, 4, 6	No vaccine	Bridging from pilot to manufacturing; Safety and reactogenicity given with DTaP; Compatibility with HbOC, HepB, IPV;
D124-P2	Infants	2, 4, 6	7VPnC	Compatibility with MMR, immunogenicity only
	Toddlers	12-15	None
D124-P501	Toddlers	12-17	MnCC	9-valent immunogenicity data for catch-up presented.
		18+	MnCC

 

Not included in the application are data from studies addressing safety and immunogenicity among children from some high-risk populations, such as children with sickle cell disease, HIV infection, Hodgkin’s disease, and nephrotic syndrome.   Also not included in the application are data from a trial of the effectiveness of 7VPnC in preventing otitis media, which was conducted in Finland.

 

Please note that an investigational meningococcal C vaccine was used in the control arm for some of the studies, including the large-scale efficacy trial.  Only two infant studies (D118-12 and D118-16) compared the safety profile of 7VPnC against a ‘no vaccine’ control.

 

The questions used to provide the outline for this briefing document should be considered as draft questions.  Actual questions at the time of the meeting may differ.

 

All efficacy data in the application derive from the Northern California Kaiser Permanente (NCKP) efficacy trial, Study 118-8.  The study design and efficacy results are described below with question #1.  Summaries of non-pivotal supporting studies are in Attachment B.

 

Draft Question #1

 

Do the data presented provide sufficient evidence of efficacy on which to base licensure of Prenevar for the requested indication:

 

For active immunization of infants and children beginning as early as 6 weeks of age to protect against invasive diseases caused by Streptococcus pneumoniae due to the capsular serotypes included in the vaccine (4, 6B, 9V, 14, 18C, 19F, 23F).

 

If not, what additional information should be obtained?

 

Study 118-08:  Evaluation of the Safety, Immunogenicity and Efficacy of Heptavalent Pneumococcal Conjugate Vaccine and Safety of Meningococcal Group C Conjugate Vaccine in Infants at 2, 4, 6 and 12-15 Months of Age in Northern California Kaiser Permanente (NCKP) Medical Care Program

 

The primary objective of this study was to determine the protective efficacy of 7VPnC against invasive pneumococcal disease caused by serotypes represented in the vaccine.  A case of invasive pneumococcal disease was defined as a positive culture of S. pneumoniae from a normally sterile body fluid (e.g. blood, CSF, joint fluid) obtained from a child presenting with an acute illness consistent with pneumococcal disease.

 

The study was initiated in October 1995; enrollment ceased August 24, 1998, after results of the planned interim analysis demonstrated substantial evidence of efficacy.  Follow-up of infants for invasive pneumococcal disease and serious adverse events continued through April 20, 1999, at which time vaccine assignments were unblinded to all study personnel and families of subjects.  The 7VPnC vaccine was then offered to subjects in the control group.

 

Multiple secondary objectives were also specified:

 

-         To assess the safety and tolerability of 7VPnC

-         To assess the safety and tolerability of MnCC

-         To determine the protective efficacy of 7VPnC among all enrolled subjects (intent-to-treat)

-         To evaluate the effectiveness of 7VPnC on overall invasive pneumococcal disease, regardless of serotype

-         To assess the effectiveness of 7VPnC on rates of acute otitis media and pneumonia as determined by computerized data sources

-         To assess the immunogencity of 7VPnC following a primary series and 4^th dose

 

 

Study Vaccines

 

      7VPnC is a liquid formulation.  Each 0.5 mL dose contains 15-26 mg of CRM₁₉₇ carrier protein, and a total pneumococcal saccharide content of 16 mg.  Serotype specific saccharide content for each component is:

     -    2 mg of polysaccharide for serotypes 4, 9V, 14, 19F, and 23F,

     -    2 mg of oligosaccharide for serotype 18C,

     -    4 mg of polysaccharide for serotype 6B

 

Each dose of 7VPnC also contains 0.5 mg of aluminum phosphate adjuvant.

The formulation contains no thimerosal or other preservatives.

 

MnCC is also manufactured by Wyeth-Lederle Vaccines and Pediatrics.  Each 0.5mL dose contains 10 mg of group C oligosaccharides coupled to CRM₁₉₇.  The vaccine contains 0.5 mg of aluminum phosphate adjuvant. 

 

The two study vaccines vials were identical in appearance.

 

During the efficacy study, 11 different pilot lots of 7VPnC, and 12 different pilot lots of MnCC were used.

 

Licensed vaccines used in the study were:  DTP-HbOC (Tetramune), OPV (Orimune), DTaP (Acel-imune), HbOC (HibTITER), MMR, Varicella, Hepatitis B (Recombivax HB), and IPV (IPOL).

 

Study Design

 

            Randomization and Blinding

 

            Healthy infants were randomly assigned to receive 7VPnC or MnCC, identified as A, B, C, or D in the following way: randomization was nested within each study site, block sizes were randomly chosen among 4, 6, 8, and 10, with treatment groups equally allocated.  Treatment assignments (A, B, C, or D) were randomly permuted within each block.  The group code assignment were entered by the study nurse into the child’s study casebook and the injection log, but were not recorded on the subject’s chart, computer records or in any other documents.  Group assignment was known to the study nurse and dedicated nurse vaccinator at each site, to the NCKP statistician, and to the NCKP and Wyeth-Lederle clinical monitors.  Group assignments were not to be disclosed to parents of children in the study, others involved with the child's care or involved in the trial, including pediatricians, study investigators, and telephone interviewers.

 

            Schedule and Dose Administration

 

            Subjects received 0.5 mL i.m. injections of either pneumococcal or meningococcal C conjugate vaccine at 2, 4, 6 and 12-15 months of age.

 

            In the original protocol, DTP-HbOC (Tetramune ) and OPV (Orimune) were given concurrently with study vaccine at 2, 4, and 6 months of age.  Subjects could also receive one or more doses of hepatitis B vaccine concurrently.

 

            Amendment # 2, implemented August 1996, allowed for the substitution of DTaP and HbOC for DTP-HbOC, and for the substitution of inactivated poliovirus vaccine (IPV) for OPV when immunizing infants for the primary series at 2, 4, and 6 months of age. 

 

            At 12-15 months of age, DTP-HbOC or DTaP and HbOC (HibTITER), MMR, and varicella vaccine could be given concurrently.

 

Study vaccines were to be administered within the following time frames:

 

-         Dose 1:  42-120 days after birth,

-         Dose 2:  35-120 days after the first dose

-         Dose 3:  35-120 days after the second dose

-         Dose 4:  12 to 15 months of age, and at least 60 days after dose 3.

 

Case Surveillance

 

Surveillance for cases of invasive pneumococcal disease was conducted weekly at each study site by review of all positive cultures for pneumococcus from normally sterile body sites among children < 9 years of age, generated from the NCKP Regional Microbiology database.  Listings of children discharged from NCKP hospitals with diagnoses compatible with invasive pneumococcal disease were conducted monthly.

 

Efficacy Endpoints

 

The primary outcome was efficacy in preventing cases of invasive disease among subjects vaccinated according to protocol caused by one of the 7 targeted pneumococcal serotypes during the per-protocol follow-up period.

 

Additional efficacy endpoints were:

-         efficacy against invasive disease under intent-to-treat

-         efficacy after one or two doses

-         efficacy against individual serotypes and subsets of the 7 targeted serotype

-         efficacy stratified by age at completion of the three-dose primary series

-         effectiveness against acute otitis media (ascertained from clinical diagnosis in computerized data sources

 

Analysis

 

The final analysis plan for invasive disease at the time of unblinding differed from that proposed in the original protocol.  The analysis plan had included group sequential procedures for as many as 3 analyses at the 3 respective case accruals of 8, 20, and 40 cases, with stopping rules for case splits at each look.   Agreement was reached in a meeting between representatives of Wyeth-Lederle and FDA on November 3, 1997, to modify the sequential analysis plan by  eliminating the look at 8 cases, and instead to provide for one interim analysis when 17 cases of invasive pneumococcal disease due to vaccine serotypes accrued among children who were vaccinated per protocol.  The test criterion at the interim analysis was specified as follows: If no more than 2 cases, out of a total of 17, were observed in the vaccinated group (7VPnC group), the vaccine was to be considered efficacious and the trial was to be stopped for evidence of efficacy.  Exact confidence limits derived from exact binomial distributions.

 

118-8:  Acceptable Case Splits for Stopping at Interim Analysis

Number of Cases		Vaccine Efficacy	95% Lower Conf. Limit
Control	Vaccinated	Estimate	one-sided	two-sided
0	17	100	80.7	75.7
1	16	93.8	66.6	59.7
2	15	86.7	51.5	42.6

Adapted from Table 2, page 84, Volume 13 of PLA

 

Results

 

Enrollment was terminated on August 24, 1998.  At that time, 37,868 infants had been randomized and received at least one immunization.  A total of

18,927 and 18,941 subjects received the 7VPnC and MnCC vaccines, respectively. 

118-8:  Primary Efficacy Analysis

 Number of Subjects and Follow-up Time

	7VPnC	MnCC	Total
Per-protocol	13,549	13,569	27,118
Follow-up time (child-year)	14,442	14,588
Intent-to-treat	18,896	18,901	37,797
Follow-up time (child-year)	26,776	26,813

 Adapted from Table 16, page 104, Volume 13 of PLA.

 

Approximately 10,000 randomized subjects were not included in the per-protocol analysis.  Children were excluded from the per protocol analysis for not having completed the primary series, failure to receive study vaccines in the designated time frames, receipt of immunoglobulin, receipt of incorrect vaccines, failure to meet entry criteria, invasive disease, and death.  Loss of health plan membership did not result in exclusion from per protocol follow-up, unless a dosing violation occurred.

 

Demographics

 

Demographic information was collected for a subset of subjects from whom local reaction and systemic event data were collected via telephone interview.  The subset was selected based on the last digit of the subject’s medical record number.

 

The two study vaccine groups appear to be well balanced with respect to race/ethnicity.

 

118-8:  Race/Ethnicity As Reported at 48 Hour Interview¹ After Dose 1

	Asian %	Black %	Hispanic %	White %	Multi- ethnic %	Other/ Unknown %	p-value2
7VPnC (N=3708)	13.4	7.7	19.6	39.3	19.4	0.6
							0.123
MnCC (N=3693)	13.0	8.4	17.9	40.5	19.3	1.0

Reproduced from Table 11, page 89, Volume 13 of PLA

¹ Telephone interviews conducted October 16, 1995 – April 30, 1998

² Chi-Square Test (sponsor’s analysis)

 

Efficacy

 

The planned interim analysis following accrual of the 17^th case of invasive pneumococcal disease due to vaccine serotype, which took place on August 20, 1998, is considered the primary efficacy analysis. 

 

Primary efficacy analysis

 

A total of 17 vaccine-serotype invasive disease cases in fully vaccinated children accrued during the per-protocol follow-up period at the time of the interim analysis.  All 17 cases were in the MnCC group.

 

Results of the intent-to-treat analysis were consistent with vaccine efficacy observed in the per-protocol analysis.   No cases of invasive disease were observed among children either fully or partially immunized with 7VPnC.

 

Vaccine Efficacy Against Invasive Pneumococcal Disease

-Primary Analysis

Adapted from Tables 17 page 105 , Volume 13 of PLA, and Table 5, page 25 of June 8, 1999 submission to the PLA.

*    Two-sided P-values were determined based on exact binomial distributions and confidence limits were also determined based on exact binomial distributions   (Sponsor’s analysis).

 

All invasive pneumococcal disease

 

Eight additional cases of invasive disease due to non-vaccine serotypes were observed at the time of the primary analysis.  Three cases occurred in the 7VPnC group and five in the MnCC group.  Vaccine efficacy for all serotypes in the intent-to-treat analysis was 88.9%, with a lower 95% confidence limit of 63.8%.

 

Serotype Distribution of Cases

 

The proportion of all invasive disease due to vaccine serotypes at the time of the primary analysis was 81.5% (22/27).  The most common vaccine serotype was 19F.  No invasive disease cases due to pneumococcal serotype 4 were observed.

 

Serotype Distribution of Cases of Invasive Pneumococcal Disease -          Cases Accrued Through August 20, 1998

Adapted from Table 18, Clinical Study Report, Volume 13 of PLA.

* Percentage of the number of all invasive pneumococcal disease cases in MnCC group.

 

Vaccine Efficacy by Dose

 

At the time of the primary analysis, 10 cases of invasive disease had accrued between the 3^rd and 4^th doses, and 7 additional cases occurred after the 4^th dose.

 

Analysis of Vaccine Efficacy Against Invasive Pneumococcal Disease by Dose- Cases Accrued Through August 20, 1998

Adapted from Table 20, Clinical Study Report, Volume 13 of PLA.

* Two-sided P-values were determined based on exact binomial distributions and confidence limits were also determined based on exact binomial distributions.

 

Invasive Disease Case Characteristics

 

Case narratives for each of the invasive disease cases were provided.  Among the 22 vaccine serotype cases at the time of the primary analysis, no deaths were reported.  Two infants < 6 months of age developed meningitis.  One child among the fully vaccinated group was hospitalized; 3 infants in the partially vaccinated group were hospitalized.  Pneumococcus was isolated from the blood of all cases; those with meningitis also had CSF isolates. One partially vaccinated infant, who was diagnosed with meningitis, had residual hearing loss; all other children recovered fully.  Pneumococcal isolates with decreased susceptibility to penicillin accounted for 41% (9/22) of the pneumococcal isolates from cases of invasive disease.

 

Characteristics of Cases of Invasive Disease at Primary Analysis: 

MnCC Group (N=22)

	Fully Vaccinated	Partially Vaccinated	Total
Characteristic	N=17	N=5	22
Age < 12 months Age ³ 12 months	7 10	5 0	12 10
Source of isolate    Blood    Spinal fluid	17 0	5 (2)*	22 (2)
Antibiotic susceptibility of isolate    Penicillin sensitive    Penicillin intermediate    Penicillin resistant	10 4 3	3 1 1	13 5 4
Hospitalized Treated outpatient	1 16	3 2	4 18
Clinical Diagnoses    Bacteremia       Meningitis       Septicemia/sepsis       Pneumonia       Periorbital cellulitis	17 (0) (2) (1) (1)	5 (2) (1) (1) (0)	22  (2) (3) (2) (1)
Immunocompromised	0	0	0
Outcome    Complete recovery/”Doing well”    Residual deficit    Deaths	17 0 0	4                  1  (hearing) 0	21 1 0

Compiled from case narratives provided in July 7, 1999 submission to PLA

*  () n of cases for non-unique characteristics

 

Follow-up analysis

 

Enrollment ceased on August 24, 1998.  Partially vaccinated subjects completed the vaccine schedule, and follow-up of such subjects was added to the continuing surveillance of efficacy outcomes and safety.  A summary and analysis of invasive disease cases accrued through April 20, 1999, were provided with the PLA.

 

Results of follow-up cases are consistent with the primary analysis.  One case of invasive disease due to vaccine serotype occurred among fully vaccinated subjects in the 7VPnC group, and 39 cases were observed in the MnCC group.

 

Efficacy Against Invasive Disease:  Follow-up Analysis

   Adapted from Tables 17 page 105 , Volume 13 of PLA, and Table 5, page 25 of June 8, 1999 submission to the PLA.

   * Two-sided P-values and confidence limits based on exact binomial distributions  (Sponsor’s analysis).

 

The single invasive disease case of vaccine serotype (19F) among the fully vaccinated 7PnC cohort presented no unusual characteristics (see Attachment A for case narrative).   Two additional cases of invasive disease of vaccine serotype (6B, 19F) occurred among 7VPnC recipients in the intent-to-treat follow-up analysis (see Attachment A for case narratives). 

 

All pneumococcal invasive disease

 

Nine cases of invasive disease due to non-vaccine serotypes had accrued at the time follow-up for invasive disease was terminated, 3 in the 7VPnC group and 6 in the MnCC group.  Only 1 additional case of invasive disease due to non-vaccine serotypes accrued since the primary analysis.  During the same interval an additional 30 cases due to vaccine serotypes accrued.  Vaccine efficacy for all serotypes in the follow-up intent-to-treat analysis was 89.1%, with a lower 95% confidence limit of 74.7%.

 

Vaccine serotypes accounted for 85% of all cases of invasive disease at the time case accrual was terminated.  Replacement of prevalent serotypes chosen for representation in the vaccine by non vaccine serotypes was not apparent during this study.

 

Invasive Disease Case Characteristics

 

Invasive disease characteristics for all cases of invasive disease regardless of serotype are presented below:

 

Characteristics of Cases of Invasive Disease:  All Cases (N=61)

Characteristic	Vaccine Serotype N= 52        n               %		Non Vaccine Serotype N= 9       n                  %		Total N=61      n               %
Age < 12 months Age ³ 12 months	18 34	33% 67%	5 4	56% 44%	23 38	38% 62%
Source of invasive disease    Blood    Spinal fluid    Thyroglossal duct cyst	52 (5)* 0	100% (9.6%) 0	8 (1) 1	89% (11%) 11%	60 (6) 1	98% (10%) 2%
Antibiotic susceptibility of isolate    Penicillin sensitive    Penicillin intermediate    Penicillin resistant	33 11 8	63% 21% 15%	8 0 1	89% 0 11%	41 11 9	67% 18% 15%
Hospitalized Treated outpatient	13           39	25% 75%	3 6	33% 67%	16 45	26% 74%
Clinical Diagnoses    Meningitis    Pneumonia	(5) (9)	(9.6%) (17%)	(1) (2)	(11%) (22%)	(11) (9)	(18%) (15%)
Immunocompromised	1	2%	1	11%	2	3%
Outcome    Complete recovery    Residual deficit    Death	48          1 3	92% 2% 5.8%	8 0 1	89% 0 11%	56 1 4	92% 2% 7%

Compiled from case narratives included in July 7, 1999 submission to PLA

*  () n and % of cases for non-unique characteristics

 

Of the 4 deaths among children with invasive disease, 2 could be attributed to invasive pneumococcal disease.  The remaining 2 deaths can be attributed to underlying disease or immunocompromising conditions (see Attachment A for case narratives).

 

The study protocol provides for assessment of immunocompetence of all children with positive cultures for S. pneumoniae from a normally sterile body site.  Assays for immunocompetence for the initial 22 cases included CBC, quantitative immunoglobulins (IgG, IgA, IgM), total hemolytic complement, and T-cell subsets for most cases.  Results of tests of immunocompetence were provided upon FDA/CBER request, for the initial 22 cases in the intent-to-treat analysis (received August 31, 1999).  Tests of immune status for the remainder of the 61 invasive disease cases have not been submitted to the PLA.

 

Two cases of invasive disease in the follow-up analysis occurred among children who were clearly immunocompromised; both subsequently died.  A child with severe combined immunodeficiency in the MnCC group was included in the intent-to-treat analysis of all vaccine serotypes.   A child with leukemia in the 7VPnC group was omitted from the follow-up intent-to-treat analysis.  It was stated that this child did not meet the case definition because of the immunocompromised status of the child, but the case was listed for completeness.  FDA requested that the case be analyzed under intent-to-treat.

 

 

Review comments regarding efficacy of invasive disease

 

Case ascertainment

 

In FDA/CBER’s review of efficacy for invasive disease, assurance was sought that no cases of invasive disease had been missed.  FDA requested all bacterial culture results for subjects during the study period.  Culture results through the study period ending August 20, 1998 were received with the PLA submission (culture data for subjects in the follow-up analysis have not been received).

 

The summary of all non-pneumococcal culture results revealed no imbalance across treatment groups.  All positive cultures were identified.  

 

118-8:  All Non Pneumococcal Blood Culture Results

For Study Subjects at the Primary Analysis (August 1998)

Vaccine Group	Negative	Non-pneumo Positive
7VPnC	2722	104
MnCC	2613	103

Adapted from Table in PLA submission of July 28, 1999. 

 

Thus, for subjects who remained in the NCKP health plan throughout the study, the likelihood that cases of invasive disease were missed appears low.

 

Meningococcal isolates through April 20, 1999, were provided.  Six blood isolates of meningococcus were identified, 3 in each vaccine group.  None of the isolates was serotype C. 

 

Follow-up

 

As of April 30, 1998, the cumulative follow-up times for the 7VPnC and MnCC groups were nearly identical at 10,047 and 10,098 child-years, respectively. Given that the estimate of vaccine efficacy (VE) is a function of the ratio of follow-up times between the two groups, precise knowledge of follow-up time is preferred.  In this trial, lack of precision of the ratio of follow-up exists because the follow-up data available on April 30, 1998 was used to project the ratio of follow-up on August 20, 1998, the date of the primary analysis.

 

Responding to FDA inquiries, Wyeth-Lederle performed an analysis (received August 31, 1999), in which variations in follow-up times were assumed in order to assess effects on confidence limits around the efficacy estimate.  It was demonstrated that if the proportion of follow-up in the 7VPnC group were differentially reduced by as much as 33%, the lower bound of the 95% confidence interval for efficacy in the primary analysis remained above 71%.  Thus, any difference in projected follow-up to actual follow-up is likely to be inconsequential.  The sponsor is in the process of determining actual follow-up times at the time of the primary analysis.

 

Calculation of the confidence interval for the point estimate is further complicated because included in the total follow-up time is follow-up time attributed to subjects who left the Kaiser health plan between their 3^rd and 4th doses or after their 4th dose, but before the study's end.  While early termination from the health plan could decrease the probability that extra cases would be ascertained, it would not be expected to introduce a systematic bias in the relative group proportions of "missed case" ascertainment. The sponsor determined that the relative group proportions of follow-up time accrued to subjects leaving the health plan were similar (7.1%, 7VPnC vs. 6.6 %, MnCC).  Adjustments to the accumulated child-years which is reduced by the loss-to-follow-up fraction, may be appropriate for calculation of confidence intervals, even though the risk reduction point estimate will not vary.

 

Protocol violations and reasons for exclusion from the per protocol analysis were provided as supplemental to the PLA.  Most common reasons for exclusions and truncation of follow-up times are shown below.  The number of subjects appears to be well balanced between study groups by reason for exclusion.

 

118-8:  Per Protocol Follow-up Exclusions by Reason

	7VPnC		MnCC
Number of subjects randomized	17,066		17,080
Number excluded from per protocol	3696		3723
Reasons for exclusion
Dose 3 not given by data cut-off	2859		2877
Dose 3 not given by age 1 year	629		607
Dose 1 given <42 days, or > 120 days	35		35
Interval between doses 1 and 2 < 35 days	15		19
Interval between dose 2 and 3 < 35 days	32		36
Received incorrect vaccine	29		48
Follow-up time truncated	1300		1289
Dose 4 not given by 16 months of age	1213		1171
Age at dose 4 < 12 months	41		69

          Excerpted from Tables 6 and 7 of September 29, 1999 submission to PLA

 

Results of the intent-to-treat analysis provide additional support for the efficacy estimate of the per protocol analysis.  Follow-up time in the intent-to-treat analysis accrues from the time of enrollment for each subject and continues through April 30, 1998.  The intent-to-treat follow-up period is unaffected by protocol violations.  The lower bound of the 95% confidence interval for invasive disease due to vaccine serotype in the intent-to-treat analysis was above 80%.

Draft Question #2:    Do the data provide adequate evidence of safety for Prenevar?

 

If not, what additional information should be obtained?

 

 

Safety Data Base

 

Safety of the 7VPnC vaccine was assessed in a total of seven clinical studies.  In five of these studies (118-3, 118-7, 118-8, 118-12, 118-16), safety was evaluated in infants.  Safety of a 4^th dose of vaccine administered at 12-15 months was evaluated in three studies (118-3, 118-7, 118-8).  Study (118-9) examined safety of a single dose in toddlers.  Study 118-2 provides the only safety data for adults in the application.

 

Safety Database: Number of Children

Who Received 7VPnC Vaccine and the Number of Doses Administered

Infant Studies	Age (mos)	Primary Series		4th Dose
		Subjects	Doses	Subjects	Doses
118-3	2, 4, 6, 12-15	106	303	58	58
118-7	2, 4, 6, 12-15	202	570	138	138
118-8 Enrollment as of 4/30/98 Data cut-off for safety	2, 4, 6, 12-15	17,066	46,305	9,047	9,047
118-12	2, 4, 6	256	740	--	--
118-16	2, 4, 6	538	1538	--	--
	TOTAL	18,168	49,456	9,243	9,243
		(20,029)	(54,817)	(11,136)	(11,136)
Older Infants (>6 Month) and Children
118-9	15-24  (1 dose)	60	60	--	--
118-12	7, 9, 15-18	54	105	24	24
Adult Studies
118-2	18-65 yrs	15	15	--	--

Adapted from Table 2, page 15, of Integrated Clinical Summary, Volume 33 part IV of PLA

 

Important contributions of the individual studies to the safety evaluation are discussed below.

 

118-8    NCKP Efficacy Trial

 

Safety data from the NCKP efficacy study accumulated through April 30, 1998, were reported in the application.  Follow-up of subjects continued until April 20, 1999.  Updated safety data consisting of line listings of ER visits, hospitalizations, and “out of plan adverse events” occurring from April 30, 1998, through December 31, 1998, were submitted as a planned update to the application on July 7, 1999.

 

     Safety Variables

    

Specific local reactions and systemic events following vaccine injections were actively monitored by the parent/guardian in a subset of 6000 infants who received DTP-HbOC concomitantly with the study vaccine.  Infants were randomly selected for active monitoring of vaccine reactions if the last digit of their medical record number was 2, 4, 6, or 8.  The same cohort of infants was monitored after each dose.

 

Injection site reactions were monitored for 48 hours following immunizations by use of diary cards.  Fever was recorded on the day of immunization, and at bedtime for 2 days after, and at any other time within 14 days that the infant felt warmer than usual.  Other systemic events were monitored for 14 days and recorded by parents on a diary card.  At approximately 48-72 hours and 10-14 days after each dose, these data were collected by telephone interviews of parents.

 

Amendment #4, implemented April 1997, provided for monitoring of acute safety data via diary cards and telephone interviews in a subset (N=1500) of the population of children who received DTaP and HbOC concurrently with the primary series of study vaccine.  At the time of implementation, 20,272 infants and children had already received at least one dose DTP-HbOC with study vaccines.

 

     Local Reactions

 

Rates of local reactions at DTP-HbOC injection sites (right leg) and 7VPnC or MnCC injections (left leg) were compared pairwise within the same child using the sign test.  Local reactions occurring within 48 hours of an injection were reported with greater frequency and severity for DTP-HbOC injection sites than 7VPnC injection sites for each dose of the primary series. 

 

Local reaction rates for 7VPnC and MnCC injection sites were also compared between treatment groups.  Rates of induration and tenderness were greater in the 7VPnC group, compared to the MnCC group for each dose of the primary series.  Clinically significant induration (> 2.4 cm) and tenderness (interferes with leg movement) were also more frequent at 7VPnC inoculation sites than at MnCC injection sites after doses 2 and 3.

 

Frequency of local reactions due to 7VPnC did not increase appreciably with sequential doses of the primary series.

 

Study 118-8:  Local Reactions within 48 hours of Inoculations Among Infants Receiving DTP-HbOC, OPV, Hepatitis B, and 7VPnC or MnCC Vaccine

Dose 1
	7VPnC N=2890 %	DTP-HbOC N=2890 %	p-Value1	MnCC N=2877 %	DTP-HbOC N=2877 %	p-Value1	p-Value2 7VPnC vs. MnCC
Erythema	12.4	21.9	0.0001	11.2	22.4	0.0001	0.124
> 2.4cm	1.2	4.6	0.0001	1.4	3.9	0.0001	0.416
Induration	10.9	22.4	0.0001	9.0	23.8	0.0001	0.013
> 2.4cm	2.6	7.2	0.0001	2.1	7.5	0.0001	0.307
Tenderness	28.0	36.4	0.0001	24.7	34.0	0.0001	0.001
Interferes with    Leg Movement	7.9	10.7	0.0001	6.7	9.2	0.0001	0.062
Dose 2
	N=2725	N=2725		N=2678	N=2678
Erythema	14.3	25.1	0.0001	11.5	27.9	0.0001		0.003
> 2.4cm	1.0	2.9	0.0001	0.8	3.4	0.0001		0.364
Induration	12.3	23.0	0.0001	7.1	24.2	0.0001		0.001
> 2.4cm	2.4	5.6	0.0001	1.1	5.4	0.0001		0.001
Tenderness	25.2	30.5	0.0001	18.3	26.4	0.0001		0.001
Interferes with       Leg Movement	7.4	8.4	0.015	4.4	5.8	0.0003		0.001
Dose 3
	N=2538	N=2538		N=2532	N=2532
Erythema	15.2	26.5	0.0001	12.7	26.8	0.0001		0.011
> 2.4cm	2.0	4.4	0.0001	1.3	4.1	0.0001		0.028
Induration	12.8	23.3	0.0001	9.7	23.2	0.0001		0.001
> 2.4cm	2.9	6.7	0.0001	1.5	6.1	0.0001		0.002
Tenderness	25.6	32.8	0.0001	18.2	28.5	0.0001		0.001
Interferes with    Leg Movement	7.8	10.0	0.0001	4.7	7.2	0.0001		0.001

Adapted from Tables 48, 49, and 50 of Study Report, volume 13, Part IV of PLA.

¹  P-value, calculated using the sign test, assesses the difference between 7VPnC injection sites and DTP-HbOC/HepB injection sites in the 7VPnC    recipients, and     between MnCC injection sites and DTP-HbOC/HepB injection sites in the MnCC recipients.

²  P-value, calculated using the Chi-Square test, assesses the difference between 7VPnC and MnCC injection sites in all subjects for which data were available.

N may vary for local reactions and dose number depending on available data.

 

After the 4^th dose, local reactions at DTP-HbOC injection sites were significantly more common that reactions at 7VPnC injection sites.  Rates of tenderness, and tenderness interfering with leg movement, were reported significantly more often among 7VPnC recipients (36% and 18%) than among MnCC control subjects (28% and 13%) (table not shown).   

 

In the subset of subjects who received DTaP concurrently with study vaccines, HbOC and study vaccine were administered in the same leg (left), and DTaP +/- Hep B was administered in the opposite leg.  The worse reaction of each leg was recorded.  Comparisons of local reactions when 7VPnC or MnCC were administered concurrently with DTaP are shown below.  Rates of erythema, induration, and tenderness interfering with movement were significantly greater for 7VPnC than for DTaP after the first dose, but not subsequent doses. 

Rates of local reactions at 7VPnC injection sites do not appear to increase with sequential doses of the primary series. 

 

Rates of erythema and induration at 7VPnC injection sites were significantly greater than rates for MnCC injection sites after doses 1 and 2.

 

Study 118-8:  Local Reactions Within 48 Hours of Injection Among Infants Receiving DTaP, and 7VPnC or MnCC Vaccine with the Primary Series

Dose 1
	7VPnC   N=693 %	DTaP   N=693 %	p-Value1	MnCC   N=691 %	DTaP   N=691 %	p-Value1	p-Value2 7VPnC vs. MnCC
Erythema	10.0	6.7	0.0006	6.5	5.6	0.3449	0.026
> 2.4cm	1.3	0.4	0.0313	0.6	0.9	0.5000	0.164
Induration	9.8	6.6	0.0021	4.2	4.3	>.999	0.001
> 2.4cm	1.6	0.9	0.1250	0.1	0.3	>.999	0.004
Tenderness	17.9	16.0	0.0533	17.9	18.9	0.2649	0.970
Interferes with    Leg Movement	3.1	1.8	0.0039	2.5	2.5	>.999	0.505
Dose 2
	N=526	N=526		N=489	N=489
Erythema	11.6	10.5	0.5118	0.5118	10.8	0.0113	0.030
> 2.4cm	0.6	0.6	>.999	>.999	1.4	0.5078	0.7173
Induration	12.0	10.5	0.3123	0.3123	7.4	0.0801	0.001
> 2.4cm	1.3	1.7	0.6250	0.6250	1.0	0.2500	0.1803
Tenderness	19.4	17.3	0.0801	0.0801	15.6	0.6776	0.069
Interferes with       Leg Movement	4.1	3.3	0.2188	0.2188	2.5	>.999	0.168
Dose 3
	N=422	N=422		N=377	N=377
Erythema	13.8	11.4	0.1433	9.3	8.2	0.5572	0.049
> 2.4cm	1.4	1.0	0.6250	2.4	1.9	0.7266	0.308
Induration	10.4	10.4	>.999	6.9	8.3	0.4731	0.066
> 2.4cm	2.4	1.9	0.6875	0.8	2.1	0.1250	0.082
Tenderness	14.7	13.1	0.2649	12.3	12.0	>.999	0.280
Interferes with    Leg Movement	2.9	1.9	0.2188	1.6	0.5	0.1250	0.240

Adapted from Tables 48, 49, and 50 of Study Report, volume 13, Part IV of PLA.

¹  P-value, calculated using the sign test, assesses the difference between 7VPnC injection sites and DTaP injection sites                               in 7VPnC recipients, and between MnCC injection sites and DTaP injection sites in the MnCC recipients.

²  P-value, calculated using the Chi-Square test, assesses the difference between 7VPnC and MnCC injection sites in all subjects for which data were available (Sponsor’s analysis).

³  P-value, calculated using Fisher’s exact test (Sponsor’s analysis)

Total N may vary depending on available data.

 

Local reactions following the 4^th dose of 7VPnC or MnCC when given concurrently with DTaP were assessed in the NCKP efficacy trial.  Subjects could have received either DTP-HbOC or DTaP and HbOC with the primary series, thus complicating the assessments.  Erythema and induration were reported more frequently for 7VPnC injection sites than for DTaP in pairwise comparisons within subjects, and more frequently than for MnCC injection sites in control subjects.

 

118-8:  Local Reactions within 48 Hours of Injection Among Children

 Vaccinated with DTaP vs. 7VPnC or MnCC Vaccine

 Dose 4

	7VPnC   N=165 %	DTaP   N=165 %	p-Value1	MnCC   N=178 %	DTaP   N=178 %	p-Value1	p-Value2 7VPnC vs. MnCC
Erythema	10.9	3.6	0.0042	4.5	4.0	>.9999	0.043
> 2.4cm	3.6	0.6	0.1250	0.0	0.0		0.0053
Induration	12.1	5.5	0.0127	4.5	3.4	0.6875	0.005
> 2.4cm	5.5	1.8	0.0703	0.0	0.0		<0.0013
Tenderness	23.3	18.4	0.0963	15.4	14.9	>.9999	0.052
Interferes with Leg Movement	9.2	8.0	0.7539	1.7	1.7		0.002

Adapted from Table 55 of Clinical Study Report, Volume 13, Part IV of PLA

¹   P-value, calculated using the sign test, assesses the difference between 7VPnC injection sites and DTaP/HepB injection sites in the 7VPnC recipients, and between MnCC injection sites and DTaP/HepB injection sites in the MnCC recipients.

²  P-value, calculated using the Chi-Square test, assesses the difference between 7VPnC and MnCC injection sites in all subjects for which data were available.

³   P-value calculated with Fisher’s Exact Test.

Subjects may have received mixed pertussis vaccine regimens concurrently in the primary series.

 

Supporting studies 118-12 and 118-16

 

Local reactions following concurrent administration of 7VPnC and DTaP with the primary series were also assessed in supporting studies 118-12 and 118-16.   In both studies, local reactions for 7VPnC and HbOC in the left leg were compared pairwise within subjects to reactions in the right leg, inoculation site of DTaP +/- Hep B.   Erythema, induration and tenderness were more common in the leg receiving 7VPnC.  Severe reactions were uncommon.

 

118-16:  Local Reactions W\ithin 72 hours of Injection

 Within Subject Comparison of Leg Vaccinated with 7VPnC and HbOC Vaccine vs. Leg Vaccinated with DTaP and HepB

Local Reaction	Dose 1:  All 7VPnC Lots     (N=487)			Dose 2: All 7VPnC Lots         (N=440)			Dose 3:   All  7VPnC Lots      (N=440)
	7VPnC Site %	DTaP Site %	p-value1	7VPnC site %	DTaP Site %	p-value1	7VPnCsite  %	DTaP site %	p-value1
Erythema	10.9	6.2	0.0002	11.6	8.6	0.053	4.3	10.9	0.049
>2.4 cm	0.6	0.6	>.9999	0.7	0.5	>.999	0.9	0.2	0.250
Induration	9.9	5.6	0.0015	10.5	6.8	0.036	10.0	6.6	0.028
>2.4 cm	1.2	1.0	>.9999	0.9	0.2	0.375	1.1	0.2	0.125
Tenderness	22.3	17.2	0.0001	17.0	13.3	0.029	15.8	13.2	0.043
Interferes w/ Movement	2.9	2.9	>.9999	3.5	1.8	0.065	1.8	2.1	>.999

Adapted from Tables 17, 18, and 19, pages 68, 69, and 71, Volume 29, Part IV of PLA

Controls received DTaP and HbOC at age 2, 4, and 6 months.  All groups received Hepatitis B at age 2 and 6 months.  IPV was administered in the arm at ages 2 and 4 months.

¹  P-value, calculated using the sign test, assesses the difference between 7VPnC injection sites and DTaP/HepB injection sites in recipients of a 7VPnC lot.

118-12:  Comparisons of Local Reactions within 72 hours Injections,

HbOC with 7VPnC Versus DTaP,  Within Subject Comparisons

Local Reaction	Dose 1			Dose 2			Dose 3
	HbOC+ 7VPnC L thigh   N=256 %	DTaP   R thigh   N=256 %	P-value*	HbOC+ 7VPnC       L thigh   N=245 %	DTaP   R thigh   N=245 %	P-value*	HbOC+ 7VPnC L thigh   N=239 %	DTaP   R thigh   N=239 %	P-value*
Erythema	11.2	4.4	0.001	12.9	5.6	0.002	16.7	6.9	0.001
> 2.4 cm	1.6	0.8	0.414	0.4	0	1.000	1.7	0.9	0.414
Induration	10.7	3.6	0.001	17.2	7.3	0.001	14.2	7.4	0.003
> 2.4 cm	2.0	0	0.063	2.1	0	0.063	0.9	0.4	0.564
Tenderness	19.8	13.1	0.001	15.2	7.6	0.001	13.2	8.1	0.005
Interferes w/ Movement	2.4	2.4	1.000	2.5	1.3	0.083	3.0	1.3	0.046
Any Reaction	27.9	16.4	0.001	28.2	15.1	0.001	28.4	15.7	0.001
Any Signific. Reaction	5.2	3.2	0.166	4.7	1.3	0.005	5.6	2.2	0.021

Adapted from Table 33, page 61, Volume27, Part IV of PLA.

The number of children with available reaction data may be smaller and vary from reaction to reaction.

Combined data of three 7VPnC lot groups.

*  P-value based on McNemar test for within-subject comparison.  In the cases where the frequencies in one or both groups are zero, Wilcoxon signed rank test was used.

 

In study 118-12, it was also possible to separate out rates of local reactions due to 7VPnC + HbOC vs. HbOC alone, as subjects in the control group did not receive 7VPnC.   Rates of local reactions in legs inoculated with both 7VPnC and HbOC were significantly greater than in control subjects.  Induration and tenderness were reported more frequently after each dose of the primary series for 7VPnC recipients.  Severe reactions were uncommon.

 

118-12:  Comparisons of Local Reactions –HbOC + 7VPnC vs. HbOC Alone

Local Reactions at Left Thigh	Dose 1			Dose 2			Dose 3
	HbOC with 7VPnC N=256	HbOC     N=86	P-value*	HbOC with 7VPnC N=245	HbOC     N=82	P-value*	HbOC with 7VPnC N=239	HbOC     N=80	P-value*
	%	%		%	%		%	%
Erythema	11.2	1.2	0.003	12.9	1.3	0.002	16.7	5.2	0.012
>2.4 cm	1.6	0	0.576	0.4	0	1.000	1.7	0	0.575
Induration	10.7	3.6	0.048	17.2	2.6	<0.001	14.2	5.2	0.041
>2.4 cm	2.0	0	0.337	2.1	0	0.336	0.9	1.3	1.000
Tenderness	19.8	10.6	0.068	15.2	10.1	0.348	13.2	3.9	0.021
Interfering Limb  Movement	2.4	2.4	1.000	2.5	0	0.343	3.0	0	0.200
Any Reactions	27.9	11.9	0.003	28.2	10.1	<0.001	28.4	11.7	0.003
Any Significant Reaction	5.2	2.4	0.373	4.7	0	0.072	5.6	1.3	0.202

Adapted from Table 32, page 67, Volume 27, Part IV of PLA.

Pilot lots were combined for these comparisons.

The number of children with available reaction data may be smaller and vary by reaction.

* P-value based on Fisher’s exact test.

 

 

Review Comments Regarding Local Reactogenicity of 7VPnC

 

Local reactions due to 7VPnC appear to be less frequent and severe than those due to DTP-HbOC, but more frequent than local reactions due to DTaP, HbOC and for the investigational vaccine MnCC.   Local reactogenicity attributable to 7VPnC did not appear to increase with sequential doses of the primary series.

 

No data are presented in the PLA addressing local and systemic reactions of 7VPnC when administered with DTaP for all 4 doses.

 

 

Systemic Reactions in NCKP Efficacy Trial  (118-8)

 

Assessment of systemic reaction rates and adverse events attributable to 7VPnC in the NCKP efficacy trial is complicated by concurrent recommended immunizations and use of an investigational vaccine (MnCC) in the comparator group.

 

Systemic Reactions with Concurrent DTP-HbOC

 

Against a background of concurrently administered DTP-HbOC , fever ³38°C and irritability were reported significantly more frequently in the 7VPnC group than in the MnCC group after each dose of the primary series.  Rates of fever >39°C increased with subsequent doses (1.3%, 3.0%, and 5.3%), and were significantly more frequent after doses 2 and 3 in the 7VPnC group, compared to the MnCC control group.  Other systemic reactions, such as prolonged crying, restless sleep, loss of appetite and vomiting were also significantly more common in the 7VPnC group for 1 or more doses of the primary series.

 

Convulsions within 48 hours of a study vaccine inoculation were reported for 2 children in the 7VPnC (1 each after doses 1 and 2), and 1 child in the MnCC group (after dose 3).

 

The list of events solicited by telephone interview in the NCKP trial is shown in the following table.

 

118-8:  Reported Systemic Events Within 48 Hours of Injection by Dose Among Infants Receiving Tetramune, OPV, Hepatitis B¹, and 7VPnC or MnCC

Systemic Reaction	Dose 1			Dose 2			Dose 3
	7VPnC   N1=2996 %	MnCC   N=2976 %	p-value2	7VPnC   N=2784 %	MnCC   N=2758 %	p-value2	7VPnC   N=2590 %	MnCC   N=2588 %	p-value2
Fever ³38°C	33.4	28.7	0.001	34.7	27.4	0.001	40.6	32.4	0.001
Fever >39°C	1.3	1.3	0.934	3.0	1.6	0.001	5.3	3.4	0.001
Irritability	71.3	67.9	0.004	69.4	63.8	0.001	68.9	61.6	0.001
Cry 3+ Hours	0.6	0.8	0.510	0.7	0.3	0.029	0.5	0.4	0.391
Restless Sleep	18.1	17.9	0.868	27.3	24.3	0.009	33.3	30.1	0.012
More  Sleep	49.2	50.6	0.294	32.5	33.6	0.393	25.9	23.4	0.040
Loss of Appetite	24.7	23.6	0.358	22.8	20.3	0.022	27.7	25.6	0.083
Vomiting	17.9	14.9	0.002	16.2	14.4	0.067	15.5	12.7	0.005
Diarrhea	12.0	10.7	0.095	10.9	9.9	0.212	11.5	10.4	0.169
Hives	0.7	0.6	0.651	0.8	0.8	0.974	1.4	1.1	0.379
Wheezing	0.1	0.1	>.9993	0.2	0.2	0.987	0.2	0.3	0.779
Blue Skin Tone	0.03	0.1	0.6243	0.1	0.0	0.5003	0.04	0.04	.9993
Gray/Ashen Skin	0.03	0.0	>.9993	0.04	0.0	.9993	0.0	0.0	-
Weak/letharg/limp	0.1	0.1	0.6873	0.1	0.1	0.6863	0.0	0.1	0.2493
Twitching	0.1	0.1	>.9993	0.1	0.1	0.6873	0.04	0.1	0.6253
Convulsions	0.3	0.0	>.9993	0.04	0.0	.9993	0.0	0.04	0.5003
Loss of Consc.	0.0	0.0	-	0.0	0.0	-	0.0	0.0	-

Adapted from Tables 56, 57, and 58, Volume 13, Part IV  of PLA.

Number of subjects reporting may vary with systemic reaction reported.

¹   91%, 58%, and 52% of infants received hepatitis B vaccine, and 91%, 93%, and 94% received OPV at doses 1, 2, and 3, respectively.

²  Chi-Square test.

³  Fisher’s Exact test

 

Systemic Reactions with Concurrent DTaP + HbOC

 

Systemic reaction rates among the actively monitored subset of infants who received DTaP with the primary series are likely relevant to current practice in the U.S.   In the NCKP efficacy trial, rates of febrile reactions were significantly greater in the 7VPnC group than in the MnCC group when administered with DTaP in the primary series (See table below).  

 

Rates of fever >39°C and irritability were significantly greater in the 7VPnC group after the 2^nd dose.  Hives were reported more commonly in the 7VPnC group after the first dose; however, no trend was apparent for subsequent doses.  Loss of appetite occurred more frequently in the 7VPnC group after each dose; the difference was significant at the 3^rd dose.

 

The list of systemic events solicited through telephone interviews in the NCKP trials are also shown in the following table. No convulsions were reported in either vaccine group.  One event, possibly consistent with a hypotonic hyporesponsive episode, was reported in the 7VPnC group after the 2^nd dose.

 

 

118-8:  Reported Systemic Events Within 48 Hours of Injection by Dose

Among Infants Receiving DTaP, HbOC, OPV or IPV, Hepatitis B, and

7VPnC or MnCC

Systemic Reaction	Dose 1			Dose 2			Dose 3
	7VPnC   N=710 %	MnCC   N=710 %	p-value1	7VPnC   N=556 %	MnCC   N=507 %	p-value1	7VPnC   N=460 %	MnCC   N=414 %	p-value1
Fever ³38°C	15.1	9.4	0.001	23.9	10.9	0.001	19.1	11.8	0.003
Fever >39°C	0.9	0.3	0.1782	2.5	0.8	0.029	1.7	0.7	0.180
Irritability	48.0	48.2	0.936	58.7	45.3	0.001	51.2	44.8	0.059
Cry 3+ Hours	0.1	0.3	>.9992	0.4	0.0	0.5012	0.2	0.5	0.6062
Restless Sleep	15.3	15.1	0.914	20.2	19.3	0.705	25.2	19.0	0.030
More  Sleep	40.7	42.0	0.637	25.6	22.8	0.296	19.5	21.9	0.380
Loss of Appetite	17.0	13.5	0.064	17.4	13.4	0.073	20.7	13.8	0.008
Vomiting	14.6	14.5	0.974	16.8	14.4	0.278	10.4	11.6	0.568
Diarrhea	11.9	8.4	0.029	10.2	9.3	0.611	8.3	9.4	0.539
Hives	1.4	0.3	0.020	1.3	1.4	0.857	0.4	0.5	>.9992
Wheezing	0.4	0.3	0.6872	0.0	0.6	0.1082	0.0	0.7	0.1062
Blue Skin Tone	0.1	0.0	0.5002	0.0	0.0	-	0.0	0.2	0.4732
Gray/Ashen Skin	0.0	0.0	-	0.0	0.0	-	0.0	0.0	-
Weak/letharg/limp	0.0	0.0	-	0.2	0.0	>.9992	0.0	0.0	-
Twitching	0.1	0.0	0.5002	0.2	0.2	>.9992	0.0	0.0	-
Convulsions	0.0	0.0	-	0.0	0.0	-	0.0	0.0	-
Loss of Consc.	0.0	0.0	-	0.0	0.0	-	0.0	0.0	-

Adapted from Tables 64, 65, and 66 of Clinical Study report, Volume 13, Part IV of PLA.

¹   Chi-Square test (Sponsor’s analysis).

²  Fisher’s Exact test (Sponsor’s analyss)

Number of subjects reporting may vary with systemic reaction reported.

 

After a 4^th dose of 7VPnC given concurrently with DTaP, rates of fever ³38°C  and >39°C within 48 hours were 21% and 1.3%, respectively (Table not shown).  Fever rates in the MnCC group did not differ significantly.  The subsets of subjects who received DTaP with study vaccine as a 4^th dose may have received mixed regimens of pertussis vaccine for the primary series.  Concurrently with the 4^th dose, 90% of subjects received HbOC, 88% received MMR, and 49% received VZV.

 

As allowed by the study protocol, some subjects received a 4^th dose of study vaccines without any concurrent immunizations.  Fever and common systemic reaction rates for these subjects are shown below.  Irritability was reported significantly more often in the 7VPNC group.  Fever rates did not differ appreciably between study groups.

 

118-8:  Reported Systemic Events Within 48 Hours of Injection Among Infants Receiving 7VPnC or MnCC Only,  Dose 4

	7VPnC N=644		MnCC N=627		p-value1
	n	%	n	%
Fever >39°C	9	1.4	6	1.0	0.467
Fever ³38°C	88	13.7	76	12.1	0.412
Irritability	294	45.6	221	35.1	0.001
Cry 3+ Hours	1	0.2	0	0.0	>.9992
Restless Sleep	133	20.7	133	21.3	0.806
More/Sounder Sleep	102	15.9	94	15.0	0.676
Loss of Appetite	125	19.4	115	18.3	0.617
Vomiting	44	6.8	39	6.2	0.653
Diarrhea	79	12.3	71	11.3	0.588

  Adapted from Table 72, Clinical Study Report, Volume 13, Part IV of PLA

  N may vary with systemic reaction

  ¹  Chi-square test

  ²  Fisher’s Exact test.

 

Systemic Reactions in Supporting Studies 118-12  and 118-16

 

In studies 118-12 and 118-16, the control groups did not receive MnCC or other investigational vaccines, and all infants received DTaP with the primary series.   Safety data from these trials provide the clearest view of systemic reactions attributable to 7VPnC.  In both studies active monitoring for fever and systemic events within 72 hours of injections were reported, rather than 48 hours as in the NCKP efficacy study.

 

Rates of systemic reactions in study 118-12 were similar between the pooled 7VPnC pilot lot groups and controls.  Rates of fever ³38°C were numerically greater in the 7VPnC groups after doses 2 and 3, however comparisons to control were not statistically significant.   Fever rates may have been spuriously low due to use of antipyretics, which were used significantly more often in the 7VPnC group after dose 2.

 

118-12:  Percent of Infants Reporting Systemic Event Within 72 Hours of Injection

Systemic Reaction	Dose 1			Dose 2			Dose 3
	7VPnC   N=256 %	Control   N=86 %	p-value3	7VPnC   N=245 %	Control   N=82 %	p-value3	7VPnC   N=239 %	Control   N=80 %	p-value3
Fever ³38°C	4.9	8.6	0.271	19.3	12.8	0.230	16.3	12.0	0.457
Fever >39°C	0.8	0.0	1.000	1.8	1.3	1.000	0.9	0.0	1.000
Drowsiness	48.6	38.8	0.132	31.5	22.8	0.156	27.4	9.1	<0.001
Fussiness	39.9	31.8	0.198	39.1	37.5	0.895	37.6	31.2	0.340
Decreased Appetite	17.8	15.3	0.740	12.7	16.5	0.448	13.2	14.3	0.848
Any Event	68.1	58.5	0.140	61.4	50.0	0.088	56.9	39.5	0.011
Use of Antipyretics	27.3	20.0	0.198	39.1	24.1	0.021	28.6	26.0	0.770

Adapted from Table 27, page 55, Volume 27, Part IV of PLA     

* P-value based on Fisher’s exact test (Sponsor’s analysis).

 

In study 118-16, conducted at Kaiser Permanente centers, two manufacturing lots and one pilot lot were compared for safety and immunogenicity.  Systemic events for the pooled 7VPnC groups versus control were provided in the clinical summary of the PLA.  Fever  ³38°C was reported more frequently after each dose; differences relative to control were statistically significant after doses 1 and 2.   Fever >39°C was reported more frequently after the 2^nd dose (3.8%).   Use of antipyretic agents was not reported in this study. 

 

118-16:  Percent of Infants Reporting Systemic Event Within 72 Hours

7VPnC (All Lots) vs Control

Systemic Reaction	Dose 1			Dose 2			Dose 3
	7VPnC N=498 %	Control N=108 %	p-value1	7VPnC N=452 %	Control N=99 %	p-value1	7VPnC N=445 %	Control N=89 %	p-value1
Fever ³38°C	21.9	10.2	0.005	33.6	17.2	0.001	28.1	23.6	0.44
Fever >39°C	0.8	0.9	1.00	3.8	0.0	0.053	2.2	0.0	0.38
Irritability	59.7	60.2	1.0	65.3	52.5	0.021	54.2	50.6	0.56
Drowsiness	50.8	38.9	0.026	30.3	31.3	0.90	21.2	20.2	1.0
Decreased Appetite	19.1	15.7	0.49	20.6	11.1