**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]{.underline} 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

+-------+-------+---------+-----------+-------------------------------+
| **St  | **Po  | **Sch   | **        | **Regulatory Objective/ Other |
| udy** | pulat | edule** | Control** | Information**                 |
|       | ion** |         |           |                               |
| **Num |       | (       |           |                               |
| ber** |       | Months) |           |                               |
+-------+-------+---------+-----------+-------------------------------+
| **D92 | In    | 2, 4, 6 | No 5VPnC  | > Saccharide model and dose   |
| -P5** | fants |         |           | > selection                   |
+-------+-------+---------+-----------+-------------------------------+
|       | Tod   | 15-18   | None      | > PNU-IMUNE®23 Boost          |
|       | dlers |         |           |                               |
+-------+-------+---------+-----------+-------------------------------+
| *     | A     | 18-60   | PNU       | > Safety, immunogenicity in   |
| *D118 | dults | yr      | -IMUNE®23 | > adults                      |
| -P2** |       |         |           |                               |
+-------+-------+---------+-----------+-------------------------------+
| *     | In    | 2, 4,   | MnCC      | > Safety and Immunogenicity   |
| *D118 | fants | 6,      |           | >                             |
| -P3** |       | 12-15   |           | > Support MnCC as control for |
|       |       |         |           | > phase 2 and 3               |
+-------+-------+---------+-----------+-------------------------------+
| *     | In    | 2, 4,   | MnCC      | > Pilot for Efficacy Study;   |
| *D118 | fants | 6,      |           | > Safety and Immun.           |
| -P7** |       | 12-15   |           | >                             |
|       |       |         |           | > Compatibility with Hep B    |
+-------+-------+---------+-----------+-------------------------------+
| *     | In    | 2, 4,   | MnCC      | > Efficacy: invasive disease, |
| *D118 | fants | 6,      |           | > AOM, pneumonia;             |
| -P8** |       | 12-15   |           | >                             |
|       |       |         |           | > Large safety data base for  |
|       |       |         |           | > adverse events;             |
|       |       |         |           | >                             |
|       |       |         |           | > Safety when given with DTP  |
|       |       |         |           | > or DTaP                     |
+-------+-------+---------+-----------+-------------------------------+
| *     | Tod   | 15-24   | 7VPnC     | > 2 Lots of 7VPnC;            |
| *D118 | dlers |         |           |                               |
| -P9** |       |         |           |                               |
+-------+-------+---------+-----------+-------------------------------+
| **    | In    | 2, 4, 6 | No        | > Pilot Lot Consistency;      |
| D118- | fants |         | vaccine   | >                             |
| P12** |       |         |           | > Safety and reactogenicity   |
|       |       |         |           | > given with DTaP;            |
|       |       |         |           | >                             |
|       |       |         |           | > Catch-up data;              |
|       |       |         |           | >                             |
|       |       |         |           | > Compatibility with HbOC,    |
|       |       |         |           | > DTaP;                       |
+-------+-------+---------+-----------+-------------------------------+
|       | In    | 7, 9    | None      |                               |
|       | fants |         |           |                               |
+-------+-------+---------+-----------+-------------------------------+
|       | Tod   | 15-18   | None      |                               |
|       | dlers |         |           |                               |
+-------+-------+---------+-----------+-------------------------------+
| **    | In    | 2, 4,   | MnCC      | > Ongoing efficacy study      |
| D118- | fants | 6,      |           | > among Navajo and            |
| P15** |       | 12-15   |           | >                             |
|       |       |         |           | > Apache;                     |
|       |       |         |           | >                             |
|       |       |         |           | > Only catch-up               |
|       |       |         |           | > immunogenicity data         |
|       |       |         |           | > provided                    |
+-------+-------+---------+-----------+-------------------------------+
|       | Tod   | Various | MnCC      |                               |
|       | dlers |         |           |                               |
+-------+-------+---------+-----------+-------------------------------+
| **    | In    | 2, 4, 6 | No        | > Bridging from pilot to      |
| D118- | fants |         | vaccine   | > manufacturing;              |
| P16** |       |         |           | >                             |
|       |       |         |           | > Safety and reactogenicity   |
|       |       |         |           | > given with DTaP;            |
|       |       |         |           | >                             |
|       |       |         |           | > Compatibility with HbOC,    |
|       |       |         |           | > HepB, IPV;                  |
+-------+-------+---------+-----------+-------------------------------+
| *     | In    | 2, 4, 6 | 7VPnC     | > Compatibility with MMR,     |
| *D124 | fants |         |           | > immunogenicity only         |
| -P2** |       |         |           |                               |
+-------+-------+---------+-----------+-------------------------------+
|       | Tod   | 12-15   | None      |                               |
|       | dlers |         |           |                               |
+-------+-------+---------+-----------+-------------------------------+
| **D   | Tod   | 12-17   | MnCC      | > 9-valent immunogenicity     |
| 124-P | dlers |         |           | > data for catch-up           |
| 501** |       |         |           | > 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 μg of
CRM~197~ carrier protein, and a total pneumococcal saccharide content of
16 μg. Serotype specific saccharide content for each component is:

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

\- 2 μg of oligosaccharide for serotype 18C,

\- 4 μg 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 μg of group C oligosaccharides coupled to
CRM~197~. 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                    **Vaccine         **95% Lower     
  Cases**                        Efficacy**        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          14,442          14,588             
  (child-year)                                               

  Intent-to-treat         18,896          18,901             37,797

  Follow-up time          26,776          26,813             
  (child-year)                                               
  ----------------------- --------------- ------------------ -------------

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 Interview^1^ After Dose 1

+--------------+------+------+-------+------+------+-------+--------+
|              | *    | *    | **    | *    | **Mu | **Oth | **     |
|              | *Asi | *Bla | Hispa | *Whi | lti- | er/** | p-valu |
|              | an** | ck** | nic** | te** | et   |       | e^2^** |
|              |      |      |       |      | hnic | *     |        |
|              | *    | *    | **%** | *    | %**  | *Unkn |        |
|              | *%** | *%** |       | *%** |      | own** |        |
|              |      |      |       |      |      |       |        |
|              |      |      |       |      |      | **%** |        |
+--------------+------+------+-------+------+------+-------+--------+
| **7VPnC      | 13.4 | 7.7  | 19.6  | 39.3 | 19.4 | 0.6   |        |
| (N=3708)**   |      |      |       |      |      |       |        |
+--------------+------+------+-------+------+------+-------+--------+
|              |      |      |       |      |      |       | 0.123  |
+--------------+------+------+-------+------+------+-------+--------+
| **MnCC       | 13.0 | 8.4  | 17.9  | 40.5 | 19.3 | 1.0   |        |
| (N=3693)**   |      |      |       |      |      |       |        |
+--------------+------+------+-------+------+------+-------+--------+

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**

+------------------+----------+----------+------------+--------------+
| Invasive         | Number   |          | Vaccine    | 95%          |
| Pneumococcal     | of Cases |          | Efficacy   | Confidence   |
| Disease          |          |          | Estimate   | Limits\* of  |
|                  |          |          | (VE)       | VE           |
+------------------+----------+----------+------------+--------------+
| (Cases through   | 7VPnC    | MnCC     |            |              |
|                  |          |          |            |              |
| August 20, 1998) |          |          |            |              |
+------------------+----------+----------+------------+--------------+
| Vaccine          |          |          |            |              |
| Serotypes        |          |          |            |              |
+------------------+----------+----------+------------+--------------+
| Per-Protocol     | 0        | 17       | 100%       | (75.4%,      |
|                  |          |          |            | 100%)        |
+------------------+----------+----------+------------+--------------+
| ######           | 0        | 22       | 100%       | (81.7%,      |
| Intent-to-Treat  |          |          |            | 100%)        |
+------------------+----------+----------+------------+--------------+
| All Serotypes    |          |          |            |              |
+------------------+----------+----------+------------+--------------+
| Per-Protocol     | 2        | 20       | 90.0%      | (58.3%,      |
|                  |          |          |            | 98.9%)       |
+------------------+----------+----------+------------+--------------+
| Intent-to-Treat  | 3        | 27       | 88.9%      | (63.8%,      |
|                  |          |          |            | 97.9%)       |
+------------------+----------+----------+------------+--------------+

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**

  ---------------- --------------- --------------- ------------ --------------
  Vaccine          Number of Cases                              
  Serotypes        (Percentage\*                                
                   due to Each                                  
                   Serotype)                                    

                   Fully                           All          
                   Vaccinated                      Randomized   
                   Children                        Children     

                   7VPnC           MnCC            7VPnC        MnCC

  19F              0               7 (35.0%)       0            8 (29.6%)

  18C              0               4 (20.0%)       0            4 (14.8%)

  6B               0               2 (10.0%)       0            3 (11.1%)

  9V               0               2 (10.0%)       0            2 (7.4%)

  14               0               1 (5.0%)        0            2 (7.4%)

  23F              0               1 (5.0%)        0            3 (11.1%)

  4                0               0 (0%)          0            0 (0%)

  Total            0               17 (85.0%)      0            22 (81.5%)

  Non Vaccine                                                   
  Serotypes                                                     

  38               1               1 (5.0%)        1            1 (3.7%)

  3                0               1 (5.0%)        0            1 (3.7%)

  19A              0               1 (5.0%)        0            1 (3.7%)

  10F              1               0 (0%)          1            0 (0%)

  18B              0               0 (0%)          0            1 (3.7%)

  11A              0               0 (0%)          0            1 (3.7%)

  23A              0               0 (0%)          1            0 (0%)

  Total            2               3 (15.0%)       3            5 (18.5%)

  All Serotypes    2               20              3            27
  Total                                                         
  ---------------- --------------- --------------- ------------ --------------

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

+-----------------+---+----------+---+-----------+---+--------------+---+-------------+
| Invasive        |   | Number   |   |           |   | Vaccine      |   | 95% Lower   |
|                 |   | of Cases |   |           |   | Efficacy     |   | CI\* of VE  |
| Pneumococcal    |   |          |   |           |   | Estimate     |   |             |
| Disease         |   |          |   |           |   | (VE)         |   |             |
+-----------------+---+----------+---+-----------+---+--------------+---+-------------+
|                 |   | 7VPnC    |   | MnCC      |   |              |   |             |
+-----------------+---+----------+---+-----------+---+--------------+---+-------------+
| Vaccine         |   |          |   |           |   |              |   |             |
| Serotypes       |   |          |   |           |   |              |   |             |
+-----------------+---+----------+---+-----------+---+--------------+---+-------------+
| ≤ 2 doses       | 0 |          | 5 |           | 1 |              | - |             |
|                 |   |          |   |           | 0 |              | 9 |             |
|                 |   |          |   |           | 0 |              | . |             |
|                 |   |          |   |           | % |              | 2 |             |
|                 |   |          |   |           |   |              | % |             |
+-----------------+---+----------+---+-----------+---+--------------+---+-------------+
| 3 doses         | 0 |          | 1 |           | 1 |              | 5 |             |
|                 |   |          | 0 |           | 0 |              | 5 |             |
|                 |   |          |   |           | 0 |              | . |             |
|                 |   |          |   |           | % |              | 3 |             |
|                 |   |          |   |           |   |              | % |             |
+-----------------+---+----------+---+-----------+---+--------------+---+-------------+
| 4 doses         | 0 |          | 7 |           | 1 |              | 3 |             |
|                 |   |          |   |           | 0 |              | 0 |             |
|                 |   |          |   |           | 0 |              | . |             |
|                 |   |          |   |           | % |              | 6 |             |
|                 |   |          |   |           |   |              | % |             |
+-----------------+---+----------+---+-----------+---+--------------+---+-------------+
| **All doses**   | * |          | * |           | * |              | * |             |
|                 | * |          | * |           | * |              | * |             |
|                 | 0 |          | 2 |           | 1 |              | 8 |             |
|                 | * |          | 2 |           | 0 |              | 1 |             |
|                 | * |          | * |           | 0 |              | . |             |
|                 |   |          | * |           | % |              | 7 |             |
|                 |   |          |   |           | * |              | % |             |
|                 |   |          |   |           | * |              | * |             |
|                 |   |          |   |           |   |              | * |             |
+-----------------+---+----------+---+-----------+---+--------------+---+-------------+
| All Serotypes   |   |          |   |           |   |              |   |             |
+-----------------+---+----------+---+-----------+---+--------------+---+-------------+
| ≤ 2 doses       | 1 |          | 7 |           | 8 |              | - |             |
|                 |   |          |   |           | 5 |              | 1 |             |
|                 |   |          |   |           | . |              | 1 |             |
|                 |   |          |   |           | 7 |              | . |             |
|                 |   |          |   |           | % |              | 2 |             |
|                 |   |          |   |           |   |              | % |             |
+-----------------+---+----------+---+-----------+---+--------------+---+-------------+
| 3 doses         | 2 |          | 1 |           | 8 |              | 6 |             |
|                 |   |          | 0 |           | 0 |              | . |             |
|                 |   |          |   |           | . |              | 1 |             |
|                 |   |          |   |           | 0 |              | % |             |
|                 |   |          |   |           | % |              |   |             |
+-----------------+---+----------+---+-----------+---+--------------+---+-------------+
| 4 doses         | 0 |          | 1 |           | 1 |              | 5 |             |
|                 |   |          | 0 |           | 0 |              | 5 |             |
|                 |   |          |   |           | 0 |              | . |             |
|                 |   |          |   |           | % |              | 3 |             |
|                 |   |          |   |           |   |              | % |             |
+-----------------+---+----------+---+-----------+---+--------------+---+-------------+
| **All doses**   | * |          | * |           | * |              | * |             |
|                 | * |          | * |           | * |              | * |             |
|                 | 3 |          | 2 |           | 8 |              | 6 |             |
|                 | * |          | 7 |           | 8 |              | 3 |             |
|                 | * |          | * |           | . |              | . |             |
|                 |   |          | * |           | 9 |              | 8 |             |
|                 |   |          |   |           | % |              | % |             |
|                 |   |          |   |           | * |              | * |             |
|                 |   |          |   |           | * |              | * |             |
+-----------------+---+----------+---+-----------+---+--------------+---+-------------+

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

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**

+------------------------+--------+---+---------+--------+---+---------------+
| Invasive Pneumococcal  | Number |   |         | V      |   | 95%           |
| Disease                | of     |   |         | accine |   | Confidence    |
|                        | Cases  |   |         | Ef     |   | Limits\* of   |
|                        |        |   |         | ficacy |   | VE            |
|                        |        |   |         | Es     |   |               |
|                        |        |   |         | timate |   |               |
|                        |        |   |         | (VE)   |   |               |
+------------------------+--------+---+---------+--------+---+---------------+
| (Cases through         | 7VPnC  |   | MnCC    |        |   |               |
|                        |        |   |         |        |   |               |
| April 20, 1999)        |        |   |         |        |   |               |
+------------------------+--------+---+---------+--------+---+---------------+
| Vaccine Serotypes      |        |   |         |        |   |               |
+------------------------+--------+---+---------+--------+---+---------------+
| Per-Protocol           | 1      | 3 |         | 97.4%  | ( |               |
|                        |        | 9 |         |        | 8 |               |
|                        |        |   |         |        | 4 |               |
|                        |        |   |         |        | . |               |
|                        |        |   |         |        | 8 |               |
|                        |        |   |         |        | % |               |
|                        |        |   |         |        | , |               |
|                        |        |   |         |        | 9 |               |
|                        |        |   |         |        | 9 |               |
|                        |        |   |         |        | . |               |
|                        |        |   |         |        | 9 |               |
|                        |        |   |         |        | % |               |
|                        |        |   |         |        | ) |               |
+------------------------+--------+---+---------+--------+---+---------------+
| ##                     | 3      | 4 |         | 93.9%  | ( |               |
| ####  Intent-to-Treat  |        | 9 |         |        | 8 |               |
|                        |        |   |         |        | 1 |               |
|                        |        |   |         |        | . |               |
|                        |        |   |         |        | 0 |               |
|                        |        |   |         |        | % |               |
|                        |        |   |         |        | , |               |
|                        |        |   |         |        | 9 |               |
|                        |        |   |         |        | 8 |               |
|                        |        |   |         |        | . |               |
|                        |        |   |         |        | 8 |               |
|                        |        |   |         |        | % |               |
|                        |        |   |         |        | ) |               |
+------------------------+--------+---+---------+--------+---+---------------+
| All Serotypes          |        |   |         |        |   |               |
+------------------------+--------+---+---------+--------+---+---------------+
| Per-Protocol           | 3      | 4 |         | 92.9%  | ( |               |
|                        |        | 2 |         |        | 7 |               |
|                        |        |   |         |        | 7 |               |
|                        |        |   |         |        | . |               |
|                        |        |   |         |        | 6 |               |
|                        |        |   |         |        | % |               |
|                        |        |   |         |        | , |               |
|                        |        |   |         |        | 9 |               |
|                        |        |   |         |        | 8 |               |
|                        |        |   |         |        | . |               |
|                        |        |   |         |        | 6 |               |
|                        |        |   |         |        | % |               |
|                        |        |   |         |        | ) |               |
+------------------------+--------+---+---------+--------+---+---------------+
| Intent-to-Treat        | 6      | 5 |         | 89.1%  | ( |               |
|                        |        | 5 |         |        | 7 |               |
|                        |        |   |         |        | 4 |               |
|                        |        |   |         |        | . |               |
|                        |        |   |         |        | 7 |               |
|                        |        |   |         |        | % |               |
|                        |        |   |         |        | , |               |
|                        |        |   |         |        | 9 |               |
|                        |        |   |         |        | 6 |               |
|                        |        |   |         |        | . |               |
|                        |        |   |         |        | 2 |               |
|                        |        |   |         |        | % |               |
|                        |        |   |         |        | ) |               |
+------------------------+--------+---+---------+--------+---+---------------+

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

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   15                 19        
  days                                                                

  Interval between dose 2 and 3 \< 35    32                 36        
  days                                                                

  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 |         | 4^th^   |       |
|                |           | Series  |         | Dose    |       |
+----------------+-----------+---------+---------+---------+-------+
|                |           | S       | Doses   | S       | Doses |
|                |           | ubjects |         | ubjects |       |
+----------------+-----------+---------+---------+---------+-------+
|                |           |         |         |         |       |
+----------------+-----------+---------+---------+---------+-------+
| 118-3          | 2, 4, 6,  | 106     | 303     | 58      | 58    |
|                | 12-15     |         |         |         |       |
+----------------+-----------+---------+---------+---------+-------+
| 118-7          | 2, 4, 6,  | 202     | 570     | 138     | 138   |
|                | 12-15     |         |         |         |       |
+----------------+-----------+---------+---------+---------+-------+
| 118-8          | 2, 4, 6,  | 17,066  | 46,305  | 9,047   | 9,047 |
|                | 12-15     |         |         |         |       |
| Enrollment as  |           |         |         |         |       |
| of 4/30/98     |           |         |         |         |       |
|                |           |         |         |         |       |
| Data cut-off   |           |         |         |         |       |
| for safety     |           |         |         |         |       |
+----------------+-----------+---------+---------+---------+-------+
| 118-12         | 2, 4, 6   | 256     | 740     | \--     | \--   |
+----------------+-----------+---------+---------+---------+-------+
| 118-16         | 2, 4, 6   | 538     | 1538    | \--     | \--   |
+----------------+-----------+---------+---------+---------+-------+
|                | TOTAL     | 18,168  | 49,456  | 9,243   | 9,243 |
+----------------+-----------+---------+---------+---------+-------+
|                |           | (       | (       | (       | (11   |
|                |           | 20,029) | 54,817) | 11,136) | ,136) |
+----------------+-----------+---------+---------+---------+-------+
| Older Infants  |           |         |         |         |       |
| (\>6 Month)    |           |         |         |         |       |
|                |           |         |         |         |       |
| and Children   |           |         |         |         |       |
+----------------+-----------+---------+---------+---------+-------+
| 118-9          | 15-24 (1  | 60      | 60      | \--     | \--   |
|                | dose)     |         |         |         |       |
+----------------+-----------+---------+---------+---------+-------+
| 118-12         | 7, 9,     | 54      | 105     | 24      | 24    |
|                | 15-18     |         |         |         |       |
+----------------+-----------+---------+---------+---------+-------+
| 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]{.underline}**-HbOC, OPV, Hepatitis B, and 7VPnC
or MnCC Vaccine

+-----------+-------+--------+------+-------+--------+------+---+-------+
| **Dose    |       |        |      |       |        |      |   |       |
| 1**       |       |        |      |       |        |      |   |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
|           | 7VPnC | DT     | p-   | MnCC  | DT     | p-   | p |       |
|           |       | P-HbOC | Valu |       | P-HbOC | Valu | - |       |
|           | N     |        | e^1^ | N     |        | e^1^ | V |       |
|           | =2890 | N=2890 |      | =2877 | N=2877 |      | a |       |
|           |       |        |      |       |        |      | l |       |
|           | \%    | \%     |      | \%    | \%     |      | u |       |
|           |       |        |      |       |        |      | e |       |
|           |       |        |      |       |        |      | ^ |       |
|           |       |        |      |       |        |      | 2 |       |
|           |       |        |      |       |        |      | ^ |       |
|           |       |        |      |       |        |      |   |       |
|           |       |        |      |       |        |      | 7 |       |
|           |       |        |      |       |        |      | V |       |
|           |       |        |      |       |        |      | P |       |
|           |       |        |      |       |        |      | n |       |
|           |       |        |      |       |        |      | C |       |
|           |       |        |      |       |        |      | v |       |
|           |       |        |      |       |        |      | s |       |
|           |       |        |      |       |        |      | . |       |
|           |       |        |      |       |        |      | M |       |
|           |       |        |      |       |        |      | n |       |
|           |       |        |      |       |        |      | C |       |
|           |       |        |      |       |        |      | C |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| Erythema  | 12.4  | 21.9   | 0.   | 11.2  | 22.4   | 0.   | 0 |       |
|           |       |        | 0001 |       |        | 0001 | . |       |
|           |       |        |      |       |        |      | 1 |       |
|           |       |        |      |       |        |      | 2 |       |
|           |       |        |      |       |        |      | 4 |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| \> 2.4cm  | 1.2   | 4.6    | 0.   | 1.4   | 3.9    | 0.   | 0 |       |
|           |       |        | 0001 |       |        | 0001 | . |       |
|           |       |        |      |       |        |      | 4 |       |
|           |       |        |      |       |        |      | 1 |       |
|           |       |        |      |       |        |      | 6 |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| I         | 10.9  | 22.4   | 0.   | 9.0   | 23.8   | 0.   | * |       |
| nduration |       |        | 0001 |       |        | 0001 | * |       |
|           |       |        |      |       |        |      | 0 |       |
|           |       |        |      |       |        |      | . |       |
|           |       |        |      |       |        |      | 0 |       |
|           |       |        |      |       |        |      | 1 |       |
|           |       |        |      |       |        |      | 3 |       |
|           |       |        |      |       |        |      | * |       |
|           |       |        |      |       |        |      | * |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| \> 2.4cm  | 2.6   | 7.2    | 0.   | 2.1   | 7.5    | 0.   | 0 |       |
|           |       |        | 0001 |       |        | 0001 | . |       |
|           |       |        |      |       |        |      | 3 |       |
|           |       |        |      |       |        |      | 0 |       |
|           |       |        |      |       |        |      | 7 |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| T         | 28.0  | 36.4   | 0.   | 24.7  | 34.0   | 0.   | * |       |
| enderness |       |        | 0001 |       |        | 0001 | * |       |
|           |       |        |      |       |        |      | 0 |       |
|           |       |        |      |       |        |      | . |       |
|           |       |        |      |       |        |      | 0 |       |
|           |       |        |      |       |        |      | 0 |       |
|           |       |        |      |       |        |      | 1 |       |
|           |       |        |      |       |        |      | * |       |
|           |       |        |      |       |        |      | * |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| I         | 7.9   | 10.7   | 0.   | 6.7   | 9.2    | 0.   | 0 |       |
| nterferes |       |        | 0001 |       |        | 0001 | . |       |
| with Leg  |       |        |      |       |        |      | 0 |       |
| Movement  |       |        |      |       |        |      | 6 |       |
|           |       |        |      |       |        |      | 2 |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| **Dose    |       |        |      |       |        |      |   |       |
| 2**       |       |        |      |       |        |      |   |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
|           | N     | N=2725 |      | N     | N=2678 |      |   |       |
|           | =2725 |        |      | =2678 |        |      |   |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| Erythema  | 14.3  | 25.1   | 0.   | 11.5  | 27.9   | 0.   |   | **0.  |
|           |       |        | 0001 |       |        | 0001 |   | 003** |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| \> 2.4cm  | 1.0   | 2.9    | 0.   | 0.8   | 3.4    | 0.   |   | 0.364 |
|           |       |        | 0001 |       |        | 0001 |   |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| I         | 12.3  | 23.0   | 0.   | 7.1   | 24.2   | 0.   |   | **0.  |
| nduration |       |        | 0001 |       |        | 0001 |   | 001** |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| \> 2.4cm  | 2.4   | 5.6    | 0.   | 1.1   | 5.4    | 0.   |   | **0.  |
|           |       |        | 0001 |       |        | 0001 |   | 001** |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| T         | 25.2  | 30.5   | 0.   | 18.3  | 26.4   | 0.   |   | **0.  |
| enderness |       |        | 0001 |       |        | 0001 |   | 001** |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| I         | 7.4   | 8.4    | 0    | 4.4   | 5.8    | 0.   |   | **0.  |
| nterferes |       |        | .015 |       |        | 0003 |   | 001** |
| with Leg  |       |        |      |       |        |      |   |       |
| Movement  |       |        |      |       |        |      |   |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| **Dose    |       |        |      |       |        |      |   |       |
| 3**       |       |        |      |       |        |      |   |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
|           | N     | N=2538 |      | N     | N=2532 |      |   |       |
|           | =2538 |        |      | =2532 |        |      |   |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| Erythema  | 15.2  | 26.5   | 0.   | 12.7  | 26.8   | 0.   |   | **0.  |
|           |       |        | 0001 |       |        | 0001 |   | 011** |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| \> 2.4cm  | 2.0   | 4.4    | 0.   | 1.3   | 4.1    | 0.   |   | **0.  |
|           |       |        | 0001 |       |        | 0001 |   | 028** |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| I         | 12.8  | 23.3   | 0.   | 9.7   | 23.2   | 0.   |   | **0.  |
| nduration |       |        | 0001 |       |        | 0001 |   | 001** |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| \> 2.4cm  | 2.9   | 6.7    | 0.   | 1.5   | 6.1    | 0.   |   | **0.  |
|           |       |        | 0001 |       |        | 0001 |   | 002** |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| T         | 25.6  | 32.8   | 0.   | 18.2  | 28.5   | 0.   |   | **0.  |
| enderness |       |        | 0001 |       |        | 0001 |   | 001** |
+-----------+-------+--------+------+-------+--------+------+---+-------+
| I         | 7.8   | 10.0   | 0.   | 4.7   | 7.2    | 0.   |   | **0.  |
| nterferes |       |        | 0001 |       |        | 0001 |   | 001** |
| with Leg  |       |        |      |       |        |      |   |       |
| Movement  |       |        |      |       |        |      |   |       |
+-----------+-------+--------+------+-------+--------+------+---+-------+

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]{.underline}**, and 7VPnC or MnCC Vaccine with
the Primary Series

+-----------+-------+-------+------+-------+-------+-------+---------+
| **Dose    |       |       |      |       |       |       |         |
| 1**       |       |       |      |       |       |       |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
|           | 7VPnC | DTaP  | p-   | MnCC  | DTaP  | p-Val | p-V     |
|           |       |       | Valu |       |       | ue^1^ | alue^2^ |
|           | N=693 | N=693 | e^1^ | N=691 | N=691 |       |         |
|           |       |       |      |       |       |       | 7VPnC   |
|           | \%    | \%    |      | \%    | \%    |       | vs.     |
|           |       |       |      |       |       |       | MnCC    |
+-----------+-------+-------+------+-------+-------+-------+---------+
| Erythema  | 10.0  | 6.7   | **   | 6.5   | 5.6   | 0     | **      |
|           |       |       | 0.00 |       |       | .3449 | 0.026** |
|           |       |       | 06** |       |       |       |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| \> 2.4cm  | 1.3   | 0.4   | 0.   | 0.6   | 0.9   | 0     | 0.164   |
|           |       |       | 0313 |       |       | .5000 |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| I         | 9.8   | 6.6   | **   | 4.2   | 4.3   | \     | **      |
| nduration |       |       | 0.00 |       |       | >.999 | 0.001** |
|           |       |       | 21** |       |       |       |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| \> 2.4cm  | 1.6   | 0.9   | 0.   | 0.1   | 0.3   | \     | 0.004   |
|           |       |       | 1250 |       |       | >.999 |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| T         | 17.9  | 16.0  | 0.   | 17.9  | 18.9  | 0     | 0.970   |
| enderness |       |       | 0533 |       |       | .2649 |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| I         | 3.1   | 1.8   | **   | 2.5   | 2.5   | \     | 0.505   |
| nterferes |       |       | 0.00 |       |       | >.999 |         |
| with Leg  |       |       | 39** |       |       |       |         |
| Movement  |       |       |      |       |       |       |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| **Dose    |       |       |      |       |       |       |         |
| 2**       |       |       |      |       |       |       |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
|           | N=526 | N=526 |      | N=489 | N=489 |       |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| Erythema  | 11.6  | 10.5  | 0.   | 0     | 10.8  | 0     | **      |
|           |       |       | 5118 | .5118 |       | .0113 | 0.030** |
+-----------+-------+-------+------+-------+-------+-------+---------+
| \> 2.4cm  | 0.6   | 0.6   | \>   | \     | 1.4   | 0     | 0       |
|           |       |       | .999 | >.999 |       | .5078 | .717^3^ |
+-----------+-------+-------+------+-------+-------+-------+---------+
| I         | 12.0  | 10.5  | 0.   | 0     | 7.4   | 0     | **      |
| nduration |       |       | 3123 | .3123 |       | .0801 | 0.001** |
+-----------+-------+-------+------+-------+-------+-------+---------+
| \> 2.4cm  | 1.3   | 1.7   | 0.   | 0     | 1.0   | 0     | 0       |
|           |       |       | 6250 | .6250 |       | .2500 | .180^3^ |
+-----------+-------+-------+------+-------+-------+-------+---------+
| T         | 19.4  | 17.3  | 0.   | 0     | 15.6  | 0     | 0.069   |
| enderness |       |       | 0801 | .0801 |       | .6776 |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| I         | 4.1   | 3.3   | 0.   | 0     | 2.5   | \     | 0.168   |
| nterferes |       |       | 2188 | .2188 |       | >.999 |         |
| with Leg  |       |       |      |       |       |       |         |
| Movement  |       |       |      |       |       |       |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| **Dose    |       |       |      |       |       |       |         |
| 3**       |       |       |      |       |       |       |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
|           | N=422 | N=422 |      | N=377 | N=377 |       |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| Erythema  | 13.8  | 11.4  | 0.   | 9.3   | 8.2   | 0     | **      |
|           |       |       | 1433 |       |       | .5572 | 0.049** |
+-----------+-------+-------+------+-------+-------+-------+---------+
| \> 2.4cm  | 1.4   | 1.0   | 0.   | 2.4   | 1.9   | 0     | 0.308   |
|           |       |       | 6250 |       |       | .7266 |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| I         | 10.4  | 10.4  | \>   | 6.9   | 8.3   | 0     | 0.066   |
| nduration |       |       | .999 |       |       | .4731 |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| \> 2.4cm  | 2.4   | 1.9   | 0.   | 0.8   | 2.1   | 0     | 0.082   |
|           |       |       | 6875 |       |       | .1250 |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| T         | 14.7  | 13.1  | 0.   | 12.3  | 12.0  | \     | 0.280   |
| enderness |       |       | 2649 |       |       | >.999 |         |
+-----------+-------+-------+------+-------+-------+-------+---------+
| I         | 2.9   | 1.9   | 0.   | 1.6   | 0.5   | 0     | 0.240   |
| nterferes |       |       | 2188 |       |       | .1250 |         |
| with Leg  |       |       |      |       |       |       |         |
| Movement  |       |       |      |       |       |       |         |
+-----------+-------+-------+------+-------+-------+-------+---------+

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 | DTaP   | p-Val | MnCC  | DTaP  | p-   | p-Va   |
|           |       |        | ue^1^ |       |       | Valu | lue^2^ |
|           | N=165 | N=165  |       | N=178 | N=178 | e^1^ |        |
|           |       |        |       |       |       |      | 7VPnC  |
|           | \%    | \%     |       | \%    | \%    |      | vs.    |
|           |       |        |       |       |       |      | MnCC   |
+-----------+-------+--------+-------+-------+-------+------+--------+
| Erythema  | 10.9  | 3.6    | **0.0 | 4.5   | 4.0   | \>.  | **0    |
|           |       |        | 042** |       |       | 9999 | .043** |
+-----------+-------+--------+-------+-------+-------+------+--------+
| \> 2.4cm  | 3.6   | 0.6    | 0     | 0.0   | 0.0   |      | **0.00 |
|           |       |        | .1250 |       |       |      | 5^3^** |
+-----------+-------+--------+-------+-------+-------+------+--------+
| I         | 12.1  | 5.5    | **0.0 | 4.5   | 3.4   | 0.   | **0    |
| nduration |       |        | 127** |       |       | 6875 | .005** |
+-----------+-------+--------+-------+-------+-------+------+--------+
| \> 2.4cm  | 5.5   | 1.8    | 0     | 0.0   | 0.0   |      | **     |
|           |       |        | .0703 |       |       |      | \<0.00 |
|           |       |        |       |       |       |      | 1^3^** |
+-----------+-------+--------+-------+-------+-------+------+--------+
| T         | 23.3  | 18.4   | 0     | 15.4  | 14.9  | \>.  | 0.052  |
| enderness |       |        | .0963 |       |       | 9999 |        |
+-----------+-------+--------+-------+-------+-------+------+--------+
| I         | 9.2   | 8.0    | 0     | 1.7   | 1.7   |      | **0    |
| nterferes |       |        | .7539 |       |       |      | .002** |
| with Leg  |       |        |       |       |       |      |        |
| Movement  |       |        |       |       |       |      |        |
+-----------+-------+--------+-------+-------+-------+------+--------+

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

<table style="width:100%;">
<colgroup>
<col style="width: 14%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2"><p>Local</p>
<p>Reaction</p></td>
<td colspan="3">Dose 1: All 7VPnC Lots (N=487)</td>
<td colspan="3">Dose 2: All 7VPnC Lots (N=440)</td>
<td colspan="3">Dose 3: All 7VPnC Lots (N=440)</td>
</tr>
<tr class="even">
<td><p>7VPnC</p>
<p>Site</p>
<p>%</p></td>
<td><p>DTaP</p>
<p>Site</p>
<p>%</p></td>
<td>p-value<sup>1</sup></td>
<td><p>7VPnC</p>
<p>site</p>
<p>%</p></td>
<td><p>DTaP</p>
<p>Site</p>
<p>%</p></td>
<td>p-value<sup>1</sup></td>
<td><p>7VPnCsite</p>
<p>%</p></td>
<td><p>DTaP</p>
<p>site</p>
<p>%</p></td>
<td>p-value<sup>1</sup></td>
</tr>
<tr class="odd">
<td>Erythema</td>
<td>10.9</td>
<td>6.2</td>
<td><strong>0.0002</strong></td>
<td>11.6</td>
<td>8.6</td>
<td>0.053</td>
<td>4.3</td>
<td>10.9</td>
<td><strong>0.049</strong></td>
</tr>
<tr class="even">
<td>&gt;2.4 cm</td>
<td>0.6</td>
<td>0.6</td>
<td>&gt;.9999</td>
<td>0.7</td>
<td>0.5</td>
<td>&gt;.999</td>
<td>0.9</td>
<td>0.2</td>
<td>0.250</td>
</tr>
<tr class="odd">
<td>Induration</td>
<td>9.9</td>
<td>5.6</td>
<td><strong>0.0015</strong></td>
<td>10.5</td>
<td>6.8</td>
<td><strong>0.036</strong></td>
<td>10.0</td>
<td>6.6</td>
<td><strong>0.028</strong></td>
</tr>
<tr class="even">
<td>&gt;2.4 cm</td>
<td>1.2</td>
<td>1.0</td>
<td>&gt;.9999</td>
<td>0.9</td>
<td>0.2</td>
<td>0.375</td>
<td>1.1</td>
<td>0.2</td>
<td>0.125</td>
</tr>
<tr class="odd">
<td>Tenderness</td>
<td>22.3</td>
<td>17.2</td>
<td><strong>0.0001</strong></td>
<td>17.0</td>
<td>13.3</td>
<td><strong>0.029</strong></td>
<td>15.8</td>
<td>13.2</td>
<td><strong>0.043</strong></td>
</tr>
<tr class="even">
<td>Interferes w/ Movement</td>
<td>2.9</td>
<td>2.9</td>
<td>&gt;.9999</td>
<td>3.5</td>
<td>1.8</td>
<td>0.065</td>
<td>1.8</td>
<td>2.1</td>
<td>&gt;.999</td>
</tr>
</tbody>
</table>

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

<table>
<colgroup>
<col style="width: 15%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 7%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="6"><p>Local</p>
<p>Reaction</p></td>
<td colspan="3">Dose 1</td>
<td colspan="3">Dose 2</td>
<td colspan="3">Dose 3</td>
</tr>
<tr class="even">
<td rowspan="5"><p>HbOC+</p>
<p>7VPnC</p>
<p>L thigh</p>
<p>N=256</p>
<p>%</p></td>
<td rowspan="5"><p>DTaP</p>
<p>R thigh</p>
<p>N=256</p>
<p>%</p></td>
<td rowspan="5">P-value<sup>*</sup></td>
<td rowspan="5"><p>HbOC+ 7VPnC</p>
<p>L thigh</p>
<p>N=245</p>
<p>%</p></td>
<td rowspan="5"><p>DTaP</p>
<p>R thigh</p>
<p>N=245</p>
<p>%</p></td>
<td rowspan="5">P-value<sup>*</sup></td>
<td rowspan="5"><p>HbOC+ 7VPnC</p>
<p>L thigh</p>
<p>N=239</p>
<p>%</p></td>
<td rowspan="5"><p>DTaP</p>
<p>R thigh</p>
<p>N=239</p>
<p>%</p></td>
<td rowspan="5">P-value<sup>*</sup></td>
</tr>
<tr class="odd">
</tr>
<tr class="even">
</tr>
<tr class="odd">
</tr>
<tr class="even">
</tr>
<tr class="odd">
<td>Erythema</td>
<td>11.2</td>
<td>4.4</td>
<td><strong>0.001</strong></td>
<td>12.9</td>
<td>5.6</td>
<td><strong>0.002</strong></td>
<td>16.7</td>
<td>6.9</td>
<td><strong>0.001</strong></td>
</tr>
<tr class="even">
<td>&gt; 2.4 cm</td>
<td>1.6</td>
<td>0.8</td>
<td>0.414</td>
<td>0.4</td>
<td>0</td>
<td>1.000</td>
<td>1.7</td>
<td>0.9</td>
<td>0.414</td>
</tr>
<tr class="odd">
<td>Induration</td>
<td>10.7</td>
<td>3.6</td>
<td><strong>0.001</strong></td>
<td>17.2</td>
<td>7.3</td>
<td><strong>0.001</strong></td>
<td>14.2</td>
<td>7.4</td>
<td><strong>0.003</strong></td>
</tr>
<tr class="even">
<td>&gt; 2.4 cm</td>
<td>2.0</td>
<td>0</td>
<td>0.063</td>
<td>2.1</td>
<td>0</td>
<td>0.063</td>
<td>0.9</td>
<td>0.4</td>
<td>0.564</td>
</tr>
<tr class="odd">
<td>Tenderness</td>
<td>19.8</td>
<td>13.1</td>
<td><strong>0.001</strong></td>
<td>15.2</td>
<td>7.6</td>
<td><strong>0.001</strong></td>
<td>13.2</td>
<td>8.1</td>
<td><strong>0.005</strong></td>
</tr>
<tr class="even">
<td>Interferes w/ Movement</td>
<td>2.4</td>
<td>2.4</td>
<td>1.000</td>
<td>2.5</td>
<td>1.3</td>
<td>0.083</td>
<td>3.0</td>
<td>1.3</td>
<td><strong>0.046</strong></td>
</tr>
<tr class="odd">
<td>Any Reaction</td>
<td>27.9</td>
<td>16.4</td>
<td><strong>0.001</strong></td>
<td>28.2</td>
<td>15.1</td>
<td><strong>0.001</strong></td>
<td>28.4</td>
<td>15.7</td>
<td><strong>0.001</strong></td>
</tr>
<tr class="even">
<td><p>Any Signific.</p>
<p>Reaction</p></td>
<td>5.2</td>
<td>3.2</td>
<td>0.166</td>
<td>4.7</td>
<td>1.3</td>
<td><strong>0.005</strong></td>
<td>5.6</td>
<td>2.2</td>
<td><strong>0.021</strong></td>
</tr>
</tbody>
</table>

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**

<table>
<colgroup>
<col style="width: 18%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="3">Local Reactions at Left Thigh</td>
<td colspan="3">Dose 1</td>
<td colspan="3">Dose 2</td>
<td colspan="3">Dose 3</td>
</tr>
<tr class="even">
<td><p>HbOC with 7VPnC</p>
<p>N=256</p></td>
<td><p>HbOC</p>
<p>N=86</p></td>
<td>P-value<sup>*</sup></td>
<td><p>HbOC with 7VPnC</p>
<p>N=245</p></td>
<td><p>HbOC</p>
<p>N=82</p></td>
<td>P-value<sup>*</sup></td>
<td><p>HbOC with 7VPnC</p>
<p>N=239</p></td>
<td><p>HbOC</p>
<p>N=80</p></td>
<td>P-value<sup>*</sup></td>
</tr>
<tr class="odd">
<td>%</td>
<td>%</td>
<td></td>
<td>%</td>
<td>%</td>
<td></td>
<td>%</td>
<td>%</td>
<td></td>
</tr>
<tr class="even">
<td>Erythema</td>
<td>11.2</td>
<td>1.2</td>
<td><strong>0.003</strong></td>
<td>12.9</td>
<td>1.3</td>
<td><strong>0.002</strong></td>
<td>16.7</td>
<td>5.2</td>
<td><strong>0.012</strong></td>
</tr>
<tr class="odd">
<td>&gt;2.4 cm</td>
<td>1.6</td>
<td>0</td>
<td>0.576</td>
<td>0.4</td>
<td>0</td>
<td>1.000</td>
<td>1.7</td>
<td>0</td>
<td>0.575</td>
</tr>
<tr class="even">
<td>Induration</td>
<td>10.7</td>
<td>3.6</td>
<td><strong>0.048</strong></td>
<td>17.2</td>
<td>2.6</td>
<td><strong>&lt;0.001</strong></td>
<td>14.2</td>
<td>5.2</td>
<td><strong>0.041</strong></td>
</tr>
<tr class="odd">
<td>&gt;2.4 cm</td>
<td>2.0</td>
<td>0</td>
<td>0.337</td>
<td>2.1</td>
<td>0</td>
<td>0.336</td>
<td>0.9</td>
<td>1.3</td>
<td>1.000</td>
</tr>
<tr class="even">
<td>Tenderness</td>
<td>19.8</td>
<td>10.6</td>
<td>0.068</td>
<td>15.2</td>
<td>10.1</td>
<td>0.348</td>
<td>13.2</td>
<td>3.9</td>
<td><strong>0.021</strong></td>
</tr>
<tr class="odd">
<td>Interfering Limb Movement</td>
<td>2.4</td>
<td>2.4</td>
<td>1.000</td>
<td>2.5</td>
<td>0</td>
<td>0.343</td>
<td>3.0</td>
<td>0</td>
<td>0.200</td>
</tr>
<tr class="even">
<td>Any Reactions</td>
<td>27.9</td>
<td>11.9</td>
<td><strong>0.003</strong></td>
<td>28.2</td>
<td>10.1</td>
<td><strong>&lt;0.001</strong></td>
<td>28.4</td>
<td>11.7</td>
<td><strong>0.003</strong></td>
</tr>
<tr class="odd">
<td>Any Significant Reaction</td>
<td>5.2</td>
<td>2.4</td>
<td>0.373</td>
<td>4.7</td>
<td>0</td>
<td>0.072</td>
<td>5.6</td>
<td>1.3</td>
<td>0.202</td>
</tr>
</tbody>
</table>

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 ≥38°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 B^1^**, and 7VPnC or
MnCC

<table>
<colgroup>
<col style="width: 18%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2">Systemic Reaction</td>
<td colspan="3">Dose 1</td>
<td colspan="3">Dose 2</td>
<td colspan="3">Dose 3</td>
</tr>
<tr class="even">
<td><p>7VPnC</p>
<p>N<sup>1</sup>=2996</p>
<p>%</p></td>
<td><p>MnCC</p>
<p>N=2976</p>
<p>%</p></td>
<td>p-value<sup>2</sup></td>
<td><p>7VPnC</p>
<p>N=2784</p>
<p>%</p></td>
<td><p>MnCC</p>
<p>N=2758</p>
<p>%</p></td>
<td>p-value<sup>2</sup></td>
<td><p>7VPnC</p>
<p>N=2590</p>
<p>%</p></td>
<td><p>MnCC</p>
<p>N=2588</p>
<p>%</p></td>
<td>p-value<sup>2</sup></td>
</tr>
<tr class="odd">
<td>Fever ≥38°C</td>
<td>33.4</td>
<td>28.7</td>
<td><strong>0.001</strong></td>
<td>34.7</td>
<td>27.4</td>
<td><strong>0.001</strong></td>
<td>40.6</td>
<td>32.4</td>
<td><strong>0.001</strong></td>
</tr>
<tr class="even">
<td>Fever &gt;39°C</td>
<td>1.3</td>
<td>1.3</td>
<td>0.934</td>
<td>3.0</td>
<td>1.6</td>
<td><strong>0.001</strong></td>
<td>5.3</td>
<td>3.4</td>
<td><strong>0.001</strong></td>
</tr>
<tr class="odd">
<td>Irritability</td>
<td>71.3</td>
<td>67.9</td>
<td><strong>0.004</strong></td>
<td>69.4</td>
<td>63.8</td>
<td><strong>0.001</strong></td>
<td>68.9</td>
<td>61.6</td>
<td><strong>0.001</strong></td>
</tr>
<tr class="even">
<td>Cry 3+ Hours</td>
<td>0.6</td>
<td>0.8</td>
<td>0.510</td>
<td>0.7</td>
<td>0.3</td>
<td><strong>0.029</strong></td>
<td>0.5</td>
<td>0.4</td>
<td>0.391</td>
</tr>
<tr class="odd">
<td>Restless Sleep</td>
<td>18.1</td>
<td>17.9</td>
<td>0.868</td>
<td>27.3</td>
<td>24.3</td>
<td><strong>0.009</strong></td>
<td>33.3</td>
<td>30.1</td>
<td><strong>0.012</strong></td>
</tr>
<tr class="even">
<td>More Sleep</td>
<td>49.2</td>
<td>50.6</td>
<td>0.294</td>
<td>32.5</td>
<td>33.6</td>
<td>0.393</td>
<td>25.9</td>
<td>23.4</td>
<td><strong>0.040</strong></td>
</tr>
<tr class="odd">
<td>Loss of Appetite</td>
<td>24.7</td>
<td>23.6</td>
<td>0.358</td>
<td>22.8</td>
<td>20.3</td>
<td><strong>0.022</strong></td>
<td>27.7</td>
<td>25.6</td>
<td>0.083</td>
</tr>
<tr class="even">
<td>Vomiting</td>
<td>17.9</td>
<td>14.9</td>
<td><strong>0.002</strong></td>
<td>16.2</td>
<td>14.4</td>
<td>0.067</td>
<td>15.5</td>
<td>12.7</td>
<td><strong>0.005</strong></td>
</tr>
<tr class="odd">
<td>Diarrhea</td>
<td>12.0</td>
<td>10.7</td>
<td>0.095</td>
<td>10.9</td>
<td>9.9</td>
<td>0.212</td>
<td>11.5</td>
<td>10.4</td>
<td>0.169</td>
</tr>
<tr class="even">
<td>Hives</td>
<td>0.7</td>
<td>0.6</td>
<td>0.651</td>
<td>0.8</td>
<td>0.8</td>
<td>0.974</td>
<td>1.4</td>
<td>1.1</td>
<td>0.379</td>
</tr>
<tr class="odd">
<td>Wheezing</td>
<td>0.1</td>
<td>0.1</td>
<td>&gt;.999<sup>3</sup></td>
<td>0.2</td>
<td>0.2</td>
<td>0.987</td>
<td>0.2</td>
<td>0.3</td>
<td>0.779</td>
</tr>
<tr class="even">
<td>Blue Skin Tone</td>
<td>0.03</td>
<td>0.1</td>
<td>0.624<sup>3</sup></td>
<td>0.1</td>
<td>0.0</td>
<td>0.500<sup>3</sup></td>
<td>0.04</td>
<td>0.04</td>
<td>.999<sup>3</sup></td>
</tr>
<tr class="odd">
<td>Gray/Ashen Skin</td>
<td>0.03</td>
<td>0.0</td>
<td>&gt;.999<sup>3</sup></td>
<td>0.04</td>
<td>0.0</td>
<td>.999<sup>3</sup></td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
</tr>
<tr class="even">
<td>Weak/letharg/limp</td>
<td>0.1</td>
<td>0.1</td>
<td>0.687<sup>3</sup></td>
<td>0.1</td>
<td>0.1</td>
<td>0.686<sup>3</sup></td>
<td>0.0</td>
<td>0.1</td>
<td>0.249<sup>3</sup></td>
</tr>
<tr class="odd">
<td>Twitching</td>
<td>0.1</td>
<td>0.1</td>
<td>&gt;.999<sup>3</sup></td>
<td>0.1</td>
<td>0.1</td>
<td>0.687<sup>3</sup></td>
<td>0.04</td>
<td>0.1</td>
<td>0.625<sup>3</sup></td>
</tr>
<tr class="even">
<td>Convulsions</td>
<td>0.3</td>
<td>0.0</td>
<td>&gt;.999<sup>3</sup></td>
<td>0.04</td>
<td>0.0</td>
<td>.999<sup>3</sup></td>
<td>0.0</td>
<td>0.04</td>
<td>0.500<sup>3</sup></td>
</tr>
<tr class="odd">
<td>Loss of Consc.</td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
</tr>
</tbody>
</table>

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

<table style="width:100%;">
<colgroup>
<col style="width: 19%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2">Systemic Reaction</td>
<td colspan="3">Dose 1</td>
<td colspan="3">Dose 2</td>
<td colspan="3">Dose 3</td>
</tr>
<tr class="even">
<td><p>7VPnC</p>
<p>N=710</p>
<p>%</p></td>
<td><p>MnCC</p>
<p>N=710</p>
<p>%</p></td>
<td>p-value<sup>1</sup></td>
<td><p>7VPnC</p>
<p>N=556</p>
<p>%</p></td>
<td><p>MnCC</p>
<p>N=507</p>
<p>%</p></td>
<td>p-value<sup>1</sup></td>
<td><p>7VPnC</p>
<p>N=460</p>
<p>%</p></td>
<td><p>MnCC</p>
<p>N=414</p>
<p>%</p></td>
<td>p-value<sup>1</sup></td>
</tr>
<tr class="odd">
<td>Fever ≥38°C</td>
<td><strong>15.1</strong></td>
<td><strong>9.4</strong></td>
<td><strong>0.001</strong></td>
<td><strong>23.9</strong></td>
<td><strong>10.9</strong></td>
<td><strong>0.001</strong></td>
<td><strong>19.1</strong></td>
<td><strong>11.8</strong></td>
<td><strong>0.003</strong></td>
</tr>
<tr class="even">
<td>Fever &gt;39°C</td>
<td>0.9</td>
<td>0.3</td>
<td>0.178<sup>2</sup></td>
<td><strong>2.5</strong></td>
<td><strong>0.8</strong></td>
<td><strong>0.029</strong></td>
<td>1.7</td>
<td>0.7</td>
<td>0.180</td>
</tr>
<tr class="odd">
<td>Irritability</td>
<td>48.0</td>
<td>48.2</td>
<td>0.936</td>
<td><strong>58.7</strong></td>
<td><strong>45.3</strong></td>
<td><strong>0.001</strong></td>
<td>51.2</td>
<td>44.8</td>
<td>0.059</td>
</tr>
<tr class="even">
<td>Cry 3+ Hours</td>
<td>0.1</td>
<td>0.3</td>
<td>&gt;.999<sup>2</sup></td>
<td>0.4</td>
<td>0.0</td>
<td>0.501<sup>2</sup></td>
<td>0.2</td>
<td>0.5</td>
<td>0.606<sup>2</sup></td>
</tr>
<tr class="odd">
<td>Restless Sleep</td>
<td>15.3</td>
<td>15.1</td>
<td>0.914</td>
<td>20.2</td>
<td>19.3</td>
<td>0.705</td>
<td>25.2</td>
<td>19.0</td>
<td><strong>0.030</strong></td>
</tr>
<tr class="even">
<td>More Sleep</td>
<td>40.7</td>
<td>42.0</td>
<td>0.637</td>
<td>25.6</td>
<td>22.8</td>
<td>0.296</td>
<td>19.5</td>
<td>21.9</td>
<td>0.380</td>
</tr>
<tr class="odd">
<td>Loss of Appetite</td>
<td>17.0</td>
<td>13.5</td>
<td>0.064</td>
<td>17.4</td>
<td>13.4</td>
<td>0.073</td>
<td><strong>20.7</strong></td>
<td><strong>13.8</strong></td>
<td><strong>0.008</strong></td>
</tr>
<tr class="even">
<td>Vomiting</td>
<td>14.6</td>
<td>14.5</td>
<td>0.974</td>
<td>16.8</td>
<td>14.4</td>
<td>0.278</td>
<td>10.4</td>
<td>11.6</td>
<td>0.568</td>
</tr>
<tr class="odd">
<td>Diarrhea</td>
<td><strong>11.9</strong></td>
<td><strong>8.4</strong></td>
<td><strong>0.029</strong></td>
<td>10.2</td>
<td>9.3</td>
<td>0.611</td>
<td>8.3</td>
<td>9.4</td>
<td>0.539</td>
</tr>
<tr class="even">
<td>Hives</td>
<td><strong>1.4</strong></td>
<td><strong>0.3</strong></td>
<td><strong>0.020</strong></td>
<td>1.3</td>
<td>1.4</td>
<td>0.857</td>
<td>0.4</td>
<td>0.5</td>
<td>&gt;.999<sup>2</sup></td>
</tr>
<tr class="odd">
<td>Wheezing</td>
<td>0.4</td>
<td>0.3</td>
<td>0.687<sup>2</sup></td>
<td>0.0</td>
<td>0.6</td>
<td>0.108<sup>2</sup></td>
<td>0.0</td>
<td>0.7</td>
<td>0.106<sup>2</sup></td>
</tr>
<tr class="even">
<td>Blue Skin Tone</td>
<td>0.1</td>
<td>0.0</td>
<td>0.500<sup>2</sup></td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
<td>0.0</td>
<td>0.2</td>
<td>0.473<sup>2</sup></td>
</tr>
<tr class="odd">
<td>Gray/Ashen Skin</td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
</tr>
<tr class="even">
<td>Weak/letharg/limp</td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
<td>0.2</td>
<td>0.0</td>
<td>&gt;.999<sup>2</sup></td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
</tr>
<tr class="odd">
<td>Twitching</td>
<td>0.1</td>
<td>0.0</td>
<td>0.500<sup>2</sup></td>
<td>0.2</td>
<td>0.2</td>
<td>&gt;.999<sup>2</sup></td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
</tr>
<tr class="even">
<td>Convulsions</td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
</tr>
<tr class="odd">
<td>Loss of Consc.</td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
<td>0.0</td>
<td>0.0</td>
<td>−</td>
</tr>
</tbody>
</table>

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
≥38°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     |         | MnCC      |          | p-va   |
|               |           |         |           |          | lue^1^ |
|               | N=644     |         | N=627     |          |        |
+---------------+-----------+---------+-----------+----------+--------+
|               | n         | \%      | n         | \%       |        |
+---------------+-----------+---------+-----------+----------+--------+
| Fever \>39°C  | 9         | 1.4     | 6         | 1.0      | 0.467  |
+---------------+-----------+---------+-----------+----------+--------+
| Fever ≥38°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      | \>.    |
|               |           |         |           |          | 999^2^ |
+---------------+-----------+---------+-----------+----------+--------+
| Restless      | 133       | 20.7    | 133       | 21.3     | 0.806  |
| Sleep         |           |         |           |          |        |
+---------------+-----------+---------+-----------+----------+--------+
| More/Sounder  | 102       | 15.9    | 94        | 15.0     | 0.676  |
| Sleep         |           |         |           |          |        |
+---------------+-----------+---------+-----------+----------+--------+
| Loss of       | 125       | 19.4    | 115       | 18.3     | 0.617  |
| Appetite      |           |         |           |          |        |
+---------------+-----------+---------+-----------+----------+--------+
| 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 ≥38°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**

<table>
<colgroup>
<col style="width: 14%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2">Systemic Reaction</td>
<td colspan="3">Dose 1</td>
<td colspan="3">Dose 2</td>
<td colspan="3">Dose 3</td>
</tr>
<tr class="even">
<td><p>7VPnC</p>
<p>N=256</p>
<p>%</p></td>
<td><p>Control</p>
<p>N=86</p>
<p>%</p></td>
<td>p-value<sup>3</sup></td>
<td><p>7VPnC</p>
<p>N=245</p>
<p>%</p></td>
<td><p>Control</p>
<p>N=82</p>
<p>%</p></td>
<td>p-value<sup>3</sup></td>
<td><p>7VPnC</p>
<p>N=239</p>
<p>%</p></td>
<td><p>Control</p>
<p>N=80</p>
<p>%</p></td>
<td>p-value<sup>3</sup></td>
</tr>
<tr class="odd">
<td>Fever ≥38°C</td>
<td>4.9</td>
<td>8.6</td>
<td>0.271</td>
<td>19.3</td>
<td>12.8</td>
<td>0.230</td>
<td>16.3</td>
<td>12.0</td>
<td>0.457</td>
</tr>
<tr class="even">
<td>Fever &gt;39°C</td>
<td>0.8</td>
<td>0.0</td>
<td>1.000</td>
<td>1.8</td>
<td>1.3</td>
<td>1.000</td>
<td>0.9</td>
<td>0.0</td>
<td>1.000</td>
</tr>
<tr class="odd">
<td>Drowsiness</td>
<td>48.6</td>
<td>38.8</td>
<td>0.132</td>
<td>31.5</td>
<td>22.8</td>
<td>0.156</td>
<td>27.4</td>
<td>9.1</td>
<td><strong>&lt;0.001</strong></td>
</tr>
<tr class="even">
<td>Fussiness</td>
<td>39.9</td>
<td>31.8</td>
<td>0.198</td>
<td>39.1</td>
<td>37.5</td>
<td>0.895</td>
<td>37.6</td>
<td>31.2</td>
<td>0.340</td>
</tr>
<tr class="odd">
<td>Decreased Appetite</td>
<td>17.8</td>
<td>15.3</td>
<td>0.740</td>
<td>12.7</td>
<td>16.5</td>
<td>0.448</td>
<td>13.2</td>
<td>14.3</td>
<td>0.848</td>
</tr>
<tr class="even">
<td>Any Event</td>
<td>68.1</td>
<td>58.5</td>
<td>0.140</td>
<td>61.4</td>
<td>50.0</td>
<td>0.088</td>
<td>56.9</td>
<td>39.5</td>
<td><strong>0.011</strong></td>
</tr>
<tr class="odd">
<td>Use of Antipyretics</td>
<td>27.3</td>
<td>20.0</td>
<td>0.198</td>
<td>39.1</td>
<td>24.1</td>
<td><strong>0.021</strong></td>
<td>28.6</td>
<td>26.0</td>
<td>0.770</td>
</tr>
</tbody>
</table>

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 ≥38°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**

<table>
<colgroup>
<col style="width: 14%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2">Systemic Reaction</td>
<td colspan="3">Dose 1</td>
<td colspan="3">Dose 2</td>
<td colspan="3">Dose 3</td>
</tr>
<tr class="even">
<td><p>7VPnC</p>
<p>N=498</p>
<p>%</p></td>
<td><p>Control</p>
<p>N=108</p>
<p>%</p></td>
<td>p-value<sup>1</sup></td>
<td><p>7VPnC</p>
<p>N=452</p>
<p>%</p></td>
<td><p>Control</p>
<p>N=99</p>
<p>%</p></td>
<td>p-value<sup>1</sup></td>
<td><p>7VPnC</p>
<p>N=445</p>
<p>%</p></td>
<td><p>Control</p>
<p>N=89</p>
<p>%</p></td>
<td>p-value<sup>1</sup></td>
</tr>
<tr class="odd">
<td>Fever ≥38°C</td>
<td>21.9</td>
<td>10.2</td>
<td><strong>0.005</strong></td>
<td>33.6</td>
<td>17.2</td>
<td><strong>0.001</strong></td>
<td>28.1</td>
<td>23.6</td>
<td>0.44</td>
</tr>
<tr class="even">
<td>Fever &gt;39°C</td>
<td>0.8</td>
<td>0.9</td>
<td>1.00</td>
<td>3.8</td>
<td>0.0</td>
<td>0.053</td>
<td>2.2</td>
<td>0.0</td>
<td>0.38</td>
</tr>
<tr class="odd">
<td>Irritability</td>
<td>59.7</td>
<td>60.2</td>
<td>1.0</td>
<td>65.3</td>
<td>52.5</td>
<td><strong>0.021</strong></td>
<td>54.2</td>
<td>50.6</td>
<td>0.56</td>
</tr>
<tr class="even">
<td>Drowsiness</td>
<td>50.8</td>
<td>38.9</td>
<td>0.026</td>
<td>30.3</td>
<td>31.3</td>
<td>0.90</td>
<td>21.2</td>
<td>20.2</td>
<td>1.0</td>
</tr>
<tr class="odd">
<td><p>Decreased</p>
<p>Appetite</p></td>
<td>19.1</td>
<td>15.7</td>
<td>0.49</td>
<td>20.6</td>
<td>11.1</td>
<td><strong>0.033</strong></td>
<td>20.4</td>
<td>9.0</td>
<td><strong>0.011</strong></td>
</tr>
</tbody>
</table>

Adapted from Table 30 of Integrated Clinical Summary, Volume 33, Part IV
of PLA.

All subjects received DTaP+HbOC at each dose, Hep B at dose 1 and 3, and
IPV at dose 1 and 2.

Pilot lot and 2 Manufacturing lots data pooled.

^1^ P-value for comparison of pooled data to control (Sponsor's
analysis).

**Review Comments Regarding Systemic Reactogenicity**

In the NCKP efficacy trial, fever and systemic reactogenicity due to
7VPnC were detectable above background rates due to DTP-HbOC and other
concurrent vaccines, as determined by comparisons to the MnCC group.
Some systemic reactogenicity is likely due to MnCC. Therefore,
comparisons to systemic reaction rates for MnCC may mask excess reaction
rates attributable to 7VPnC.

In both the NCKP efficacy study, and in the supporting study 118-16,
when administered with DTaP and other concurrent vaccines in the primary
series, increased rates of fever ≥38°C, and fever \>39°C were associated
with 7VPnC, compared to control groups. Increased use of antipyretic
agents was reported int study 118-12. Irritability, decreased appetite,
and drowsiness were also associated with 7VPnC, but without consistent
pattern.

Rates of fever increased with sequential doses when 7VPnC was
administered with DTP-HbOC. When administered with DTaP and HbOC, rates
of fever and systemic reactions did not appear to increase with
sequential doses of 7VPnC.

Across studies, when 7VPnC was administered against a background of the
most relevant concurrent vaccines (DTaP, HbOC, IPV, Hep B), rates of
fever ≥38°C, and \>39°C, were reported most frequently after dose 2. By
dose, rates of fever ≥38°C ranged from 5%-22% after dose 1, 19%-34%
after dose 2, and 19-28% after dose 3. Fever \>39°C was reported for
0.6%-0.9% after dose 1, 1.8%-3.8% after dose 2, and 0.9%-2.2% after dose
3.

**Adverse Events**

**NCKP Efficacy Study (118-8)**

All subjects in the NCKP efficacy trial were followed for adverse
events. Hospitalizations within 60 days of study vaccines, emergency
room visits within 30 days, and outpatient clinic visits within 30 days
of each vaccine dose were recorded. Rates of outpatient clinic visits
for diagnoses of interest (i.e. seizures, allergic reactions, including
hives, and wheezing, shortness of breath and asthma) were also assessed
and provided in the PLA.

Events resulting in study termination were also reported. Incidence of
SIDS in the study population was to be evaluated and compared to the
SIDS rate in the entire NCKP population and to the overall state-wide
rate. Diagnoses of neurologic disorders and anaphylactic reactions were
to be followed for outcome.

#### Deaths

Eighteen deaths (8 in 7VPnC recipients and 10 in MnCC recipients)
occurred in the NCKP efficacy trial on or prior to April 30, 1998. None
of the deaths were considered to be related to study vaccines by the
investigators or the sponsor.

Sudden Infant Death Syndrome (SIDS) was listed as the cause of 9 deaths
(5 in the MnCC group, and 4 in the 7VPnC group). All of the deaths
attributed to SIDS occurred ≥ 5 days after study inoculations.

#### Other causes of deaths were accidental (n=2), homicide (n=2), congenital anomalies (n=2), complications of prematurity (n=1), and bacterial leptomeningitis (n=1), Leigh's syndrome (1). 

An additional 12 deaths (2 in 7VPnC, 10 in MnCC) were reported in a
planned safety update, received September 13, 1999, for the period May
1,1998, through December 31, 1998. Causes of death in the 7VPnC group
were diabetic ketoacidosis (1) and traumatic asphyxia (1). Causes of
death in the MnCC group were SIDS (3), drowning (2), pneumococcal
meningitis (1), SCIDS (1), glioblastoma (1), metachromatic
leukodystrophy (1), and pneumonia in a child with Werdnig-Hofffman
disease (pneumococcal meningitis and SCIDS case were discussed among
case characteristics, above, and in attachment A). None of the deaths
were judged related to study vaccines by the investigators.

The rate of SIDS for cases through December 31, 1998, were compared to
State of California rates for 1996 and 1997:

118-8: Rate of SIDS in Study Groups Compared with California SIDS Rates

  -------------------- ----------- ------------ ------------ --------------
                       7VPnC       MnCC         State CA     State CA
                                                1996         1997^\*^

  Number of SIDS cases 4           8                         

  Number vaccinated^1^ 18,927      18,941                    

  Rate per 1000        0.2         0.4          0.6          0.6
  -------------------- ----------- ------------ ------------ --------------

Reproduced from October 18, 1999 submission to PLA

^\*^ 1997 rate is provisional

^1^Number of subjects receiving at least 1 dose

**Hospitalizations**

Statistical analysis of comparative rates of hospitalizations for
particular diagnoses was possible because of the size of the study.
Rates of hospitalizations reported within 3, 14, 30 and 60 days were
calculated.

Rates of hospitalizations for febrile seizures within 30 days and 60
days of a study vaccine dose were significantly greater in 7VPnC group
than the MnCC group during the primary series and across all doses, when
given concurrently with whole cell pertussis vaccine.

Rate of hospitalization for asthma within 60 days of a vaccine dose was
significantly greater in the 7VPnC during the primary series when
administered concurrently with acellular pertussis.

Rate of hospitalizations for gastroenteritis within 14 days of a vaccine
dose was significantly greater in the 7VPnC group, regardless of
concomitant pertussis vaccine.

Hospitalizations for epilepsy within 30 days of a vaccine dose were more
significantly more frequent in the MnCC group

**Emergency Room Visits**

Rate of ER visits for croup within 3 days, breath holding and urinary
tract infections within 30 days of a vaccine dose were significantly
more frequent in the 7VPnC group.

ER visits for gastroesophageal reflux and cellulitis were more common in
the MnCC group.

**Outpatient Clinic Visits**

Outpatient visits for seizures within 30 days of a vaccine dose, and for
asthma after the booster dose were more significantly more frequent in
the MnCC group.

**Serious Adverse Events Considered Related to Study Vaccines**

In the NCKP efficacy trial, six serious adverse events were considered
by investigators to be possibly, probably or definitely related study
vaccines. Four of these events were seizures, and 3 of the 4 seizures
occurred in the 7VPnC group.

All seizure events considered serious and possibly related to study
vaccines occurred among children receiving concurrent DTP-HbOC.

#### 118-08: Serious Adverse Events Considered 

#### Possibly, Probably or Definitely Related to Study Vaccines

+--------------------------+---------------------+--------------------+
| ####### Event            | **Treatment Group** |                    |
+--------------------------+---------------------+--------------------+
|                          | **7VPnC**           | **MnCC**           |
+--------------------------+---------------------+--------------------+
| Seizures                 | 3                   | 1                  |
+--------------------------+---------------------+--------------------+
| Allergy/Rash             | 0                   | 1                  |
+--------------------------+---------------------+--------------------+
| Apnea                    | 0                   | 1                  |
+--------------------------+---------------------+--------------------+

Reproduced from Table 75, page 243 of Clinical Study Report for Study
118-P8 in PLA.

**Adverse Events Resulting in Termination from the Study**

A total of 127 subjects were dropped from the study due to an adverse
event, of which 85 experienced some type of seizure activity (most not
temporally related to vaccine) and per protocol, were dropped from the
study. Other adverse events for which more than one subject was dropped
included allergic reaction/rash (n=4), idiopathic thrombocytopenic
purpura (n=4), evolving neurological disorder/developmental delay (n=8),
trauma/shaken baby (n=6), and apnea/breath holding (n=3).

Ten of these events were considered at least possibly related to
immunization with study vaccine by the investigator. These included 5
episodes of seizure (2 in MnCC recipients, 3 in 7VPnC recipients), 3
allergic-type reactions (2 in MnCC recipients, 1 in 7VPnC recipient),
and 2 episodes of apnea/breath-holding (2 in MnCC recipients). All of
these events were temporally related to immunization in that they
occurred either on the day of or one to two days after immunization.

**118-8: Number of Adverse Events**

Resulting in Study Termination by Vaccine Group

  ------------------------------- ------------------- -------------------
  **Adverse Event**               **7VPnC**           **MnCC**

  Any                             53                  74

  Seizures                        40                  43

  ITP                             0                   4

  Infection/Pneumonia             2                   4

  Allergic reaction/Rash          1                   3

  Evolving Neurol.                3                   5
  Disorder/Develop Delay                              

  Stroke                          0                   2

  Apnea/Breath Holding            0                   3

  Congenital Heart Disease        2                   0

  Neoplasm/Histiocytosis          2                   1

  Head Trauma/Shaken baby         2                   4
  ------------------------------- ------------------- -------------------

# Compiled from Table 14.3.2.3 of Clinical Study Report, Part IV of PLA (Updated October 12, 1999)

List is not comprehensive of all events; some children with more than 1
adverse event.

**Seizures Events in NCKP Study (118-8)**

In the NCKP efficacy study, information about seizure events was
collected through hospitalizations, emergency room visits, and clinic
databases. Among the actively monitored subset, "convulsions" were
listed among the solicited events. Seizures were also be a reason for
study termination.

FDA asked the sponsor to provide an integrated summary of all seizure
events in which discrete events would be counted only once, and acute
events were distinguished from follow-up visits or an ongoing seizure
disorder by means of chart review. The sponsor also reviewed other
potential sources of information, including spontaneous reports from
clinic study nurses (not in the original PLA). Using all data sources,
the number of subjects that experienced acute seizure events occurring
within 3, 14, and 30 days of a study vaccine dose were assessed.

118-08: Number of Subjects with Acute Seizure Events

  -------------------- ----------------------- ---------------------------
  Period after Study   Number of Children      
  Vaccine              Experiencing Acute      
                       Seizure Event           

                       7VPnC                   MnCC

  Within 30 days       32                      41

  Within 14 days       21                      21

  Within 3 days        8                       4
  -------------------- ----------------------- ---------------------------

From October 18, 1999 submission to PLA.

Of the 8 recipients of 7VPnC with acute seizure events within 3 days of
inoculation, 7 were febrile seizures, and 7 had received a whole cell
pertussis vaccine concurrently with study vaccines. Two subjects with
febrile seizures were also diagnosed with urinary tract infections. The
one subject in the 7VPnC group who had a seizure after DTaP was thought
to have a viral infection.

Of the 4 subjects in the MnCC group with acute seizure events within 3
days, two had febrile seizures. One subject had a history of cerebral
palsy, and another had a history of seizures. One event, an afebrile
seizure, could not be clearly distinguished from a breath-holding
episode.

**118-08: Characteristics of Acute Seizure Events**

Occurring within 3 Days of Study Vaccine

+----------------------+-----------------------+-----------------------+
|                      | 7VPnC                 | MnCC                  |
+----------------------+-----------------------+-----------------------+
| Acute Seizure Events | 8                     | 4                     |
+----------------------+-----------------------+-----------------------+
| Febrile              | 7                     | 2                     |
|                      |                       |                       |
| Afebrile             | 1                     | 2                     |
+----------------------+-----------------------+-----------------------+
| Concurrent DTP       | 7                     | 3                     |
|                      |                       |                       |
| Concurrent DTaP      | 1                     | 1                     |
+----------------------+-----------------------+-----------------------+
| Post dose 1          | 1                     | 0                     |
|                      |                       |                       |
| Post dose 2          | 2                     | 1                     |
|                      |                       |                       |
| Post dose 3          | 3                     | 3                     |
|                      |                       |                       |
| Post dose 4          | 2                     | 0                     |
+----------------------+-----------------------+-----------------------+

From October 18, 1999 submission to PLA.

In a safety update for the period ending December 31, 1998, one
additional seizure episode occurring within 3 days of a study vaccine
was reported: A febrile seizure 3 days post 4^th^ dose of 7VPnC.

**Seizure Events in Supporting Studies**

In study 118-12, two subjects in the 7VPnC group experienced seizures
temporally related to vaccine. Both subjects received DTaP concurrently
(See attachment A for narratives). No seizures were reported in the
control group.

No seizure events related to study vaccines were reported in other
supporting studies conducted among infants.

**Immune Thrombocytopenic Purpura (ITP)**

Four cases of ITP were reported as reasons for study termination in the
NCKP trial for the period ending April 30, 1998. All cases were in the
MnCC vaccine group. Onset of illness ranged from 46 to 191 days
following a dose of study vaccines. One child had varicella in the month
preceding onset of ITP.

ITP Case Characteristics

+-------------+-----------+-----------+---------+---------------------+
| Study       | Age       | Days      | Vaccine | Concurrent Vaccines |
| Vaccine     |           | Since     |         |                     |
|             | months    | Vaccine   | Dose    |                     |
+-------------+-----------+-----------+---------+---------------------+
| MnCC        | 3         | 56        | 2       | DTP-HbOC, OPV       |
+-------------+-----------+-----------+---------+---------------------+
| MnCC        | 6         | 46        | 2       | DTP-HbOC, OPV, HepB |
+-------------+-----------+-----------+---------+---------------------+
| MnCC        | 10.5      | 62        | 3       | DTP-HbOC, OPV, HepB |
+-------------+-----------+-----------+---------+---------------------+
| MnCC        | 13        | 191       | 3       | DTP-HbOC, OPV, HepB |
+-------------+-----------+-----------+---------+---------------------+

Compiled from case narratives and October 18, 1999 submission to PLA

**Safety Update**

Deaths, and line listings of hospitalizations within 60 days and
emergency room visits within 30 days of a vaccine dose were provided for
the period June 1 through December 31, 1998, without rate calculations,
statistical comparisons, or narratives.

Adverse events in the safety update considered possibly or probably
related to study vaccines by study investigators were compiled from the
line listings, and are summarized below. The seizure event, which
occurred 3 days after a dose of 7VPnC, was noted above.

118-8: Adverse Events Possibly or Probably Related to Vaccine During
Safety Follow-up, May 1, 1998 through December 31, 1998

  ------------ ------------------ ----------------- ----------- -----------
  Vaccine      Adverse Event      Source of Report  Days Since  Vaccine
  Group                                             Vaccine     Dose

  7VPnC        Febrile Seizure    ER,               8           4
                                  Hospitalization               

               Febrile Seizure    ER                3           4

  MnCC         Fever              ER                1           3

               Fever, Hives       ER                1           2

               Fever, Irritable   ER                2           4

               Local Swelling     ER                3           3

               Fever, Local       ER                0           3
               reaction                                         
  ------------ ------------------ ----------------- ----------- -----------

Compiled from line listings provided in July 7, 1999 submission to the
PLA.

Question #3: Do the data presented support concurrent use with vaccines
according to the recommended schedule of immunizations?

**Hemophilus influenza type B**

Compatibility of 7VPnC with Hib responses in the primary series was
examined in the context of DTP-HbOC in study 118-03, and with DTaP +
HbOC in studies 118-12 and 118-16.

In study 118-03, no decreases in Hib responses were observed when 7VPnC
was administered concurrently with DTP-HbOC in the primary series.

.

**118-03: Hib-PRP Responses Post Dose 3**

**Concurrent Administration of DTP-HbOC and 7VPnC or MnCC**

+----------+-------+------------------+-----------------+-------------+
| Study    | N     | GMC (μg/mL)      | \% ≥ 0.15μg/mL  | \% ≥ 1.0    |
| Group    |       |                  |                 | μg/mL       |
|          |       | (95% CI)         | (95% CI)        | (95%CI)     |
+----------+-------+------------------+-----------------+-------------+
| 7VPnC    | 94    | 7.29             | 100             | 89.4        |
|          |       |                  |                 |             |
|          |       | (5.3, 10.0)      | (96-100)        | (81-95)     |
+----------+-------+------------------+-----------------+-------------+
| MnCC     | 86    | 5.58             | 97.9            | 86.5        |
|          |       |                  |                 |             |
|          |       | (4.1, 7.6)       | (93, 100)       | (78-93)     |
+----------+-------+------------------+-----------------+-------------+

Adapted from Tables 30a, and 31a, Volume 8, Part IV of PLA

In studies 118-12 and 118-16 Hib-PRP responses were assessed for groups
receiving either 7VPnC or control (no vaccine) administered concurrently
with DTaP + HbOC. In study 118-12, data for the 3 pilot 7VPnC lot groups
were pooled. In study 118-16, data from the preferred manufacturing lot
data is represented. No evidence of interference of 7VPnC with
concurrent HbOC was observed; a slight enhancing effect was apparent.

**Hib-PRP GMCs Post Dose 3**

Concurrent Administration of DTaP + HbOC and 7VPnC

  ---------- ------- ------------------ ---------- ---------------- ----------
  Study      7VPnC                      Control:                    p-value
                                        No 7VPnC                    

             N       GMC (95% CI)       N          GMC (95% CI)     

  118-12     214     6.21 (5.17, 7.44)  67         4.36 (3.07,      0.067^1^
                                                   6.19)            

  118-16     159     11.93 ( 9.61,      83         7.79 (5.72,      0.017^2^
                     14.81)                        10.61)           
  ---------- ------- ------------------ ---------- ---------------- ----------

Adapted from Table 10, page 58, Volume 25, and Table 9a, page 54, Volume
29, Part IV of PLA.

^1^ p-value based on ANCOVA model (sponsor's analysis)

^2^ Preferrred manufacturing lot N vs. control . p-value based on ANOVA
(sponsor's analysis)

Hib-PRP responses following concurrent and separate administration of
7VPnC and HbOC with the 4^th^ dose were assessed in studies 118-03 and
118-07. In both studies, the primary series of 7VPnC was administered
with DTP-HbOC. In study 118-07, DTaP and HbOC were administered
concurrently with 7VPnC, or one month after. Differences in GMCs between
groups were statistically significant, however in both groups the GMCs
were relatively high, and proportions responding at ≥ 1.0 μg/mL exceeded
97%.

**118-07: Hib-PRP Responses Post Dose 4**

Concurrent Administration of DTP, HbOC and 7VPnC

  ------------------ -------- --------- ------------ ------------- --------------
  Study Group        N        GMC                    \% ≥          \% ≥ 1.0 μg/mL
                              (μg/mL)                0.15μg/mL     

  7VPnC + DTaP +     47       22.73     p=0.009^1^   100           97.9
  HbOC                                                             

  DTaP + HbOC only   26       47.86                  100           100
  ------------------ -------- --------- ------------ ------------- --------------

Adapted from Table 26, page 72, Volume 11, part IV of PLA

^1^ Fishers exact (Sponsor's analysis)

In study 118-03, 7VPnC or MnCC were administered concurrently with
DTaP + HbOC at the 4^th^ dose, after use of DTP-HbOC for the primary
series. Direct statistical comparisons between 7VPnC and MnCC groups
were not made in the PLA. The proportion of subjects with anti Hib-PRP
antibody ≥ 1.0 μg/mL appears to differ substantially between groups, and
the lower 95% CI of the response rate extends to 70%.

**118-03: Hib-PRP Responses Post Dose 4**

Concurrent Administration of DTaP + HbOC and 7VPnC or MnCC

+-------------+--------+----------------+-------------+--------------+
| Study Group | N      | GMC (μg/mL)    | \% ≥        | \% ≥ 1.0     |
|             |        |                | 0.15μg/mL   | μg/mL        |
|             |        | (95% CI)       |             |              |
|             |        |                | (95%CI)     | (95%CI)      |
+-------------+--------+----------------+-------------+--------------+
| 7VPnC       | 26     | 19.7           | 100         | 88.5         |
|             |        |                |             |              |
|             |        | (10.3, 37.6)   | (86.8, 100) | **(69.9,**   |
|             |        |                |             | 97.6)        |
+-------------+--------+----------------+-------------+--------------+
| MnCC        | 33     | 21.6           | 100         | 100          |
|             |        |                |             |              |
|             |        | (13.44, 34.73) | (89.4, 100) | (89.4, 97.6) |
+-------------+--------+----------------+-------------+--------------+

Adapted from Tables 30a and 31a, Statistical Report, Volume 8, Part IV
of PLA

Hib-PRP response rates at the 4^th^ dose following priming with
DTP-HbOC, presented above, may not be most relevant to current practice,
as DTaP is used predominantly with all doses of the primary series. Data
for concurrent immunizations using DTaP for all doses of the primary
series and for the 4^th^ dose are not included in the PLA.

**Inactivated Poliovirus Vaccine**

Responses to IPV (IPOL) following concurrent immunization with 7VPnC
and IPV in the primary series was evaluated in a single study, 118-16.
IPV was administered at 2 and 4 months of age. Serum neutralizing
antibody titers were determined at 7 months. Data for the preferred
manufacturing lot only is shown below for simplicity of presentation.

The lower limit of the 90% confidence interval for the difference
between group in percent responders at an antibody titer 1:10 was 13.3%.
This difference exceeded 10% difference criteria for equivalence for
this serotype. Results of the comparison between pilot lot and control
were similar.

No interference between 7VPnC and polio type II and III was observed.

The clinical significance of this apparent interference of 7VPnC with
IPV I responses is not clear. The sponsor points out that responses at 7
months may not represent peak responses following immunization at 2 and
4 months. The responder cut-off at 1:10 differs from the customary
responder criteria of 1:8. Response rates for polio type I exceed
response rates for polio type III in both groups, which met the
difference criteria. No other studies in the PLA address concurrent
immunization of 7VPnC and IPV.

118-16: Percent of Subjects Achieving Defined Levels to IPV Administered
Concurrently with 7VPnC

+---------+-------+----------------+-------------+---------+----------+
|         |       | \% Subjects    |             | Manufa  |          |
|         |       | (95% CI)^1^    |             | cturing |          |
|         |       | Achieving      |             | . Lot   |          |
|         |       | Given Antibody |             |         |          |
|         |       | Level          |             | versus  |          |
|         |       |                |             | Control |          |
+---------+-------+----------------+-------------+---------+----------+
|         |       | Manufacturing  | Control     | Dif     | 90%      |
|         |       | Lot            | Group       | ference | Lower    |
|         |       |                |             |         | Limit^2^ |
|         |       | N=156          | N = 80      |         |          |
+---------+-------+----------------+-------------+---------+----------+
| Polio I | ≥     | 88.96          | 93.59       | -4.63   | -13.29   |
|         | 1:10  |                |             |         |          |
|         |       | (82.9, 93.5)   | (85.6,      |         |          |
|         |       |                | 97.9)       |         |          |
+---------+-------+----------------+-------------+---------+----------+
| Polio   | ≥     | 94.16          | 93.59       | 0.57    | -6.31    |
| II      | 1:10  |                |             |         |          |
|         |       | (89.1, 97.3)   | (85.6,      |         |          |
|         |       |                | 97.9)       |         |          |
+---------+-------+----------------+-------------+---------+----------+
| Polio   | ≥     | 83.77          | 80.77       | 3.00    | -6.61    |
| III     | 1:10  |                |             |         |          |
|         |       | (76.9, 89.3)   | (70.2,      |         |          |
|         |       |                | 88.9)       |         |          |
+---------+-------+----------------+-------------+---------+----------+

Adapted from Table 10, page 56, Volume 29, Part IV of PLA

^1^ Exact 95% confidence intervals calculated using StatXact (sponsor's
analysis).

^2^ Exact 90% confidence intervals calculated using StatXact (sponsor's
analysis).

Studies of the compatibility of 7VPnC with OPV are not presented here
for lack of relevance to current practice.

**Hepatitis B**

Responses to Hepatitis B following concurrent immunization with 7VPnC
and Hepatitis B vaccines in the primary series were evaluated in two
studies: 118-7 (Recombivax HB), and 118-16 (Engerix-B).

In study 118-16, Hepatitis B vaccine was administered at 0-2 weeks, 2
months, and 6 months of age. Concurrent immunizations included
DTaP/HbOC, IPV, and either 7VPnC or no vaccine control. In the table
below, only results for the preferred manufacturing lot are presented;
results for the pilot lot were similar.

Non interference of 7VPnC and Hepatitis B vaccine was demonstrated in
this study.

> **Study 118-16: Percent of Subjects**
>
> **Achieving ≥ 10 mIU/mL Hepatitis B Antibody Level, Post Dose 3**

+---------------------+-----------+-----------------+-----------------+
| Concurrent Study    | N         | Percent         | 95% CI^1^       |
| Vaccine             |           | Achieving       |                 |
|                     |           |                 |                 |
|                     |           | ≥ 10 mIU/mL     |                 |
+---------------------+-----------+-----------------+-----------------+
| 7VPnC               | 146       | 99.35%          | 96.4%, 100%     |
+---------------------+-----------+-----------------+-----------------+
| Control: No 7VPnC   | 80        | 96.15%          | 89.1%, 99.2%    |
+---------------------+-----------+-----------------+-----------------+

Adapted from Table 10, page 56, Volume 29, Part IV of PLA

\* Exact 95% confidence intervals calculated using StatXact (sponsor's
analysis).

In study 118-07, Hepatitis B vaccine was administered at 2, 4, and 6
months of age. Concurrent immunizations included DTP-HbOC, OPV, and
either 7VPnC or MnCC.

**Study 118-07: Percent of Subjects**

> **Achieving ≥ 10 mIU/mL Hepatitis B Antibody Level**

+---------------------+-----------+-----------------+-----------------+
| Concurrent Study    | N         | Percent         | 95% CI          |
| Vaccine             |           | Achieving       |                 |
|                     |           |                 |                 |
|                     |           | ≥ 10 mIU/mL     |                 |
+---------------------+-----------+-----------------+-----------------+
| 7VPnC               | 81        | 92.6%           | 84.6%, 97.2%    |
+---------------------+-----------+-----------------+-----------------+
| MnCC                | 41        | 100%            | 93%, \--        |
+---------------------+-----------+-----------------+-----------------+

Adapted from Table 34 page 59 and Table 53 page 71, Volume 12, Part IV
of PLA

These data suggest that 7VPnC may interfere with Hepatitis B vaccine
responses when administered on the 2, 4, and 6 months schedule. The
lower bound of the 95% confidence interval for the proportion of
subjects attaining the clinically relevant antibody titer of 10 mIU/mL
was less than 85%. GMCs for Hep B responses were not provided. No
statistical comparison of the difference between responses to Hep B
vaccine by concurrent 7VPnC or MnCC vaccines were provided in the study
report.

**DTaP**

Compatibility of 7VPnC with DTaP responses in the primary series was
examined in study 118-12. The control group received concurrent vaccines
only. In the tables below, data from the 3 pilot lots of 7VPnC were
combined for comparisons to control.

GMCs for tetanus toxoid were significantly higher in the control group,
which did not receive 7VPnC, but the proportion of subjects exceeding
relevant antibody levels were similar in the two groups.

Forty-five percent (45%) of the children who received concurrent 7VPnC
achieved a 4-fold rise in fimbriae, as compared to 62.5% of the children
in the control group. The significance level of the difference was
0.015, and the 90% lower confidence limit of the difference was -30.8%.

> **Study 118-12: Comparisons of GMCs of Antibody to Antigens in**

**DTaP Between 7VPnC Recipients and Control, Post Dose 3**

+-----------+----------------+-----------------+-------+--------------+
| Antigen   | GMC (95%       |                 |       | Ratio of GMC |
|           | Confidence     |                 |       |              |
|           | Interval) of   |                 |       | of           |
|           | Post Dose 3    |                 |       | Concurrent   |
|           | Antibody       |                 |       |              |
|           |                |                 |       | 7VPnC to     |
|           |                |                 |       | Control      |
|           |                |                 |       |              |
|           |                |                 |       | (with 90%    |
|           |                |                 |       | CI)          |
+-----------+----------------+-----------------+-------+--------------+
|           | with           | without         | P-val |              |
|           | Concurrent     | Concurrent      | ue^2^ |              |
|           | 7VPnC          | 7VPnC           |       |              |
|           |                |                 |       |              |
|           | N^1^= 214      | N^1^ = 67       |       |              |
+-----------+----------------+-----------------+-------+--------------+
| ##### Di  | 0.88 (0.79,    | 0.80 (0.63,     | 0.741 | 1.04 (0.87,  |
| phtheria  | 0.97)          | 1.01)           |       | 1.23)        |
+-----------+----------------+-----------------+-------+--------------+
| Tetanus   | 3.45 (3.11,    | 4.14 (3.39,     | 0.037 | 0.80 (0.67,  |
|           | 3.83)          | 5.07)           |       | 0.95)        |
+-----------+----------------+-----------------+-------+--------------+
| Pertussis | 19.05 (17.15,  | 17.83 (14.93,   | 0.404 | 1.09 (0.92,  |
| Toxin     | 21.15)         | 1.28)           |       | 1.29)        |
+-----------+----------------+-----------------+-------+--------------+
| Fimbriae  | 3.29 (2.79,    | 4.17 (3.24,     | 0.316 | 0.81 (0.58,  |
|           | 3.86)          | 5.37)           |       | 1.14)        |
+-----------+----------------+-----------------+-------+--------------+
| 69K       | 40.11 (35.52,  | 50.93 (41.65,   | 0.067 | 0.80 (0.65,  |
|           | 45.29)         | 2.27)           |       | 0.98)        |
+-----------+----------------+-----------------+-------+--------------+
| FHA       | 43.77 (39.50,  | 46.70 (39.85,   | 0.595 | 0.95 (0.81,  |
|           | 48.49)         | 4.74)           |       | 1.12)        |
+-----------+----------------+-----------------+-------+--------------+

Adapted from Table 21, page 49 of Statistical Report, Volume 27, Part IV
of PLA

^1^ Maximum number of samples available; actual varies slightly with
antigen.

^2^ P-values based on an ANCOVA model (Sponsor's analysis)

> **Study 118-12: Comparisons of Seroconversion Rates to Antigens in
> DTaP Between 7VPnC Recipients and Control, Post Dose 3**

+------------+----------------+---------------+-------+--------------+
| Antigen    | \% Children    |               |       | Difference   |
|            | Achieving      |               |       | in           |
|            | Antibody Level |               |       | Proportion   |
|            | (95% CI^2^)    |               |       | (Concurrent  |
|            |                |               |       | -- Control)  |
|            |                |               |       | and 90% CI\* |
+------------+----------------+---------------+-------+--------------+
|            | With           | Without       | P-Val |              |
|            | Concurrent     | Concurrent    | ue^2^ |              |
|            | 7VPnC          | 7VPnC         |       |              |
|            |                |               |       |              |
|            | N^1^ = 214     | N^1^ = 67     |       |              |
+------------+----------------+---------------+-------+--------------+
| Diphtheria |                |               |       |              |
+------------+----------------+---------------+-------+--------------+
| ≥ 0.01 IU  | 100 (98.2,     | 100 (94.5,    | 1.000 | 0 (-3.5,     |
| /mL        | 100.0)         | 100.0)        |       | 6.1)         |
+------------+----------------+---------------+-------+--------------+
| ≥ 0. 1 IU  | 100 (98.2,     | 97.0 (89.4,   | 0.056 | 3.0 (-1.1,   |
| /mL        | 100.0)         | 99.7)         |       | 10.7)        |
+------------+----------------+---------------+-------+--------------+
| Tetanus    |                |               |       |              |
+------------+----------------+---------------+-------+--------------+
| ≥ 0.01 IU  | 100 (98.2,     | 100 (94.5,    | 1.000 | 0 (-3.5,     |
| /mL        | 100.0)         | 100.0)        |       | 6.1)         |
+------------+----------------+---------------+-------+--------------+
| ≥ 0. 1 IU  | 100 (98.2,     | 100 (94.5,    | 1.000 | 0 (-3.5,     |
| /mL        | 100.0)         | 100.0)        |       | 6.1)         |
+------------+----------------+---------------+-------+--------------+
| Pertussis  |                |               |       |              |
| Toxin      |                |               |       |              |
+------------+----------------+---------------+-------+--------------+
| ≥ 2 fold   | 82.2 (76.3,    | 83.3 (72.1,   | 1.000 | -1.1 (-11.9, |
| rise       | 87.2)          | 91.4)         |       | 9.8)         |
+------------+----------------+---------------+-------+--------------+
| ≥ 4 fold   | 74.0 (67.5,    | 69.7 (57.1,   | 0.526 | 4.3 (-6.6,   |
| rise       | 79.9)          | 80.5)         |       | 16.4)        |
+------------+----------------+---------------+-------+--------------+
| Fimbriae   |                |               |       |              |
+------------+----------------+---------------+-------+--------------+
| ≥ 2 fold   | 62.6 (55.6,    | 75.0 (62.6,   | 0.073 | -12.4        |
| rise       | 69.3)          | 85.0)         |       | (-24.7,      |
|            |                |               |       | -0.6)        |
+------------+----------------+---------------+-------+--------------+
| ≥ 4 fold   | 44.7 (37.7,    | 62.5 (49.5,   | **0.  | **-17.8      |
| rise       | 51.8)          | 74.3)         | 015** | (-30.8,      |
|            |                |               |       | -6.0)**      |
+------------+----------------+---------------+-------+--------------+
| 69K        |                |               |       |              |
+------------+----------------+---------------+-------+--------------+
| ≥ 2 fold   | 79.9 (73.8,    | 87.9 (77.5,   | 0.199 | -8.0 (-18.1, |
| rise       | 85.2)          | 94.7)         |       | 2.6)         |
+------------+----------------+---------------+-------+--------------+
| ≥ 4 fold   | 65.6 (58.6,    | 77.3 (65.3,   | 0.095 | -11.7        |
| rise       | 72.0)          | 86.7)         |       | (-23.6,      |
|            |                |               |       | -0.2)        |
+------------+----------------+---------------+-------+--------------+
| FHA        |                |               |       |              |
+------------+----------------+---------------+-------+--------------+
| ≥ 2 fold   | 78.4 (72.1,    | 78.8 (66.9,   | 1.000 | -0.4 (-11.9, |
| rise       | 83.8)          | 87.9)         |       | 10.8)        |
+------------+----------------+---------------+-------+--------------+
| ≥ 4 fold   | 66.4 (59.4,    | 69.7 (57.1,   | 0.654 | -3.3 (-15.9, |
| rise       | 72.8)          | 80.5)         |       | 8.3)         |
+------------+----------------+---------------+-------+--------------+

Reproduced from Table 22, page 50, Volume 27, Part IV of PLA

^1^ Maximum number of samples available; actual varies slightly with
antigen.

^2^ Exact P-values and exact confidence intervals computed using
StatXact.

Responses to DTaP administered with 7VPnC at the 4^th^ dose were also
examined in study 118-7. However, these data may not be most relevant to
current practice, as all subjects had been primed with DTP-HbOC. No data
were presented in the PLA addressing responses to 4 doses of DTaP
administered concurrently with 7VPnC.

**MMR**

Responses to measles, mumps and rubella following concurrent
administration with 7VPnC were examined in studies 118-3 and 124-2.

In study 118-3, subjects received 4 doses of 7VPnC or MnCC. Concurrently
with the 4^th^ dose, subjects were randomized to receive MMR or HbOC.
Proportions seroconverting in the MnCC group are provided here for
comparison; no statistical comparisons are presented in the PLA.

**Study 118-3: Percent of Subjects Seroconverting to**

**MMR when Administered Concurrently with 7VPnC**

+------------+--------+------------------+--------+--------------------+
| Antigen    | 7VPnC  |                  | MnCC   |                    |
+------------+--------+------------------+--------+--------------------+
|            | N      | \%               | N      | \%                 |
|            |        | S                |        | Seroconverters^1^  |
|            |        | eroconverters^1^ |        |                    |
|            |        | (95%CI)          |        | (95%CI)            |
+------------+--------+------------------+--------+--------------------+
| Measles    | 27     | 93%              | 28     | 100%               |
|            |        |                  |        |                    |
|            |        | (76%, 99%)       |        | (88%, 100%         |
+------------+--------+------------------+--------+--------------------+
| Mumps      | 27     | 82%              | 28     | 82%                |
|            |        |                  |        |                    |
|            |        | (62%, 94%)       |        | (63%, 94%)         |
+------------+--------+------------------+--------+--------------------+
| Rubella    | 27     | 89%              | 28     | 89%                |
|            |        |                  |        |                    |
|            |        | (71%, 98%)       |        | (72%, 98%)         |
+------------+--------+------------------+--------+--------------------+

Reproduced from Table 30b, Statistical Report, Volume 8, Part IV of PLA.

^1^ Antibodies measured by ELISA using Biowhittaker assay kits and
reported in Predicted Index Value (PIV). Results with PIV ≥ 1 are
considered seropositive.

Although no significant differences are apparent between the study arms,
response rates to mumps and rubella are low by historical standards.

**Draft Question #4: Please comment on the "Catch-Up" schedule proposed
for the package insert.**

**Catch-up Schedules**

The catch-up schedule proposed for inclusion in the vaccine label is
reproduced below:

> **For Previously Unvaccinated Older Children**
>
> Previously unvaccinated infants should be vaccinated according to the
> following schedule:

  --------------------------------- -------------------------------------
  Age at first dose                 Total number of 0.5 mL doses

                                    

  7-11 months of age                3\*

                                    

  12-23 months of age               2\*\*

                                    

  24+ months of age                 1
  --------------------------------- -------------------------------------

\* 2 doses at least 4 weeks apart; third dose after the one-year

birthday, separated from second dose by at least 2 months.

> \*\* 2 doses at least 2 months apart.

The efficacy trial provided evidence of protection after 3 doses of
7VPnC until the 4^th^ dose was administered, and subsequently after the
4^th^ dose. To make inferences about long-term protection from available
immunogenicity data based on data from the efficacy trial, it may also
be relevant to make comparisons to post dose 4 antibody levels.

Of the 188 subjects in the NCKP efficacy study who received 3 doses
7VPnC concurrently with DTP-HbOC in the primary series, and had at least
one serum sample drawn, 88 met the eligibility criteria for the primary
series immunogenicity analysis, and 68 met criteria for 4^th^ dose
immunogenicity analyses. GMCs for pneumococcal serotypes pre and post
doses 3 and 4 are shown below.

**118-8: Geometric Mean Concentration of Pneumococcal Antibodies**

**Prior to and Following the Primary Series and 4^th^** Dose

  -------------- -------------- -------------- ------------- -------------
                 Pre dose 3     Post dose 3    Pre dose 4    Post dose 4

  Serotype       N=86^1^        N=88^1^        N=68          N=68

  4              0.078          1.458          **0.314**     2.384

  6B             0.327          4.696          1.714         14.446

  9V             0.180          1.994          0.572         3.510

  14             0.198          4.601          1.451         6.521

  18C            0.146          2.160          **0.496**     3.431

  19F            0.374          1.394          0.550         **2.067**

  23F            0.174          1.848          **0.435**     3.820
  -------------- -------------- -------------- ------------- -------------

Adapted from Tables 39 and 42, Volume 13 Part IV of PLA.

^1^ N=87 for pre GMC and N=87 for post GMC, but N=86 in this table
because one subject had pre but no post concentration and another
subject had post but no pre concentration.

Pre dose 4, GMCs had declined to less than 0.50 μg/mL for 3 of the
pneumococcal serotypes (4, 18C, and 23F). Post dose 4, GMCs exceeded 2
μg/mL for all serotypes. Response to the 4^th^ dose was least robust for
serotype 19F.

(Pre and post dose 4 pneumococcal serological data when 7VPnC was given
with concurrent DTaP were available for only 9 subjects).

Available immunogenicity data from various vaccine schedules obtained in
various trials are summarized in the table on the following page, with
comparisons to antibody levels observed in the efficacy trial after the
primary series, but not after the 4^th^ dose.

It should be noted that in the age group \> 24 months, all catch-up data
in the PLA derives from study of a 9-valent formulation. Data from small
studies (N\<30) of an investigational 9-valent formulation intended to
support catch-up schedules indicate that GMCs for the 9-valent
formulation were numerically greater than GMCs for the 7-valent
formulation for some serotypes following similar dosing schedules in
different studies. In study 124-2, immunogenicity of 7VPnC and 9-valent
PnC were directly compared during the primary series; these data
bridging 9VPnC to 7VPnC were not included in the application. Responses
observed with the 9-valent formulation in this age group may not be
representative of responses due to Prevenar.

Two 23-valent pneumococcal polysaccharide (23VPS) vaccines are licensed
and available in the U.S. The 23VPS vaccines are recommended for
selected immunocompetent individuals over the age of 2 years, including
Alaskan and certain American Indian populations. No data comparing
responses to 7VPnC and 23VPS vaccine in children over the age of 2 years
were provided in the PLA. Comparative responses to 7VPnC and 23VPS in
adults following a single dose are available from study 118-02 (see
attachment B). These data demonstrated superior responses to 7VPnC only
for serotype 19F.

Safety and immunogenicity data for responses to 23VPS following a
primary series of 7VPnC during infancy were not provided in the PLA. In
study 92-05 (attachment B), children 15-18 months received 23VPS after a
primary series of a 5-valent conjugate formulation. While a "booster"
response to 23VPS among children primed with 5-vaent conjugate vaccine
was apparent, the study design did not provide for comparisons of
responses to 23VPS and 5-valent conjugate vaccine at the 4^th^ dose.
Thus, based on data submitted to the PLA, it remains to be demonstrated
whether children over the age of 2 years respond better to 7VPnC than to
a licensed 23-valent pneumococcal polysaccharide vaccine, whether primed
with 7VPnC in infancy or not.

Catch-Up Studies: Geometric Mean Concentrationsfor all Serotypes and
'Age, Dose' Regimens

<table>
<colgroup>
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td><p>Age group</p>
<p>(months)</p>
<p># doses</p></td>
<td>Study**</td>
<td><p>Sample</p>
<p>size</p></td>
<td>4</td>
<td>6B</td>
<td>9V</td>
<td>14</td>
<td>18C</td>
<td>19F</td>
<td><h1 id="f">23F</h1></td>
<td><p>*Number of serotypes exceeding</p>
<p>118-8</p></td>
</tr>
<tr class="even">
<td><p>7-11,</p>
<p>2 doses</p></td>
<td>118-12</td>
<td>37 – 38</td>
<td>2.785</td>
<td>1.159</td>
<td>1.330</td>
<td>4.895</td>
<td>1.983</td>
<td>1.807</td>
<td>1.729</td>
<td>4</td>
</tr>
<tr class="odd">
<td><p>7-11,</p>
<p>3 doses*</p></td>
<td>118-12</td>
<td>22</td>
<td>2.336</td>
<td>3.663</td>
<td>2.113</td>
<td>9.329</td>
<td>2.312</td>
<td>1.600</td>
<td>2.504</td>
<td>7*</td>
</tr>
<tr class="even">
<td rowspan="2"><p>12-17,</p>
<p>1 dose</p></td>
<td>118-09</td>
<td>25</td>
<td>0.746</td>
<td>0.232</td>
<td>0.535</td>
<td>0.373</td>
<td>0.628</td>
<td>0.666</td>
<td>0.443</td>
<td>0</td>
</tr>
<tr class="odd">
<td>118-15</td>
<td>98 –103</td>
<td>2.985</td>
<td>0.547</td>
<td>1.015</td>
<td>0.856</td>
<td>1.390</td>
<td>1.097</td>
<td>0.797</td>
<td>1</td>
</tr>
<tr class="even">
<td rowspan="2"><p>12-17,</p>
<p>2 doses*</p></td>
<td>118-15</td>
<td>82 – 84</td>
<td>3.908</td>
<td>4.670</td>
<td>1.935</td>
<td>6.919</td>
<td>2.252</td>
<td>3.780</td>
<td>3.287</td>
<td>7*</td>
</tr>
<tr class="odd">
<td><p>124-501</p>
<p>(9-valent)</p></td>
<td>18</td>
<td>10.32</td>
<td>31.55</td>
<td>7.083</td>
<td>22.12</td>
<td>9.866</td>
<td>7.237</td>
<td>8.348</td>
<td>7*</td>
</tr>
<tr class="even">
<td rowspan="3"><p>18-23,</p>
<p>1 dose</p></td>
<td>118-09</td>
<td>33</td>
<td>1.617</td>
<td>0.442</td>
<td>2.125</td>
<td>0.450</td>
<td>1.653</td>
<td>1.312</td>
<td>0.690</td>
<td>2</td>
</tr>
<tr class="odd">
<td>118-15</td>
<td>45 – 48</td>
<td>2.906</td>
<td>0.804</td>
<td>0.890</td>
<td>0.719</td>
<td>1.487</td>
<td>0.963</td>
<td>1.497</td>
<td>2</td>
</tr>
<tr class="even">
<td><p>124-501</p>
<p>(9-valent)</p></td>
<td>25</td>
<td>16.16</td>
<td>1.905</td>
<td>2.299</td>
<td>0.822</td>
<td>2.618</td>
<td>1.823</td>
<td>0.711</td>
<td>4</td>
</tr>
<tr class="odd">
<td><p>18-23,</p>
<p>2 doses*</p></td>
<td>118-15</td>
<td>52 – 54</td>
<td>3.36</td>
<td>4.918</td>
<td>1.805</td>
<td>6.689</td>
<td>2.651</td>
<td>3.174</td>
<td>2.710</td>
<td>7*</td>
</tr>
<tr class="even">
<td><p>24+</p>
<p>1 dose</p></td>
<td><p>124-501</p>
<p>(9-valent)</p></td>
<td>85</td>
<td>6.205</td>
<td>3.272</td>
<td>3.491</td>
<td>2.054</td>
<td>3.975</td>
<td>1.866</td>
<td>1.628</td>
<td>6</td>
</tr>
<tr class="odd">
<td>118-8<sup>†</sup>, DTP/HbOC</td>
<td>118-08</td>
<td>87 – 88</td>
<td>1.458</td>
<td>4.696</td>
<td>1.994</td>
<td>4.606</td>
<td>2.160</td>
<td>1.394</td>
<td>1.848</td>
<td></td>
</tr>
<tr class="even">
<td>118-8<sup>†</sup>, DTaP</td>
<td>118-08</td>
<td>31 – 32</td>
<td>1.474</td>
<td>2.181</td>
<td>1.519</td>
<td>5.052</td>
<td>2.235</td>
<td>1.540</td>
<td>1.478</td>
<td></td>
</tr>
</tbody>
</table>

Adapted from Table 45, page 110, Volume 33, Part IV of PLA

\* All seven serotypes exceeded post dose 3 GMCs in study 118-8;
historical comparisons using similar assays.

\*\* Study vaccine is Prevenar, unless otherwise indicated

Geometric means exceeding 118-8 geometric mean are bolded

^†^ GMCs following 3 doses

**Draft Questions to the Committee**

**#1: Do the data presented provide sufficient evidence of efficacy for
Prevenar at 2, 4, 6, and 12-15 months of age?**

**If not, what additional information should be requested?**

**#2: Do the data presented provide adequate evidence of safety for
Prenevar?**

**If not, what additional information should be requested?**

**#3: Do the data presented support concurrent use with vaccines
according to the recommended schedule of immunizations?**

**#4: Please comment on the proposed "catch-up" schedule?**

**Attachment A: Narratives of Selected Cases and Events**

**Study 118-8: Cases of Invasive Disease Among 7VPnC Recipients**

**[Per Protocol]{.underline}**

A 24-month old Causcasian male, who received 4 doses of 7VPnC, presented
in the ER with temperature 99.6 °F, cough and URI of 3 days duration.
Ceftriaxone was given and the child was seen in clinic next day when the
blood culture was obtained. Chest X-ray showed a right lower lobe
pneumonia. He was treated outpatient with ceftriaxone and oral
antibiotics and recovered fully. The isolate was serotype 19F,
penicillin sensitive. There was no evidence the child was
immunocompromised.

**[ITT]{.underline}**

A 12.5 month old African-american female who received 1 dose of 7VPnC
became ill with fever (104.8°F), nasal discharge, and injection of
throat and ears 317 days after the 1^st^ dose. She was treated with
trimethoprim/sulfa p.o., ceftriaxone, and then amoxicillin. She
recovered fully. The isolate was serotype 6B, penicillin sensitive.
There was no evidence the child was immunocompromised.

A 2.5 year old Caucasian male, who received 4 doses 7VPnC per schedule,
was diagnosed with acute megaloblasitc leukemia, and received one round
of chemotherapy prior to onset of pneumococcal bacteremia, 570 days
after 4th dose. The isolate was serotype 19F and penicillin resistant.
He was treated with vancomycin, but died 2 months later. This case was
classified as intent-to-treat, despite being fully vaccinated, due to
his immunocompromised condition.

**Study 118-8: Deaths Among Subjects with Invasive Disease**

**[MnCC Group]{.underline}**

An 8-month old Caucasian female was diagnosed with pneumococcal
pneumonia and meningitis. The child developed cerebral edema and
cerebral infarcts. Pneumococcal serotype 14, relatively resistant to PCN
grew from blood and CSF. Causes of death were listed as cardiopulmonary
failure due to metabolic derangement (not specified), failure to thrive,
and bilateral cerebral infarcts. There was no evidence the child was
immunocompromised (results of immune function tests not provided).

A 28-month old male with a history of asthma, was diagnosed with RML,
RLL, and LLL pneumonia, and respiratory distress. Pneumococcal serotype
19F, PCN sensitive, grew from a blood culture. The child was not
receiving corticosteroids prior to hospitalization. There was no
evidence the child was immunocompromised (results of immune function
tests not provided).

A 4-month old Hispanic male with severe combined immunodeficiency
disease (SCIDS) developed pneumonia with RLL consolidation. Blood
culture grew a non- vaccine serotype 18B, sensitive to PCN. He
recovered, but died over a year later after unsuccessful bone marrow
transplant.

**[7VPnC Group]{.underline}**

A 2.5-year old Caucasian male in the 7VPnC group with acute
megaloblastic leukemia, recovered from pneumococcal bacteremia due to a
PCN resistant pneumococcal serotype 19F, but died at home 6 weeks later
(described above).

**Study 118-8: Acute Seizures within 3 Days of Study Inoculation as
Serious Adverse Events Considered by Investigator to Be Possibly,
Probably, or Definitely Related to Study Vaccines**

**[7VPnC Subjects]{.underline}**

07-1132: A 5-month-old male infant who was immunized with 7VPnC on
1/22/97 and 4/23/97. He also received DTP-HbOC, OPV, and Hep B vaccines
concurrently. Twelve hours following the second dose, the subject
experienced a seizure lasting approximately 3 minutes. Following the
seizure, the subject's temperature was 100°F. He was brought to the ER
for observation and discharged with a diagnosis of febrile seizure. This
event is considered possibly related to immunization by both the
investigator and the medical monitor for the sponsor because of the
close temporal association of the event with the immunization.

10-0662: A 7.5-month-old female received three doses of 7VPnC on
10/21/96, 1/23/97, and 3/21/97. She was also immunized with Tetramune,
OPV, and hepatitis B at the same visits. Three hours following the third
dose, she developed a fever of 100.8°F and experienced a tonic seizure
lasting approximately 2 minutes. Following an examination in the ER, the
subject was discharged. Later that evening, she experienced another
seizure, was seen in the ER where her urine was positive for *E. coli*.
She was started on trimethoprim/sulfamethoxazole and on 3/22/97 was
afebrile. She experienced another febrile seizure on 3/27/97 and was
started on phenobarbital. The febrile seizures were thought most likely
due to the UTI, but a possible causal relationship with investigational
vaccine could not be ruled out by both the investigator and the medical
monitor for the sponsor because of the temporal association.

12-0397: A 10-month-old male received three doses of 7VPnC on 7/8/96,
9/10/96, and 11/7/96. He also received Tetramune and OPV concurrently
with all doses and hepatitis B vaccine with doses 1 and 2. On 11/8/96,
the mother reported that the child had a rectal temperature of
"109.48°F," and that the infant's body was jerking and that his eyes
rolled back into his head. The episode lasted from 30 to 45 minutes.
When his temperature was rechecked 2 hours later, it was 99.8°F. Based
on the medical history provided, it is likely that the subject
experienced a febrile seizure possibly related to immunization as
assessed by both the investigator and the medical monitor. Although it
is considered a serious event associated with a high fever, a
temperature of109.48°F is most likely an inaccurate report. This subject
was discontinued from the study at the request of the parents.

**[MnCC Subjects]{.underline}**

04-0343: A 7-month-old Caucasian female with no significant past medical
history prior to this episode, was immunized with MnCC on 3/23/96 and
5/17/96. She also received Tetramune and OPV concurrently. On 5/17/96,
later in the afternoon, she experienced an episode of emesis and
appeared pale with dusky lips. Her temperature was 101°F. She had a
second episode of emesis followed by shaking of her head and left arm.
This was associated with continuing fever. She was brought to the ER and
a presumptive diagnosis of febrile seizure secondary to immunization was
made. She was subsequently dropped from the study. Based on the history,
this event is suggestive of a febrile seizure. The study vaccine was
administered concurrently with Tetramune and OPV. Since the exact cause
of the fever and resulting seizure cannot be determined, a possible
relationship to study vaccine cannot be ruled out as assessed by the
investigator and the medical monitor for the sponsor.

**118-8: Acute Seizure Events Within 3 Days of Study Vaccine Resulting
in Termination from the Study**

**[7VPnC]{.underline}**

15-0159: This 4 month old received 7VPnC, Tetramune and OPV on 1/16/96
and 3/11/96, and Hep B vaccine on 1/16/96. Approximately 45 minutes
after receiving his second dose of vaccine, he experienced an episode of
focal seizures, characterized by a blank stare, left eyelid twitching,
and eye deviation. This was followed by bilateral clonic seizures
lasting 3 minutes. He experienced another seizure 3 days later lasting 3
minutes. Head CT and EEG were unremarkable. He was dropped from the
study, and the investigator considered these events to be possibly
related to immunization.

**[MnCC]{.underline}**

14-1265: This subject received a 3 doses of MnCC, with DTaP, and HbOC on
4/28/98. Two days after the 3^rd^ dose, while afebrile and nursing, the
infant stiffened and arms shook. The event last 1 minute followed by
sleep. The event was diagnosed as probable seizure versus possible GE
reflux or breath holding episode. The investigator coded the event as
not being related to study vaccine, however the subject was dropped from
further doses per study protocol.

13-0217: This subject was an 8-month old female who received 3 doses of
MnCC, Tetramune, OPV and Hepatitis B. On the day of immunization, she
developed a fever of 104.5°F, and experienced a grand mal seizure. The
subject had a history of seizures and was diagnosed with epilepsy and
discontinued from further study participation. The investigator
considered this event not related to study vaccine, but possibly related
to DTP vaccine.

**118-8: Acute Seizure Events Within 3 Days of Study Vaccine Considered
Possibly Vaccine Related By The Medical Monitor For The Sponsor**

**[7VPnC]{.underline}**

07-0843: This subject was a 6-month-old female who received three doses
of 7VPnC on 9/30/96, 12/02/96, and 2/3/97, respectively. She also
received Tetramune and OPV concurrently with each study vaccine, and
received hepatitis B vaccine concurrently with the 1^st^ and 3^rd^
vaccinations. The subject was reported as having a tactile fever and
irritability for 3 days following the third dose. On 2/6/97, 3 days
after dose 3, she experienced 20 episodes of eye fluttering, and on
2/8/97 she experienced 10 such episodes. She was admitted to the
hospital on 2/8/97. During the 2-day hospitalization, she experienced
4-5 more episodes. Physical and neurological evaluations were normal,
and the EEG and CSF were unremarkable. The infant was discharged on
2/10/97 with the diagnoses of possible new onset seizures and meningitis
ruled out. A possible causal relationship to study vaccine cannot be
ruled out for these possible seizures because of the temporal
association to the third dose of study vaccine.

08-0876: This subject was a 17-month-old male who was immunized with his
4^th^ dose of 7VPnC on 10/7/97. He also received MMR and DTaP at the
same visit. During the night of 10/9/97, more than 48 hours following
immunization, the child developed a fever of 104.0°F and experienced a
seizure lasting approximately 2 minutes. He was seen on 10/10/97 in the
clinic where he presented with a temperature of 102.0°F. Physical exam
was otherwise normal, CBC revealed a WBC of 2.9, and blood culture was
negative. Diagnosis was viral syndrome. The investigator considered this
event unrelated to immunization. Because of the temporal association, a
possible relationship to study vaccine cannot be ruled out even though
other routine pediatric vaccines were administered simultaneously.

**118-8: Acute Seizure Events Within 3 Days of Study Vaccine Regardless
of Investigator's Assessment of Relatedness to Study Vaccine**

**[7VPnC]{.underline}**

03-0588: This subject was vaccinated with the 4^th^ dose of 7VPnC and
DTP on June 27, 1997. The next day the subject became febrile to 105.3
(not specified how temperature was taken), and had 2 seizures. The
subject was taken to urgent care at the local hospital where
acetamenophen was given. Subject also had tenderness in left leg that
interfered with movement until July 1, 1997. The investigator coded this
event as being possibly related to study vaccination.

20-2576: This subject was a 2 month old male who was immunized with
7VPnC, Tetramune, and IPV on 3/10/98. Approximately 11 hours later the
infant woke up from a nap and was noted to have his eyes deviated
upwards. He had a weak cry and his body stiffened. At the ER his rectal
temperature was 102.2°F. Four hours later the child had a 10 minute
episode of leg and arm stiffness with eyes rolled back. Urine revealed
pyuria and \> 100,000 E. coli. Because of the underlying urinary tract
infection, the event was considered unrelated to immunization.

**Seizure Events in Supporting Studies**

**Study 118-12**

**[7VPnC]{.underline}**

Subject 4-25 was immunized with 7VPnC on 10/18/96. Four days after
vaccination (10/22/96) the infant had seizure activity lasting about 3
minutes. The subject was seen in the ER and hospitalized for
observation. EEG, CT Scan, and MRI were normal. The patient was
discharged on 10/25/96 with a diagnosis of questionable new onset
seizure disorder. There was no family history of seizure and no
medications were given. The investigator judged a possible temporal
relationship between vaccination and this event. Subject was taken off
the study.

Subject (1-76) experienced seizures 1 day after a 3^rd^ dose of vaccine
that lasted 5-10 minutes and resulted in a 3 day hospitalization. The
investigator judged the event only remotely related to vaccine.

Attachment B

A brief description of the supporting studies submitted to the PLA with
summary findings of regulatory significance follows:

**118-P16: Bridging Study Comparing the Safety and Immunogenicity of a
Full-Scale Manufacturing Lot of Heptavalent Pneumococcal Conjugate
Vaccine to a Pilot Plant Lot in Healthy Infants Immunized at 2, 4 and 6
Months of Age**

Vaccine lots used in the pivotal efficacy study were produced in
sub-manufacturing scale quantities. The primary objective of this study
was to demonstrate comparability of initial manufacturing lots of 7VPnC
to previous pilot scale lots, in terms of safety and immunogenicity.
Such "bridging" of pilot to manufacturing scale is intended to evaluate
whether the vaccine used in the efficacy trial is clinically equivalent
to the vaccine intended for marketing. Compatibility of 7VPnC with
simultaneously administered inactivated polio (IPV) and hepatitis B
vaccines was also evaluated. The study was initiated February 12, 1998
and conducted at 7 sites through the Kaiser Permanente Vaccine Study
Center. A protocol amendment provided for "catch-up" immunizations of
subjects randomized to the control group; inoculations were to occur at
7 and 9 months of age. Immunogenicity data from the "catch-up" portion
of the study were not submitted with the application. At the time of the
study report, it was described as ongoing.

**Study Design and Conduct**

Two manufacturing lots were compared to the pilot lot for
immunogenicity. A "no vaccine control was included for safety
comparisons. The manufacturing lots differed in type of aluminum
phosphate used and type of vial.

D118-P16: Study design and subject allocation

+-------+----------------------+--------+-----------------------------+
| Va    | # Vaccine lot        | N      | # Con                       |
| ccine |                      |        | current vaccines & schedule |
| group | (lower left thigh    | p      |                             |
|       |                      | lanned | (all groups)                |
|       | @ 2, 4, 6 months)    | (eval  |                             |
|       |                      | uable) |                             |
+-------+----------------------+--------+-----------------------------+
| 1     | Pilot scale lot      | 175    | DTaP (right thigh) @ 2, 4,  |
|       |                      |        | 6 mos)                      |
|       | (Adjuphos adjuvant;  | \      |                             |
|       |                      | (150\) | HbOC (upper left thigh) @   |
|       | blow-molded vials)   |        | 2, 4, 6 mos)                |
|       |                      |        |                             |
|       | Lot# 7-5018-013A     |        | IPV (left upper deltoid) @  |
|       |                      |        | 2, 4 mos)                   |
|       |                      |        |                             |
|       |                      |        | Hepatitis B (upper right    |
|       |                      |        | thigh) \@2, 6 mos)          |
+-------+----------------------+--------+-----------------------------+
| 2     | Full-scale           | 175    |                             |
|       | manufacturing lot    |        |                             |
|       | "P" (Adjuphos        | \      |                             |
|       | adjuvant;            | (150\) |                             |
|       |                      |        |                             |
|       | Blow-molded vials)   |        |                             |
|       |                      |        |                             |
|       | Lot# 7-5018-016A     |        |                             |
+-------+----------------------+--------+-----------------------------+
| 3     | Full-scale           | 175    |                             |
|       | manufacturing lot    |        |                             |
|       | "N" (w/Lederle AlPO4 | \      |                             |
|       | adjuvant; single     | (150\) |                             |
|       | dose tubing vials)   |        |                             |
|       |                      |        |                             |
|       | Lot# 7-5029-002A     |        |                             |
+-------+----------------------+--------+-----------------------------+
| 4     | Control group        | 125    |                             |
|       |                      |        |                             |
|       | (no control vaccine  | \      |                             |
|       | or placebo)          | (100\) |                             |
+-------+----------------------+--------+-----------------------------+

Infants randomized to the 7VPnC vaccine groups were followed until blood
was drawn 1 month after the 3^rd^ dose (7 months of age). Infants
randomized to the control group participated until blood was drawn 1
month after the second catch-up immunization (10 months of age).

**Monitored Parameters and Endpoints**

Signs and symptoms of local and systemic reactions were recorded by
caretakers for 3 days following each dose. Prompted local reactions
included erythema, induration, and tenderness. The worse local reaction
on each leg will be recorded. Prompted systemic reactions included
irritability, change in sleep patterns, vomiting, diarrhea, hives,
wheezing, change in skin tone, lethargic/limp, loss of consciousness and
fever. Parents were also queried about whether fever medication was
given.

IgG antibody concentration (GMC) to 7VPnC vaccine serotypes was measured
before the first dose and one month after the third dose. Responses to
polio and hepatitis B were assessed at 7 months of age.

The study had 2 co-primary immunogenicity endpoints for all 7 vaccine
serotypes: 1) GMCs, and 2) response rates above defined threshold
antibody concentrations. Threshold values for each serotype were
determined by the maximal difference in serum antibody concentrations
between immunized and unimmunized children at the 7-month bleed observed
in previous studies using lots of vaccine from clinical scale production
(i.e., studies D118-P12 and D118-P8).

**118-16: Threshold Serum Antibody Concentrations**

**Used to Determine Percent Responders**

  --------------------- -------------------------------------------------
  **Serotype**          **Threshold Concentration Level (**μ**g/mL)**

  4                     0.15

  6B                    0.25

  9V                    0.28

  14                    0.38

  18C                   0.21

  19F                   0.26

  23F                   0.18
  --------------------- -------------------------------------------------

The following figure illustrates the choice of threshold value for
serotype 6B.

**Maximal Difference in GMC:**

> **Immunized and Unimmunized Populations**
>
> **(Based on Combined Data from Study 118-8 and 118-12)**

**Serotype 6B**

![](media/image1.wmf)

Pre-defined criteria demonstrating acceptable bridging were: 1) ≤ 2-fold
difference in GMTs between pilot and manufacturing lot ; 2) ≤ 10%
difference in response rate between pilot and manufacturing lot at the
defined threshold values for each serotype. Thus, successful
demonstration of bridging in this study required multiple comparisons
(14), due to the multivalent nature of the vaccine. The sponsor
identified the preferred manufacturing lot for initial comparisons as
lot N.

**Results: Bridging**

Successful bridging of lot N to the pilot lot was demonstrated for all 7
serotypes, as shown in the following tables:

**118-16: Comparisons of Post-dose 3 GMCs of Pneumococcal Antibodies**

+---------+-------------+--------------+-------------+---------------+
| GMC     |             |              | Manuf. N    |               |
| (μg/mL) |             |              | Lot         |               |
|         |             |              | (Lederle    |               |
|         |             |              | Alum)       |               |
|         |             |              |             |               |
|         |             |              | versus      |               |
|         |             |              | Pilot Lot   |               |
+---------+-------------+--------------+-------------+---------------+
|         | Pilot Lot   | Manuf.       | Ratio       | 90% Lower     |
|         |             |              |             | Limit\*       |
|         |             | N Lot        |             |               |
|         |             |              |             |               |
|         |             | (Lederle     |             |               |
|         |             | Alum)        |             |               |
+---------+-------------+--------------+-------------+---------------+
| S       | N=152       | N=159        |             |               |
| erotype |             |              |             |               |
+---------+-------------+--------------+-------------+---------------+
| 4       | 1.53        | 2.03         | 1.33        | 1.11          |
+---------+-------------+--------------+-------------+---------------+
| 6B      | 3.62        | 2.97         | 0.82        | 0.65          |
+---------+-------------+--------------+-------------+---------------+
| 9V      | 1.45        | 1.18         | 0.82        | 0.69          |
+---------+-------------+--------------+-------------+---------------+
| 14      | 5.83        | 4.64         | 0.80        | 0.64          |
+---------+-------------+--------------+-------------+---------------+
| 18C     | 2.09        | 1.96         | 0.93        | 0.78          |
+---------+-------------+--------------+-------------+---------------+
| 19F     | 1.91        | 1.91         | 1.00        | 0.84          |
+---------+-------------+--------------+-------------+---------------+
| 23F     | 2.21        | 1.71         | 0.78        | 0.63          |
+---------+-------------+--------------+-------------+---------------+

\* The lower limit of the 90% confidence interval. The 90% confidence
interval was derived based on t-distribution of the difference between
the two lot groups in the mean of log concentrations.

Adapted from Table 6, page 46, Volume 29, Part IV of PLA.

###### 118-16: Comparisons of Proportions of Subjects 

**Achieving Given Antibody Concentrations**

+---------+-------+-------------+------------+---+---------+------------+
| \%      |       |             |            |   | Manuf.  |            |
| S       |       |             |            |   | N Lot   |            |
| ubjects |       |             |            |   | (       |            |
| (95%    |       |             |            |   | Lederle |            |
| CI)     |       |             |            |   | Alum)   |            |
| Ac      |       |             |            |   | versus  |            |
| hieving |       |             |            |   | Pilot   |            |
| Given   |       |             |            |   | Lot     |            |
| A       |       |             |            |   |         |            |
| ntibody |       |             |            |   |         |            |
| Level   |       |             |            |   |         |            |
+---------+-------+-------------+------------+---+---------+------------+
| S       | Level | Pilot Lot   | Manuf. N   | D |         | 90% Lower  |
| erotype | (μ    |             | Lot        | i |         | Limit\*    |
|         | g/mL) | N=152       | (Lederle   | f |         |            |
|         |       |             | Alum)      | f |         |            |
|         |       |             |            | e |         |            |
|         |       |             | N=159      | r |         |            |
|         |       |             |            | e |         |            |
|         |       |             |            | n |         |            |
|         |       |             |            | c |         |            |
|         |       |             |            | e |         |            |
+---------+-------+-------------+------------+---+---------+------------+
| 4       | 0.15  | 99.34       | 99.37      | 0 |         | -3.81      |
|         |       |             |            | . |         |            |
|         |       | (96.3, 100) | (96.5,     | 0 |         |            |
|         |       |             | 100)       | 3 |         |            |
+---------+-------+-------------+------------+---+---------+------------+
| 6B      | 0.25  | 96.71       | 97.48      | 0 |         | -4.21      |
|         |       |             |            | . |         |            |
|         |       | (92.4,      | (93.6,     | 7 |         |            |
|         |       | 99.0)       | 99.4)      | 7 |         |            |
+---------+-------+-------------+------------+---+---------+------------+
| 9V      | 0.28  | 100         | 95.60      | - |         | -9.91      |
|         |       |             |            | 4 |         |            |
|         |       | (97.6, 100) | (91.1,     | . |         |            |
|         |       |             | 98.3)      | 4 |         |            |
|         |       |             |            | 0 |         |            |
+---------+-------+-------------+------------+---+---------+------------+
| 14      | 0.38  | 98.03       | 94.34      | - |         | -9.76      |
|         |       |             |            | 3 |         |            |
|         |       | (94.3,      | (89.5,     | . |         |            |
|         |       | 99.6)       | 97.4)      | 6 |         |            |
|         |       |             |            | 9 |         |            |
+---------+-------+-------------+------------+---+---------+------------+
| 18C     | 0.21  | 100         | 97.48      | - |         | -7.52      |
|         |       |             |            | 2 |         |            |
|         |       | (97.6, 100) | (93.6,     | . |         |            |
|         |       |             | 99.4)      | 5 |         |            |
|         |       |             |            | 2 |         |            |
+---------+-------+-------------+------------+---+---------+------------+
| 19F     | 0.26  | 97.37       | 96.23      | - |         | -6.91      |
|         |       |             |            | 1 |         |            |
|         |       | (93.3,      | (91.9,     | . |         |            |
|         |       | 99.3)       | 98.7)      | 1 |         |            |
|         |       |             |            | 4 |         |            |
+---------+-------+-------------+------------+---+---------+------------+
| 23F     | 0.18  | 96.71       | 98.11      | 1 |         | -3.40      |
|         |       |             |            | . |         |            |
|         |       | (92.4,      | (94.5,     | 4 |         |            |
|         |       | 99.0)       | 99.7)      | 0 |         |            |
+---------+-------+-------------+------------+---+---------+------------+

\* Exact confidence limit using StatXact.

Adapted from Table 7, page 48, Volume 29, Part IV of PLA

**Safety**

Local and systemic reaction rates among infants receiving vaccine from
the pilot lot, or the preferred manufacturing lot, were similar for each
dose. The sponsor pooled reactogenicity data from all 3 lots for
presentation in the clinical summary. The pooled reactogenicity data
from this study provided an important source of safety data in the
context of co-administration of DTaP, IPV, and Hep B vaccines (selected
tables shown with discussion of safety, above).

One death occurred during the study, 47 days after the first dose of
7VPnC; reported cause of death was Sudden Infant Death Syndrome (SIDS).

No seizures or other significant or unusual adverse reactions were
reported for any vaccine group.

**Study Conclusions**

Bridging of manufacturing scale to pilot scale based on pre-defined
immunogenicity criteria was successfully demonstrated.

**D118-P12: A randomized double-blind trial of the safety and
immunogenicity of three lots of heptavalent (4, 6B, 9V, 14, 18C, 19F,
23F) pneumococcal conjugate vaccine administered to healthy infants at
2, 4 and 6 months of age**

The primary objective of this study was to evaluate 3 independently
produced pilot scale lots of 7VPnC for consistency of manufacture by
comparing their safety and immunogenicity. Demonstration of consistency
of production is required for vaccine licensure. Assessment of
compatibility of 7VPnC with HbOC and DTaP when co-administered was a
secondary objective. This multi-center study was initiated in September,
1996 and completed in March, 1998.

Approximately 300 subjects were randomized to one of four treatment
groups (75 per group). Subjects in three groups received one of three
lots of the 7-valent conjugate pneumococcal vaccine at 2, 4, and 6
months of age, administered concurrently with HbOC, DTaP, and IPV/OPV.
Subjects in the 4^th^ group received only HbOC, DTaP and IPV/OPV. The
study was double-blind with respect to vaccine lots, however,
unvaccinated control subjects could be identified.

118-12: Study Design

+------+----------------------+------+--------------------------------+
| Vac  | # Vaccine lot        | N    | #                              |
| cine |                      |      | Concurrent vaccines & schedule |
| g    | (lower left thigh @  |      |                                |
| roup | 2, 4, 6 mos)         |      | (all groups)                   |
+------+----------------------+------+--------------------------------+
| 1    | Lot A 7-5018-011A    | 75   | ACEL-IMUNE (right thigh) @ 2,  |
|      |                      |      | 4, 6 mos)                      |
|      |                      |      |                                |
|      |                      |      | HibTITER (upper left thigh) @  |
|      |                      |      | 2, 4, 6 mos)                   |
|      |                      |      |                                |
|      |                      |      | OPV @ 2, 4, and 6 mos,         |
|      |                      |      |                                |
|      |                      |      | or                             |
|      |                      |      |                                |
|      |                      |      | IPV right thigh or upper       |
|      |                      |      | extremity                      |
|      |                      |      |                                |
|      |                      |      | @ 2 and 4 mos                  |
+------+----------------------+------+--------------------------------+
| 2    | Lot B 7-5018-010A    | 75   |                                |
+------+----------------------+------+--------------------------------+
| 3    | Lot C 7-5018-008A    | 75   |                                |
+------+----------------------+------+--------------------------------+
| 4    | Control group        | 75   |                                |
|      |                      |      |                                |
|      | (no control vaccine  |      |                                |
|      | or placebo           |      |                                |
|      | administered)        |      |                                |
+------+----------------------+------+--------------------------------+

Subjects in the control group were re-enrolled and administered two
doses of the 7VPnC vaccine at 7 and 9 months of age, with a boost at
15 - 18 months of age. Serological data from these subjects contribute
to the data to support regimens for "catch-up" immunizations.

Parents were asked to monitor their children for local reactions
(induration, erythema, and tenderness), systemic events (fussiness,
drowsiness, decreased appetite, and temperature), and use of
antipyretics on the day of each immunization and for three days
following each immunization, and to record such information on a symptom
report form.

Blood was collected from each subject prior to the first immunization
(at 2 months of age), prior to the third immunization (at 6 months of
age), and one month after the third dose (at 7 months of age). Serum
samples were analyzed for IgG antibodies to all seven pneumococcal
vaccine serotypes by standard ELISA methods. Sera were also analyzed for
antibody responses to the components of DTaP and Hib-PRP.

Post dose 3 antibody concentration (GMC) for each of the 7 vaccine
serotypes was the primary immunogenicity endpoint. Two-fold difference
between GMCs in pairwise comparisons between lots was the pre-specified
primary immunogencity criteria for determining consistency of antibody
responses among lots.

The 2-fold, 90% CI criterion for GMCs was breeched for 3 comparisons
(serotype 6B, Lot A to Lot B, serotype 6B, Lot A to Lot C, and serotype
14, Lot B to Lot C). However, the magnitude of the differences in GMCs
was not large, and no pattern suggestive of a failed lot of vaccine was
evident. Moreover, with 21different comparisons in this analysis, the
opportunities to exceed set are increased due to chance alone. Thus, the
immunogenicity data provide evidence of lot-consistency.

**118-12: Comparisons of GMCs of three 7VPnC lots**

# Ratio of GMC between Lots (with 90% Confidence Interval)

+----------+-------------------+-------------------+-------------------+
| #        | # Lot A to Lot B  | **Lot A to Lot    | **Lot B to Lot    |
| Serotype |                   | C**               | C**               |
+----------+-------------------+-------------------+-------------------+
| **4**    | 0.76 (0.59, 0.97) | 1.15 (0.91, 1.47) | 1.52 (1.19, 1.95) |
+----------+-------------------+-------------------+-------------------+
| **6B**   | **1.32 (0.86,     | **1.58 (1.04,     | 1.19 (0.78, 1.82) |
|          | 2.02)**           | 2.38)**           |                   |
+----------+-------------------+-------------------+-------------------+
| **9V**   | 0.93 (0.72, 1.20) | 0.77 (0.60, 0.99) | 0.83 (0.64, 1.07) |
+----------+-------------------+-------------------+-------------------+
| **14**   | 1.42 (1.03, 1.95) | 0.91 (0.66,1.25)  | **0.64 (0.46,     |
|          |                   |                   | 0.88)**           |
+----------+-------------------+-------------------+-------------------+
| **18C**  | 0.98 (0.76, 1.26) | 0.74 (0.58, 0.95) | 0.76 (0.59, 0.97) |
+----------+-------------------+-------------------+-------------------+
| **19F**  | 1.10 (0.83, 1.44) | 1.00 (0.76, 1.30) | 0.91 (0.69, 1.19) |
+----------+-------------------+-------------------+-------------------+
| **23F**  | 1.16 (0.81, 1.65) | 1.19 (0.85, 1.68) | 1.03 (0.73, 1.45) |
+----------+-------------------+-------------------+-------------------+

Adapted from Table 9, page 37, Volume 27, Part IV of PLA

Sufficient blood samples were available after 2 and after 3 doses of
vaccine to examine the time course of the antibody response to
pneumococcal antigens. Responses to at least 2 vaccine serotypes (6B and
23F) following 2 doses of vaccine were not robust. The GMC for serotype
6B after 2 doses was similar to the pre-dose 1 GMCs for both the pooled
7VPnC groups.

**118-12: Kinetics of Pneumococcal IgG Response GMC (μg/mL) and 95% CI**

+----------------+-----------------+-----------------+----------------+
| #              | # Po            |                 |                |
|                | oled 7VPnC Lots |                 |                |
| # Serotype     |                 |                 |                |
+----------------+-----------------+-----------------+----------------+
|                | Pre Dose 1      | Post Dose 2     | Post Dose 3    |
|                |                 |                 |                |
|                | N = 211         | N = 218         | N = 211        |
+----------------+-----------------+-----------------+----------------+
| 4              | 0.10            | 1.25            | 1.59           |
|                |                 |                 |                |
|                | (0.08, 0.12)    | (1.10, 1.43)    | (1.41, 1.79)   |
+----------------+-----------------+-----------------+----------------+
| 6B             | **0.44**        | **0.45**        | 2.63           |
|                |                 |                 |                |
|                | **(0.37,        | **(0.38,        | (2.14, 3.24)   |
|                | 0.53)**         | 0.54)**         |                |
+----------------+-----------------+-----------------+----------------+
| # 9V           | 0.22            | 0.94            | 1.56           |
|                |                 |                 |                |
|                | (0.19, 0.26)    | (0.82, 1.07)    | (1.38, 1.77)   |
+----------------+-----------------+-----------------+----------------+
| 14             | 0.28            | 2.36            | 4.56           |
|                |                 |                 |                |
|                | (0.22, 0.36)    | (1.96, 2.84)    | (3.88, 5.37)   |
+----------------+-----------------+-----------------+----------------+
| 18C            | 0.24            | 0.99            | 2.30           |
|                |                 |                 |                |
|                | (0.20, 0.28)    | (0.87, 1.12)    | (2.03, 2.61)   |
+----------------+-----------------+-----------------+----------------+
| 19F            | 0.51            | 0.93            | 1.60           |
|                |                 |                 |                |
|                | (0.42, 0.62)    | (0.81, 1.07)    | (1.40, 1.83)   |
+----------------+-----------------+-----------------+----------------+
| 23F            | 0.22            | 0.38            | 1.38           |
|                |                 |                 |                |
|                | (0.18, 0.26)    | (0.33, 0.45)    | (1.16, 1.64)   |
+----------------+-----------------+-----------------+----------------+

Adapted from Table 13, page 41, Volume 27 of PLA.

**Safety**

The power of the present study to identify safety concerns and to
describe the reactogenicity profile of 7VPnC was increased by pooling
subjects who received one of the three 7VPnC lots for making comparisons
to the control group. This approach is justified based on the similar
immunogenicity and safety profiles of the three vaccine lots.

Vaccine reactogenicity data from this trial were discussed above.

Serious adverse events were reported for 18 (7%) of 256 subjects in the
pooled 7VPnC groups and 4 (4.7%) of 84 subjects in the control group.
The most common serious adverse event was bronchiolitis or RSV
bronchiolitis, accounting for 9 of the 22 serious adverse events. No
statistical analysis of serious significant events was provided or
performed by the sponsor, due to the small number of events in each
treatment group.

No deaths occurred during the study period.

Two seizures were recorded during the study period, both in subjects who
received 7VPnC (discussed above, and see attachment A).

Another subject who received 7VPnC was terminated from the study for
inconsolable crying on the day of receiving dose 2, considered by the
investigator as moderate in severity, and possibly related to
immunization.

**118-12: Healthy Infants Previously Enrolled as Control Group were
Immunized with Heptavalent Pneumococcal Conjugate Vaccine Administered
at 7, 9, and 15-18 Months of Age**

Amendments 2 and 4 to 118-12 provided for immunization of control
subjects at 7 and 9 months of age, with a 4^th^ dose to be administered
at 15-18 months of age. This part of the trial, completed in December
1998, was intended to provide safety and immunogenicity data to support
catch-up immunization schedules.

The trial was conducted open-label. Of the 54 control subjects enrolled,
38 were analyzed for immunogenicity after 2 doses, and 22 after a 3^rd^
dose at 15-18 months.

Results of immunogenicity assessments are included in the summary table
for Catch-up Immunizations.

**Study 92-05: A randomized, controlled, blinded, multicenter trial of
the safety and immunogenicity of 2 models of pentavalent (6B, 14 18C,
19F, 23F) pneumococcal conjugate vaccine at 3 dose levels as a primary
immunization series in infants at 2, 4, and 6 months of age with a
booster dose of polysaccharide vaccine at 15-18 months of age**

This study of pentavalent pneumococcal conjugates was initiated in May,
1993 and completed in January, 1996. The purpose of the study was to
determine the optimal formulation (oligosaccharide vs polysaccharide)
and saccharide dose level (5, 2, or 0.5 μg) of a vaccine for use in
infants. The 5 vaccine serotypes studied were among those chosen for
inclusion in Prevenar.

A protocol amendment provided for a booster dose of PNU-IMUNE®23 to be
given at 15-18 months of age to children who had completed the primary
series.

This is the only study in the PLA that provides safety and
immunogenicity for a dose of pneumococcal polysaccharide vaccine
following a vaccination series with pneumococcal conjugate vaccines.

Subjects were randomized equally to one of 6 treatment groups, or a 'no
vaccine' control group (N=60/group). Investigational vaccines were
inoculated into the left thigh at 2, 4, and 6 months of age. All
subjects also received DTP-HbOC (Tetramune) in the right thigh.

Local and systemic symptoms during the first 3 days post-inoculation
were recorded by the parent/guardian on symptom report forms that were
returned to the investigator. Subjects were monitored for adverse events
for the entire study duration (7 months).

Serum antibody concentration to each of the 5 serotypes contained in the
vaccine were determined by ELISA, at 2, 4, 6, and 15 months of age, and
one month after inoculations following the 6 and 15 month inoculations,
and at 24 months of age. Antibody to Hib PRP was assessed for all
groups. Antibodies to diphtheria, tetanus, pertussis antigens (PT,
pertactin, FHA, and Fim 2) were assessed only for the 2 μg
polysaccharide model, as this was the model chosen for subsequent
development.

In the primary series, local reactions did not differ substantially
among the 5-valent conjugates, and local reactions were no more common
at the sites of 5-valent PnC than at the HbOC injection sites. Rates of
systemic reactions among groups receiving the different 5-valent PnC
conjugates were similar. However, when compared to the control group,
fever ≥38°C, and fever \>39 °C occurred with greater frequency among the
5-valent PnC treated groups with each dose of the primary series. The
highest fever rates were reported for the 5μg PS conjugate: 39% with
≥38°C; 9% with \>39 °C after the 3^rd^ dose, compared to 19% and 0% for
the control group. These data suggest that febrile reactions may be
related to polysaccharide antigen content of the vaccine formulation.

No deaths were reported during the study period. No convulsions were
reported within 3 days following any dose. One hypotonic-hyporesponsive
episode was recorded after the 1^st^ dose in a recipient of 2 μg OS;
this episode was considered probably related to study vaccine. Four
episodes of high-pitched crying and six episodes of persistent crying
were reported in the study vaccine groups; all were considered
definitely or probably study vaccine related. No such episodes occurred
in the control group. All occurred after the first dose, and none
received subsequent study vaccines. No clear dose effect was apparent,
although 2 infants with high-pitched cries received 5μg PS.

Results of the immunogenicity assessments supported the manufacturer's
choice of the polysaccharide model and the 2 μg polysaccharide dose.
GMC's to Hib PRP post dose 3 were significantly enhanced by
co-administration of all 5VPnC formulations, and particularly so for the
chosen 2 μg dose group. No interference with responses to diphtheria,
tetanus, pertussis antigens were observed after the 3^rd^ dose.

Pre and post dose sera for the 23V-polysaccharide booster were available
for 16 to 20 subjects per group. Pre dose antibody concentrations were
significantly lower for the control group, which did not receive 5VPnC
with the primary series. Following boost, the 5VPnC treated groups
achieved a substantial increase in GMCs to all serotypes. Little
appreciable response to polysaccharide vaccine was observed among the
"unprimed" control group, as might be expected among children under 2
years of age.

**Study 92-05: Antibody Responses to Vaccine Serotypes following
Administration of 23-Valent Polysaccharide Vaccine (PNU-IMUNE®23) as
4^th^ Dose at 15-18 months of Age, GMCs (μg/mL) and 95% CI**

+--------+--------------+---------------+--------------+--------------+
| **Vac  | P5VPnC (PS)  |               |              | Control      |
| cine** |              |               |              |              |
|        |              |               |              | N=16         |
| **Sero |              |               |              |              |
| type** |              |               |              |              |
+--------+--------------+---------------+--------------+--------------+
|        | 5 μg         | 2 μg          | 0.5 μg       |              |
|        |              |               |              |              |
|        | N=18         | N=17          | N=20         |              |
+--------+--------------+---------------+--------------+--------------+
| 6B Pre | 0.9 (0.5,    | 1.4 (0.7,     | 0.4 (0.2,    | 0.1 (0.1,    |
|        | 1.7)         | 3.2)          | 0.8)         | 0.3)         |
| Post   |              |               |              |              |
|        | 18.0 (9.1,   | 16.6 (7.4,    | 18.9 (9.5,   | 0.2 (0.1,    |
|        | 35.6)        | 37.4)         | 37.4)        | 0.6)         |
+--------+--------------+---------------+--------------+--------------+
| 14 Pre | 0.7 (0.5,    | 0.6 (0.3,     | 0.6 (03,     | 0.0 (0.0,    |
|        | 1.2)         | 1.5)          | 0.9)         | 0.0)         |
| Post   |              |               |              |              |
|        | 10.4 (5.5,   | 11.4 (5.5,    | 21.0 (11.3,  | 0.0 (0.0,    |
|        | 19.6)        | 23.5)         | 39.0)        | 0.1)         |
+--------+--------------+---------------+--------------+--------------+
| 18C    | 0.3 (0.2,    | 0.3 (0.2,     | 0.2 (0.1,    | 0.0 (0.0,    |
| Pre    | 0.5)         | 0.5)          | 0.2)         | 0.1)         |
|        |              |               |              |              |
| Post   | 4.5 (3.0,    | 6.3 (3.6,     | 10.3 (7.4,   | 1.2 (0.6,    |
|        | 6.9)         | 10.9)         | 14.4)        | 2.3)         |
+--------+--------------+---------------+--------------+--------------+
| 19F    | 0.7 (0.5,    | 1.1 (0.4,     | 0.9 (0.3,    | 0.1 (0.0,    |
| Pre    | 1.1)         | 2.7)          | 2.5)         | 0.2)         |
|        |              |               |              |              |
| Post   | 18.7 (9.6,   | 29.6 (15.0,   | 13.7 (9.2,   | 0.2 (0.1,    |
|        | 36.3)        | 58.3)         | 20.5)        | 0.4)         |
+--------+--------------+---------------+--------------+--------------+
| 23F    | 0.5 (0.2,    | 0.5 (0.2,     | 0.4 (0.1,    | 0.0 (0.0,    |
| Pre    | 1.0)         | 1.3)          | 0.9)         | 0.1)         |
|        |              |               |              |              |
| Post   | 7.0 (3.7,    | 8.1 (3.5,     | 4.2 (1.7,    | 0.2 (0.1,    |
|        | 13.2)        | 18.7)         | 10.4)        | 0.7)         |
+--------+--------------+---------------+--------------+--------------+

Adapted from Table 6, page 51, Volume 1 of Clinical Section of PLA.

Conjugate oligosaccharide formulations data not shown for simplicity of
presentation.

**118-02: A randomized, double-blind, controlled trial of the acute
safety of heptavalent (4, 6B, 9V, 14, 18C, 19F, 23F) pneumococcal
conjugate vaccine as a single injection in healthy adults**

This study was intended to demonstrate safety of 7VPnC in adults before
initiation of studies in children and infants. Initiated in December
1994 and completed February 1995, this was the first clinical study
conducted under U.S. IND using the 7-valent pneumococcal conjugate
vaccine (7VPnC).

Thirty adult subjects, 18 to 60 years of age, were enrolled at a single
center, and randomized to receive a single dose of either 7VPnC or
23-valent pneumococcal polysaccharide vaccine (PNU-IMUNE®23). Local and
systemic reactions were assessed over the first 72 hours post
inoculation through use of diary cards; data entry was solicited for
specific local and systemic reactions. Blood samples were obtained
before, and one month after inoculations, for assessment and comparison
of antibody responses to polysaccharide antigens common to 7VPnC and the
licensed pneumococcal polysaccharide vaccine.

Local reactions (erythema, induration, or tenderness) were reported for
93% of 7VPnC recipients, and 73% of PNU-IMUNE®23 recipients; more severe
local reactions occurred with similar frequency (33%) in both groups.
Any systemic reaction (decreased appetite, vomiting, headache, rash,
muscle pain, joint pain, fever) was reported for 60% of 7VPnC recipients
and 27% of PNU-IMUNE®23 recipients. Fever (≥ 38.0 °C) was reported for 1
subject in the 7VPnC group, and 2 subjects who received PNU-IMUNE®23. No
adverse events were reported during the 1-month post-immunization
observation period.

Antibody responses to the 7 pneumococcal serotypes included in 7VPnC did
not differ significantly in this small study. An exception was the
response to serotype 23F, which was significantly greater in the
conjugate vaccine group.

**Study 118-02: Geometric Mean Concentrations (95% CI)**

Pre- and Post-Inoculation of 7VPnC and PNU-IMUNE23 in Adults

+--------+-----+-----------+----------+---------+-----------+--------+
| Se     | Vi  | 7VPnC     |          | PNU-    |           | p-va   |
| rotype | sit |           |          | IMUNE23 |           | lue^1^ |
|        |     | N=14      |          |         |           |        |
|        |     |           |          | N=15    |           |        |
+--------+-----+-----------+----------+---------+-----------+--------+
|        |     | GMC       | 95% CI   | GMC     | 95% CI    |        |
|        |     |           |          |         |           |        |
|        |     | (μg/mL)   |          | (μg/mL) |           |        |
+--------+-----+-----------+----------+---------+-----------+--------+
| 4      | Pre | 1.1       | 0.4, 3.3 | 0.6     | 0.3, 1.4  | 0.37   |
|        |     |           |          |         |           |        |
|        | P   | 5.6       | 3.1,     | 2.9     | 1.2, 6.7  | 0.32   |
|        | ost |           | 10.3     |         |           |        |
+--------+-----+-----------+----------+---------+-----------+--------+
| 6B     | Pre | 3.7       | 1.8, 7.8 | 2.2     | 1.0, 4.5  | 0.26   |
|        |     |           |          |         |           |        |
|        | P   | 22.7      | 12.1,    | 11.9    | 5.6, 25.1 | 0.37   |
|        | ost |           | 42.4     |         |           |        |
+--------+-----+-----------+----------+---------+-----------+--------+
| 9V     | Pre | 1.5       | 0.7, 3.3 | 1.5     | 0.8, 2.8  | 0.97   |
|        |     |           |          |         |           |        |
|        | P   | 7.6       | 3.2,     | 8.5     | 4.4, 16.3 | 0.79   |
|        | ost |           | 18.1     |         |           |        |
+--------+-----+-----------+----------+---------+-----------+--------+
| 14     | Pre | 1.9       | 0.5, 7.0 | 1.1     | 0.3, 4.5  | 0.53   |
|        |     |           |          |         |           |        |
|        | P   | 38.1      | 12.1,    | 14.1    | 3.4, 58.4 | 0.35   |
|        | ost |           | 119.6    |         |           |        |
+--------+-----+-----------+----------+---------+-----------+--------+
| 18C    | Pre | 1.9       | 1.0, 3.8 | 1.1     | 0.5, 2.7  | 0.33   |
|        |     |           |          |         |           |        |
|        | P   | 20.3      | 8.7,     | 7.7     | 3.3, 18.0 | 0.18   |
|        | ost |           | 47.2     |         |           |        |
+--------+-----+-----------+----------+---------+-----------+--------+
| 19F    | Pre | 6.7       | 4.0,     | 4.8     | 2.2, 10.4 | 0.46   |
|        |     |           | 11.3     |         |           |        |
|        | P   | 28.4      |          | 16.0    | 9.2, 27.8 | 0.19   |
|        | ost |           | 16.3,    |         |           |        |
|        |     |           | 49.4     |         |           |        |
+--------+-----+-----------+----------+---------+-----------+--------+
| 23F    | Pre | 1.1       | 0.5, 3.1 | 1.0     | 0.3, 2.9  | 0.82   |
|        |     |           |          |         |           |        |
|        | P   | 34.1      | 14.1,    | 5.1     | 1.9, 13.2 | **\<   |
|        | ost |           | 82.4     |         |           | 0.01** |
+--------+-----+-----------+----------+---------+-----------+--------+

Reproduced from Table 3 of IND 5832, amendment 160, clinical study
report

^1^ GMTs compared suing analysis of covariance model; group comparisons
adjusted for pre-immunization log-titers (Sponsor's analysis)

**Study 118-03: A Randomized Double-Blind, Trial of the Safety and
Immunogenicity of Heptavalent (4, 6B, 9V, 18C, 19F, 23F) Pneumococcal
Conjugate Vaccine and Meningococcal Group C Conjugate Vaccine in Healthy
Infants at 2, 4, and 6 Months of Age, followed by a Booster Dose at
12-15 months of Age of the Same Vaccines.**

The objectives of the study were to determine the safety and
immunogenicity of 7VPnC among infants, and to assess the safety of
meningococcal polysaccharide C vaccine (MnCC) as a control for 7VPnC.
Safety data from the MnCC served to support continued use of MnCC as a
control in subsequent phase II and III studies. The 4-study conducted
from February 1995 through June 1997, at 4 study sites. The original
protocol was amended to allow for open-label study of the "booster
dose". Potential interference with concurrent DTP, HbOC, and MMR was
also assessed.

A total of 212 healthy infants were randomized 1:1 to receive 7VPnC or
MnCC at 2, 4, and 6 months of age in the left thigh. Each infant also
received DTP-HbOC in the right thigh, and OPV with the primary series.

As a 4^th^ dose, 7VPnC subjects were again randomized 1:1 to receive
either HbOC, or MMR.

Subjects were actively monitored for local and systemic reactions and
antipyretic use for 3 days after each dose. Adverse events included
clinic visits within 7 days of a dose, hospitalizations during the
24-month study period, or any event resulting in study termination.

Blood samples were obtained for IgG antibody concentration (ELISA)
assessments pre dose 1, pre and post doses 3 and 4, and at 24 months of
age. Opsonophagocytic antibody for the 7 pneumococcal serotypes was also
assessed.

**Immunogenicity**

After the primary series, GMCs ranged from 0.98 μg/mL for serotype 9V,
to 3.48 μg/mL for serotype 14. Antibody levels declined substantially
after the primary series for some serotypes; pre dose 4 GMCs were lowest
for serotypes 4 (0.20 μg/mL) and 18C (0.22 μg/mL). After the 4^th^ dose,
GMCs for each serotype exceeded 2.0 μg/mL. Duration of antibody levels
assessed at 24 months of age were not included in the PLA.

**118-03: GMC (μg/mL) of Pneumococcal Antibodies**

**Prior to and Following the Primary Series and 4^th^** Dose

  ---------- ---------- -------- -------- -------- ---------- -------- ---------
  Serotype   4          6B       9V       14       18C        19F      23F

  Pre dose 1 0.05       0.31     0.12     0.18     0.09       0.28     0.11
  (N=90)                                                               

  Post dose  1.36       1.37     0.98     3.48     1.24       3.45     1.80
  3 (N=90)                                                             

  **Pre dose **0.20**   0.68     0.37     1.77     **0.22**   0.76     0.35
  4** (N=55)                                                           

  Post dose  2.32       8.13     3.75     9.33     3.01       4.50     5.11
  4 (N=55)                                                             
  ---------- ---------- -------- -------- -------- ---------- -------- ---------

Adapted from Tables, 6, 7, and 9, pages 50, 51, 57 Volume 7, Part IV of
PLA

**Safety**

No deaths occurred during the study period. Five 7VPnC recipients were
hospitalized, none for events within 1 week of vaccinations or for
events considered related to vaccine by investigators. One subject in
the 7VPnC group had onset of a seizure disorder 8 months after the 4^th^
dose.

Seven subjects were withdrawn from the study due significant adverse
events: 4 7VPnC recipients and 3 MnCC recipients. In the 7VPnC group, 3
infants were discontinued for persistent or unusual cry, and one for an
apparent hypotonic-hyporesponsive episode accompanied by urticaria.

The sponsor concluded that there were no trends in adverse events that
were clinically significant for either study vaccine.

**Study 118-07: A Randomized, Double-Blind Trial of the Safety and
Immunogenicity of Heptavalent Pneumococcal Conjugate Vaccine and
Meningococcal Group C Conjugate Vaccine in Healthy Infants at 2, 4 and 6
Months of Age with a Booster Dose Administered at 12-15 Months of Age**

This was a phase II study conducted within the Northern California
Kaiser Permanente health care system, a population similar to that of
the subsequent efficacy study. The study, initiated in June, 1995, and
completed July, 1997, served as a pilot study for the large-scale safety
and efficacy trial of 7VPnC. The stated primary objective was to gain
experience with respect to the safety and immunogenicity of MnCC and
7VPnC.

The main contributions of this study to the PLA are: 1) reactogenicity
data for 7VPnC given against a background of DTP-HbOC in the primary
series, and DTaP as a 4^th^ dose; 2) compatibility of 7VPnC with
concurrent immunizations.

Protocol amendment 1 provided for a 4^th^ dose to be administered at
15-18 months of age with or without DTaP and HbOC. Amendment 2 allowed
for assessing duration of post dose 4 antibody levels at 24 months of
age; however, data addressing duration of antibody were not included in
the PLA.

A total of 302 healthy 2 month old infants were randomized (2:1) to
receive 7VPnC or MnCC at 2, 4, and 6 months of age, which was injected
into the left thigh muscle. All subjects received DTaP and HbOC vaccines
at 2, 4 and 6 months of age into the anterior thigh muscle of the right
leg, and a dose of OPV at 2, 4 and 6 months of age. One-half of the
subjects in each cohort were also randomized to receive Hepatitis B
vaccine in the right thigh at 2, 4, and 6 months of age.

Local and systemic reactions during the first 48 hours post dose were
assessed by parents or caretakers and recorded on diary cards. Systemic
events and body temperature were recorded daily on days 0, 1, and 2
post-immunization, and at any time within 14 days post-immunization.
Data was collected by telephone interviews at 48-72 hours and again at
10-14 days.

Adverse events included hospitalizations within 60 days and emergency
room visit within 30 days of vaccination, and any event resulting in
study termination.

Blood samples were obtained immediately prior to the first dose of
vaccine and the 4^th^ dose, and one month following the 3^rd^ (7 months)
and 4^th^ (13 months) doses. IgG antibody concentration (GMC) and
response rates at 0.15 and 0.5 μg/mL serum levels to 7VPnC vaccine
serotypes were assessed.

A substantial decline in % of subjects achieving 0.50 μg/mL was observed
between dose 3 and dose 4 for some serotypes; only 15% of subjects were
able to maintain 0.50 μg/mL of serum antibody for serotype 4 until the
4^th^ dose. Although the serum antibody concentration associated with
protection from disease is unknown, these data indicate that protection
against disease afforded by 3 doses of 7VPnC may vary considerably with
serotype. It is noteworthy that no cases of invasive disease due to
serotype 4 were observed in the efficacy trial in either vaccine group;
the ability of 7VPnC to protect against invasive disease due to serotype
4 may not have been effectively tested.

One infant experienced a hyporesponsive episode on the day of the 1^st^
dose of 7VPnC; the event was considered probably related to 7VPnC and no
additional doses were administered. Two additional events, both in the
7VPnC group, resulted in study termination: inconsolable crying 1 day
after 1^st^ dose, and fever, fussiness, vomiting 2 days after dose 2.
This latter event resulted in hospitalization, but investigators did not
consider the event related to vaccine.

No deaths or seizures were reported during the study period.

**Study 118-09: A Randomized, Double-Blind Trial Comparing the Safety
and Immunogenicity of Two Lots of Heptavalent (4, 6B, 9V, 14, 18C, 19F,
23F) Pneumococcal Conjugate Vaccine in Toddlers 15-24 Months of Age**

This was a single-center, randomized and double-blind study, initiated
in May 1995, and completed November, 1995. The original objectives of
the study were to assess safety and immunogenicity among toddlers
following a single dose of 7VPnC from two pilot lots. The role of the
study in the PLA is to support a catch-up schedule.

Sixty healthy toddlers, age 12-24 months were randomized to receive a
single dose of 7VPnC from one of two pilot lots. Subjects were actively
monitored for local and systemic reactions.

Immunogenicity results were categorized by age at enrollment: 12-17
months and 18-23 months. Immunogenicity results for the two lots were
similar, so they were combined for inclusion in the tables for "Catch-Up
Immunizations".

Safety and immunogenicity data were presented by age at vaccinations:
12-17 months and 18-23 months. Local reactions occurred with similar
frequency in the two age groups. More severe, clinically significant,
local reactions were uncommon.

Systemic reactions occurred more commonly in the younger age group.
Fever ≥38.0°C was reported by 52% (13 of 25) subjects in the 12-17 month
age group, vs. 24% (8 of 33) in the 18-23 age group. No subject in
either group reported fever \>39°. Fussiness, drowsiness, decreased
appetite and antipyretic use were all reported more frequently in the
younger age group.

No serious or unusual adverse events were reported.

**Study 118-15: A Double-Blinded, Controlled Study of the Efficacy,
Immunogenicity, Safety and Tolerability, and Effectiveness of a
Pneumococcal Conjugate Vaccine Containing Seven Serotypes (6B, 14, 19F,
23F, 18C, 4 and 9V) Compared to a Control Meningococcal C Vaccine in
Navajo and Apache Indian Infants**

The primary objective of the study is to demonstrate effectiveness of
7VPnC in preventing invasive pneumococcal disease occurring in infants
and toddlers. Subjects received either 7VPnC or meningococcal C
conjugate (MnCC).

Randomization was 1:1 for 40 allocation units based on geographical
criteria. All subjects in a unit receive the same vaccine. Infants 6
weeks to \< 7 months of age receive 3 doses at least 1 month apart and a
4^th^ dose at 12-15 months. Infants 7 to 12 months of age receive 2
doses at least 1 month apart and a 3^rd^ dose at 12-15 months. Infants
12 to 24 months of age receive 2 doses, approximately 2 months apart.
Total planned enrollment is 18,000 children. The study is ongoing.

Only subjects who received the first vaccination after 12 months of age
and who consented to participate in a serology subset were included in
the data submitted to the PLA to support catch-up schedules. There were
204 subjects available at the time of the analysis. Results are shown in
the summary table for catch-up immunizations.

No safety data were provided.

**Study 124-2: Safety and Immunogenicity of a Booster Dose of Nine
Valent (1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F) Pneumococcal Conjugate
Vaccine Administered Concurrently with MMR in Toddlers 12-15 Months of
Age.**

The original study compared safety and immunogenicity of 7VPnC and 9VPnC
vaccines. A total of 184 subjects were randomized 1:1 to receive 7VPnC
or 9VPnC at 2, 4, and 6 months of age. An amendment to the study
provided for a 4^th^ dose of 9VPnC to be given to children of both
groups at 12-15 months of age, administered concurrently with MMWR. No
other vaccines were administered concurrently with the 4^th^ dose. A
total of 75 subjects were analyzed for immunogenicity to MMR.

Antibody responses to measles, mumps and rubella were determined by
ELISA methods. Seroconversion was defined as a change from seronegative
to seropositive or a 4-fold rise in antibody titer.

No comparative immunogenicity data (7VPnC vs. 9VPnC) were provided in
the PLA. Only data intended to support concurrent immunization of 7VPNC
with MMR were provided. Because the MMR concurrent immunization data was
obtained using 9VPnC at the 4^th^ dose, these data may not be adequate
to support concurrent immunization of MMR with Prevenar.

**Study 124-501: A Randomized, Blinded, Controlled Trial Evaluating the
Effect of Immunization with 9-valent Pneumococcal Conjugate Vaccine on
Nasopharyngeal Carriage of S. pneumoniae in Israeli Toddlers Enrolled in
Day Care Centers**

Immunogenicity data from this study were intended to support catch-up
vaccination schedules. Subjects age 12-17 months were randomized 1:1 to
receive two injections 2-3 months apart of either 9VPnC or MnCC.
Subjects age 18-35 months were randomized 1:1 to receive a single
injection of 9VPnC or MnCC.

The 9-valent formulation used in this study contains pneumococcal
conjugates for all serotypes represented in the 7-valent formulation,
plus serotypes 1 and 5. The 9-valent vaccine is reconstituted from a
lyophylized preparation, while Prevenar is a liquid formulation. Safety
and immunogenicity data for the 9-valent formulation may not be directly
applicable to Prevenar.

Attachment C

**Preliminary Review Comments Regarding Otitis Media Analysis**

FDA's review of the otitis media analysis from the NCKP study has not
been completed, and VRBPAC members will not be asked to comment on these
data at the meeting. Furthermore, data from the Finnish otitis media
efficacy trial was only recently announced and have not yet been
submitted to the license application. Unlike the NCKP trial, the Finnish
otitis media trial design utilized tympanocentesis, allowing a
pneumococcal serotype specific diagnosis. The sponsor projects that the
QCed Finnish trial data will be submitted to a license application in
early 2000.

Some preliminary review comments based on the sponsor's analysis of the
NCKP trial follow.

Otitis media analysis overview

The effect of immunization on the occurrence of acute otitis media was
examined as a secondary endpoint in the NCKP efficacy study. Cases of
otitis media were identified through the computerized databases of
Kaiser Permanente. Identification of an "episode" of acute otitis media
(AOM) was made when a Kaiser clinician checked off a box on a patient
encounter form, provided no other visits for otitis media had occurred
in the preceding 21 days. This latter provision was intended to identify
discrete episodes of otitis media, by reducing the number of clinic
visits that were more likely to be follow-up visits. A separate
check-off box was provided for otitis media with effusion; visits
checked as otitis media with effusion did not contribute to the AOM
analysis. Uniform diagnostic criteria of acute otitis media were not
specified; diagnoses were based on normal clinical practice.

The follow-up period for all cases in the otitis media analysis ended on
April 30, 1998. For the per-protocol analysis, follow-up began 14 days
after the 3^rd^ dose. In the intent-to-treat analysis, follow-up began
after each randomized subject received the first dose of vaccine and
continued until April 30, 1998.

The final analysis plan differed from the analysis described in the
original protocol. One primary endpoint and 6 secondary otitis media
endpoints were specified in a revised analysis plan, as agreed upon by
representatives of NCKP, Wyeth-Lederle, and FDA/CBER, in November 1998,
prior to unblinding of the otitis media data set.

A total of 52,789 AOM episodes had been identified at the time the
otitis media database was locked on April 30, 1998. The sponsor's
analyses are summarized below:

Summary of Vaccine Effect on Acute Otitis Media

+------------------+----------+--------------+----------+--------------+
| Acute Otitis     | Per      |              | Intent-  |              |
| Media            | protocol |              | to-Treat |              |
|                  | Analysis |              | Analysis |              |
| Outcome          |          |              |          |              |
+------------------+----------+--------------+----------+--------------+
|                  | Est.     | (95% Conf.   | Est.     | (95% Conf.   |
|                  | Risk     | Interval)    | Risk     | Interval)    |
|                  | R        |              | R        |              |
|                  | eduction |              | eduction |              |
+------------------+----------+--------------+----------+--------------+
| All AOM Episodes | 7.0%     | (4.1%, 9.7%) | 6.4%     | (3.9%, 8.7%) |
|                  |          |              |          |              |
| \- Primary       |          |              |          |              |
| Outcome          |          |              |          |              |
+------------------+----------+--------------+----------+--------------+
| First AOM        | 5.4%     | (2.3%, 8.4%) | 4.9%     | (2.3%, 7.5%) |
| Episode          |          |              |          |              |
+------------------+----------+--------------+----------+--------------+
| Frequent AOM     | 9.5%     | (3.2%,       | 9.2%     | (4.3%,       |
|                  |          | 15.3%)       |          | 13.9%)       |
+------------------+----------+--------------+----------+--------------+
| Tympanostomy     | 20.3%    | (1.8%,       | 20.6%    | (4.0%,       |
| Tube             |          | 35.4%)       |          | 34.3%)       |
|                  |          |              |          |              |
| Placement        |          |              |          |              |
+------------------+----------+--------------+----------+--------------+
| All AOM Visits   | 8.9%     | (5.8%,       | 7.8%     | (5.2%,       |
|                  |          | 11.8%)       |          | 10.5%)       |
+------------------+----------+--------------+----------+--------------+
| Ruptured Ear     | 55.6%    | (-59.3%,     | 57.1%    | (-18.7%,     |
| Drum with        |          | 90.0%)       |          | 86.5%)       |
|                  |          |              |          |              |
| Vaccine Serotype |          |              |          |              |
| Isolates         |          |              |          |              |
+------------------+----------+--------------+----------+--------------+

Adapted from Table 10 of the Integrated Clinical Summary, Volume 33,
Part IV of PLA.

Primary acute otitis media endpoint: Overall incidence of acute otitis
media episodes

Overall incidence of acute otitis media episodes (new visits) during per
protocol follow-up was chosen as the primary otitis media endpoint.
Results of secondary analyses were to be considered exploratory if
efficacy for the primary endpoint was not demonstrated. Choice of
overall incidence of AOM episodes as the primary endpoint was based on
its inclusiveness of all discrete episodes of AOM, whether recurrent or
first episode. Overall incidence of AOM in the 7VPnC group was reduced
by 7% (95% CI 4.1%, 9.7%); results of the intent-to-treat analysis were
similar.

Secondary otitis media endpoints

Six secondary acute otitis media endpoints were specified on a per
protocol basis. In addition, all otitis media endpoints were analyzed
using the principle of intent-to-treat.

> Risk of at least one episode
>
> Risk of first episode of acute otitis media, or the proportion of
> children with any AOM episode, was the primary otitis media endpoint
> in the original protocol. Risk of first episode remained among the
> secondary endpoints in the revised analysis plan. Reduction in the
> risk of first episode was 5.4% (95% CI: 2.3% to 8.4%). Results of the
> intent-to-treat analysis were consistent with the per protocol
> analysis.

Frequent otitis media

> Frequent otitis media was defined as 3 episodes (new visits) within 6
> months, or 4 episodes within a 1-year period of follow-up. A total of
> 1,647 (13.9%) children in the 7VPnC group met the definition of
> frequent acute otitis media, compared to 1,809 (15.2%) children in the
> MnCC group. The risk reduction for frequent otitis media was 9.5% (95%
> CI: 3.2% ,15.3%). Results of the intent-to-treat analysis were
> consistent with the per protocol analysis.
>
> Two alternative definitions of frequent acute otitis media were used
> in exploratory analyses:

-   4 episodes (new visits) within 6 months, or 5 episodes within 12
    months of follow-up.

-   5 episodes within 6 months, or 6 episodes within 12 months of
    follow-up.

> In the per protocol analysis, risk reduction for 4 episodes in 6
> months, or 5 episodes in 12 months was 11.9% (95% CI: 1.6%, 21.1%).
>
> For 5 episodes/6 months or 6 episodes/12 months, risk reduction was
> 22.8% (95% CI: 6.7%, 36.2%)
>
> The apparent trend toward increased effectiveness with more frequent
> episodes was less clear for the intent-to-treat analysis.

Tympanostomy tube placement

> A total of 157 (1.3%) children in the 7VPnC group had tympanostomy
> tubes placed during the per-protocol follow-up, compared to 198 (1.7%)
> children in the MnCC group. The reduction in tube placement was 20.3%
> (95% CI: 1.8% to 35.4%). Results of the intent-to-treat analysis were
> consistent with the per protocol analysis.

Overall incidence of otitis media visits ("All Visits")

> A total of 22,478 clinic visits for acute otitis media were recorded
> in the 7VPnC group during the per-protocol follow-up period, compared
> to 24,914 visits in the MnCC group. For this endpoint, a subject may
> be counted multiple times for the same otitis media episode, as all
> follow-up visits for AOM would also be included in the analysis.

Ruptured eardrums due to pneumococcal infection

> Although the otitis media database was "locked" April 30, 1998, cases
> of ruptured tympanic membranes were analyzed by the sponsor for data
> accumulated through 2 later time points. Results at the time of the
> planned analysis were not presented in the PLA. Data for ruptured
> membranes presented in the table above, apply to cases accrued through
> November 6, 1998. Although not prospectively defined, this analysis
> took place prior to unblinding of the otitis media dataset. Of 13
> cases of ruptured eardrums due to vaccine serotypes recorded during
> the per-protocol follow-up period, 4 were in the 7VPnC group and 9 in
> the MnCC group. The estimate of risk reduction was 55.6% (95% CI:
> --59.3% to 90%).
>
> An additional analysis was conducted of cases accrued through March
> 24, 1999; 16 cases of ruptured eardrums of vaccine serotype accrued in
> the per protocol analysis; 4 were in the 7VPnC group. For the
> per-protocol population, risk of tympanic membrane rupture was reduced
> by 66.7% (95% CI --10%, 92.2%).
>
> Analyses of cases of ruptured eardrums accrued after April 30, 1998,
> were not prospectively defined. Therefore, these analyses should be
> considered exploratory.
>
> For data collected through March 24, 1999, vaccine serotypes accounted
> for 79.3% (23/29) of all isolates from ruptured eardrums. The most
> common isolate was serotype 19F, which accounted for 65.2% (15/23) of
> all vaccine serotype isolates from ruptured eardrums, and all 6
> isolates due to vaccine serotype in the 7VPnC group.

Sponsor's commentary of effect of 7VPnC on acute otitis media

The sponsor acknowledges that the "check off" system for recording
episodes of acute otitis media on the patient encounter form likely
results in diagnoses which are not highly specific. The estimate of
vaccine efficacy would be expected to be lower than an estimate based on
a more specific diagnosis. Culture data obtained from tympanocentesis in
a Finnish otitis media trial (not submitted with the PLA) were used to
estimate the proportion of acute otitis media due to pneumococcus in the
NCKP trial. Making some assumptions, the sponsor proposed that a
reasonable estimate of vaccine efficacy against acute otitis media
caused by vaccine serotypes could be 80%.

Among the assumptions are:

1)  50% of episodes reported as acute otitis media in the NCKP trial
    would meet a clinical case definition in the Finnish trial.

2)  59% of clinical otitis media is caused by bacteria (data from the
    Finnish trial)

3)  41% of bacterial otitis media is caused by pneumococcus (data from
    Finnish trial)

4)  66% of pneumococcal otitis media is due to vaccine serotypes

It then follows that:

100% (reported AOM) \* 0.5 (clinical AOM) \* 0.59 (bacterial AOM) \*
0.41 (pneumococcal AOM) \* 0.66 (vaccine serotypes) \* 0.8 (presumed
vaccine efficacy) = 6% (approximate demonstrated efficacy in Kaiser
trial).

FDA Review Comments Regarding Sponsor's Otitis Media Analysis

The assumptions made in the sponsor's commentary appear to be
reasonable, and lead one to conclude that true vaccine efficacy for AOM
due to vaccine serotype is likely much greater than was demonstrated in
the NCKP trial for AOM due to all causes. However, other reasonable
assumptions would lead to different estimates.

Criteria used to diagnose acute otitis media in the Finnish trial are
similar to diagnostic criteria used in the U.S., i.e., abnormal tympanic
membrane (in regard to color, position, mobility), with signs or
symptoms of acute infection, such as fever, ear ache, irritability.
Therefore, the initial assumption that only 50% of AOM reported by
Kaiser clinicians would qualify as clinical episodes of AOM in Finland,
may be spuriously low. For the alternative estimate below, an assumption
of 80% diagnostic concordance was used.

In the sponsor's commentary, the proportion of clinical otitis media due
to bacterial causes (59%), and proportion of bacterial AOM due to
pneumococcus (41%) are based on data from the Finnish trial, in which
tympanocentesis was performed for all children diagnosed with clinical
AOM. These data have not yet been submitted to the license application.
However, these estimates appear reasonable, and may well be applicable
to children in northern California.

The assumption that 66% of pneumococcal AOM is due to vaccine serotypes
is also taken from the Finnish data. However, data are available from
the NCKP trial showing that 85% of all invasive isolates were of vaccine
serotype. Of isolates from ruptured tympanic membranes in the NCKP
study, 79% were of vaccine serotype. Based on these data, one might
choose 80% to estimate the proportion due to vaccine serotype.

Using these alternative assumptions, which appear equally reasonable:

100% \* 0.8 (clinical AOM) \* 0.59 (bacterial causes) \* 0.41
(pneumococcal serotype) \* 0.8 (vaccine serotype) \* vaccine efficacy =
6%

Under these assumptions: Vaccine Efficacy = 39%.

Labeling issues

The Indications and Usage section of the proposed label includes the
following language:

**Prevenar is indicated for active immunization of infants and children
beginning as early as 6 weeks of age for:**

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

The proposed indication does not reflect the primary otitis media
endpoint, overall incidence of acute otitis media. Nevertheless, ear
tube placement is an outcome that has appeal for being clearly defined
and easily understood. Ear tube placement was also the endpoint which
showed the greatest point estimate of efficacy in the per protocol
analysis, 20.3%. However, the 95% confidence intervals for this outcome
were wide, with a lower bound of only 1.8% in the per protocol analysis.

Should Prevenar be licensed based on available data from the NCKP study,
the following points weigh against including the proposed otitis media
indication in the vaccine label:

1)  Otitis media was not the primary outcome of the efficacy trial.

2)  The trial was not specifically designed to identify cases of acute
    otitis media using prospectively defined diagnostic criteria.

3)  Ear tube placement was one of a number of otitis media endpoints,
    and was not prospectively designated as one of the two most
    important secondary endpoints for otitis media.

4)  Criteria for inserting ear tubes were not prospectively defined.

5)  Despite demonstration of statistical significance, there is much
    uncertainty around the estimate of risk reduction for ear tube
    placement.

6)  Results of a clinical trial (Finnish) specifically designed to
    evaluate efficacy of 7VPnC to protect against otitis media due to
    vaccine serotype will be available in the near future.

7)  The estimate of efficacy for the primary otitis media endpoint,
    while statistically significant, was low (7%) for a preventive
    vaccine indication. A vaccine indication based on the demonstrated
    level of efficacy may be misleading to the public.

In favor of including a description of otitis media results in the
clinical pharmacology section of the vaccine label are the following
points:

1\) This is the first vaccine for which a preventive effect against
acute otitis media cases appears to have been demonstrated.

2\) A balanced presentation of the AOM results would provide clinicians
and the public a basis for realistic expectations of the effects of
Prevenar on rates of AOM.

3\) The preventive effects of Prevenar on AOM may enter into the
risk/benefit assessment when considering use of the vaccine.

The Clinical Pharmacology section of the proposed label includes a
tabular summary of efficacy of the 7VPnC to protect against otitis
media, which is reproduced below:

Reduction in Otitis Media After Immunization with Prevenar Against
Otitis Media

+------------------+------------+------------+------------+------------+
|                  | Per        |            | ITT        |            |
|                  | Protocol   |            |            |            |
|                  |            |            | N=34,146   |            |
|                  | N=23,746   |            |            |            |
+------------------+------------+------------+------------+------------+
|                  | \%         | 95 % CI    | \%         | 95 % CI    |
|                  | Reduction  |            | Reduction  |            |
+------------------+------------+------------+------------+------------+
| All episodes OM  | 7.0        | 4.1, 9.7   | 6.4        | 3.9, 8.7   |
+------------------+------------+------------+------------+------------+
| All OM visits    | 8.9        | 5.8, 11.8  | 7.8        | 5.2, 10.5  |
+------------------+------------+------------+------------+------------+
| Frequent OM      | 9.5        | 3.2, 15.3  | 9.2        | 4.3, 13.9  |
|                  |            |            |            |            |
| 3 episodes/6mo;  | 11.9       | 1.6, 21.1  | 10.0       | 2.4, 17.0  |
| 4/yr             |            |            |            |            |
|                  | 22.8       | 6.7, 36.2  | 12.3       | 0.0, 23.2  |
| 4 epidoses/6mo;  |            |            |            |            |
| 5/yr             |            |            |            |            |
|                  |            |            |            |            |
| 5 episodes/6mo;  |            |            |            |            |
| 6/yr             |            |            |            |            |
+------------------+------------+------------+------------+------------+
| Ear Tube         | 20.3       | 1.8, 35.4  | 20.6       | 4.0, 34.3  |
| placement        |            |            |            |            |
+------------------+------------+------------+------------+------------+

Risk of first episode of acute otitis media was identified as the
primary otitis media endpoint in the original protocol, and remained
among the secondary endpoints. For this endpoint, children could be
counted only once as having otitis media. "First episode" may more
accurately reflect vaccine benefit for the typical child, as it is not
driven by the subset of children who were diagnosed multiple times as
having AOM. This endpoint is informative and would provide balance to
the vaccine label.

The alternative definitions of frequent AOM were not prospectively
defined, and are likely to be highly correlated with the prospectively
defined endpoint of frequent AOM. Typically, such exploratory analyses
are not described in product labels. Moreover, ITT results are not
consistent with per protocol results for the case definition of 5
episodes/6mos, 6/yr.

Prevention of visits for otitis media is listed 2^nd^ in the summary
table of the proposed label. While this endpoint may have
medico-economic implications, it is not descriptive of clinical
outcomes. Prevention of health care visits has not been the basis of
previous vaccine licensures. The description of this endpoint may not be
appropriate for a vaccine label.

FDA clinical and statistical review of the otitis media data is ongoing.

Attachment D

**Preliminary Review Comments Regarding Pneumonia Analysis**

FDA's review of the pneumonia analysis has not been completed, and
VRBPAC members will not be asked to comment on these data at the
meeting. However, some preliminary review comments based on the
sponsor's analysis are presented.

The effectiveness of 7VPnC in preventing the occurrence of pneumonia was
examined as a tertiary endpoint in the NCKP efficacy trial. Cases of
pneumonia were identified retrospectively through the computerized
databases of Kaiser Permanente. Identification of an episode of clinical
pneumonia was made when a Kaiser clinician checked off a box on an ER or
outpatient clinic encounter form, and when the episode was more than 30
days from any prior pneumonia diagnosis. X-rays obtained within --1 to
+5 days of the clinical diagnosis were used to identify cases for the
primary and secondary analyses.

Follow-up for cases in the pneumonia analysis ended on April 30, 1998.
In the per-protocol analysis, follow-up began 14 days after the 3^rd^
dose was administered. In the intent-to-treat analysis, follow-up began
after each randomized subject received the first dose and continued
until April 30, 1998.

Primary pneumonia endpoint: Clear consolidation

The primary pneumonia endpoint was clear consolidation, based on the
readings of two study radiologists. Clear consolidation was defined as
an area of opacity 2.5 cm or greater at longest diameter with well
defined edges. Investigators' selection of clear consolidation as the
primary pneumonia endpoint was based on the following rationale provided
in a January 19, 1999 submission to FDA/CBER:

1\) Consolidation is "\...reasonably reproducibly detected among
observers (kappas of 0.57 and 0.79, references provided)."

2\) Consolidation is more frequently associated with bacterial pneumonia
than other causes of pneumonia. "Classic" (single lobe with well-defined
alveolar consolidation) radiologic findings remain less likely to have
viral or atypical pneumonia.

3\) Utility of clear consolidation endpoint was previously demonstrated
for a Hib-conjugate vaccine in a Gambian study.

**Results of the primary pneumonia endpoint analysis, as agreed upon
between FDA and the sponsor, were not provided in the PLA.** In an
addendum to the clinical summary, the following explanation was provided
explaining why the prospectively-defined primary pneumonia analysis was
abandoned: "As the readings progressed, it became apparent that this
definition was not specific enough to allow good agreement between the
radiologists. Furthermore, an additional set of 53 films with abnormal
radiology department reports, but read as normal by the pediatric
investigators, was inadvertently not provided to the study radiologists
for reading with the original set, introducing a procedural
irregularity."

A preliminary analysis of the "pneumonia with clear consolidation"
endpoint was presented during a pre-PLA submission meeting between
representatives of FDA and Wyeth-Lederle (May 6, 1999). These analyses
indicated that vaccination with 7VPnC provided no statistically
significant preventive effect on pneumonia with clear consolidation.
That analysis was not included in the PLA.

**Secondary pneumonia endpoint: Clinical pneumonia with abnormal chest
X-ray**

Clinical pneumonia with chest X-ray read as abnormal by the on-site
clinical radiologist was prospectively defined as the sole secondary
pneumonia endpoint. A chest X-ray could be read as abnormal on the basis
of an effusion, an infiltrate, or consolidation. Although clearly
identified in the pneumonia analysis plan as the sole secondary
pneumonia endpoint, clinical pneumonia with abnormal chest X-ray was
described in the clinical study report and in the integrated summary of
the PLA as the primary pneumonia endpoint.

A total of 45 cases were identified among 11,849 children in the 7VPnC
group and 70 cases among 11,897 children in the MnCC group in the
per-protocol population through April 30, 1998. Vaccine effectiveness
was 35% (95% CI 4.2, 56.4) in the sponsor's analysis.

In the intent-to-treat analysis, 61 cases were recorded in the 7VPnC
group and 91 cases in the MnCC group. Vaccine effectiveness was 33% (95%
CI 6.2, 52.3) in the sponsor's analysis.

# Ancillary endpoints

FDA/CBER had requested that all episodes of clinical pneumonia, and all
episodes of clinical pneumonia with chest X-ray taken (irrespective of
X-ray reading), be analyzed to examine consistency of the results. It
was not FDA/CBER's intention or understanding that these outcomes be
considered endpoints for the purpose of efficacy claims. In the final
analysis plan submitted to FDA on March 3, 1999, prior to unblinding,
these analyses were not among the prospectively defined study endpoints.

In the clinical study report, episodes of clinical pneumonia and all
episodes of clinical pneumonia with chest X-ray taken were identified as
secondary endpoints. The proposed label submitted with the PLA includes
a table, shown below, in which results of the analyses of clinical
pneumonia and clinical pneumonia with chest X-ray are shown.

**Table 4**

**Reduction in Pneumonia After Immunization With Prevenar**

+----------------------+-----------+-----------+----------+-----------+
| # Clinical Pneumonia | # Per     |           | #        |           |
|                      |  Protocol |           |  Intent- |           |
|                      |           |           | to-Treat |           |
|                      | N=23,746  |           |          |           |
|                      |           |           | N=34,146 |           |
+----------------------+-----------+-----------+----------+-----------+
|                      | # %       | # 95% CI  | # % R    | # 95% CI  |
|                      | Reduction |           | eduction |           |
+----------------------+-----------+-----------+----------+-----------+
| # Any                | # 11      | # -1, 21  | # 10     | # 0.1, 20 |
+----------------------+-----------+-----------+----------+-----------+
| #                    | # 12      | # -2, 25  | # 13     | # 0.2, 24 |
| With Any Chest X-Ray |           |           |          |           |
+----------------------+-----------+-----------+----------+-----------+
| # With               | # 35      | # 4, 56   | # 32     | # 5, 52   |
| Abnormal Chest X-Ray |           |           |          |           |
+----------------------+-----------+-----------+----------+-----------+

# 

# 

# Clinical pneumonia with chest X-ray taken

In the per-protocol analysis of clinical pneumonia with chest X-ray
taken, 323 cases were recorded for the 7VPnC group and 372 cases were
recorded for the MnCC group. The estimate of vaccine effectiveness was
12% (95% CI --2.2, 24.7).

In the intent-to-treat analysis of clinical pneumonia with chest X-ray
taken, 393 cases were recorded for the 7VPnC group and 456 cases for the
MnCC group. The estimate of vaccine effectiveness was 13% (95% CI 0.2,
24.1) in the sponsor's analysis.

# All clinical pneumonia

During the per protocol follow-up, 500 episodes of clinical pneumonia
were identified in the 7VPnC group, and 566 in the MnCC group. The
estimate of vaccine effectiveness in preventing clinical pneumonia was
11 % (95% CI --0.8, 21.1).

In the intent-to-treat analysis, 615 episodes of clinical pneumonia were
reported for the 7VPnC group, and 694 in the MnCC group. The estimate of
vaccine effectiveness was 10% (95% CI 0.10, 19.8) in the sponsor's
analysis.

# Review comments regarding the pneumonia analysis 

Information about pneumonia was collected in the Kaiser patient database
as part of routine data collection. Clinicians were not provided a
common set of diagnostic criteria on which to base a diagnosis of
clinical pneumonia. No clinical guidelines were utilized to distinguish
cases of probable bacterial from probable viral pneumonia. Upper
respiratory secretions were not uniformly collected for cultures or
rapid diagnostic tests to rule out other pathogens, nor were results of
such tests considered in the diagnostic algorithm. Likewise, results of
blood cultures were not considered in the diagnosis of pneumonia.

As the investigators pointed out in their rationale for choosing the
primary pneumonia endpoint, consolidation on chest X-ray had been shown
to be associated with bacterial causes more frequently than with viral
causes. Pneumonia with consolidation was therefore thought to be an
endpoint with high specificity for pneumococcus, and represented the
most likely scenario for demonstrating vaccine efficacy for pneumonia in
the infant and toddler age groups. **However, this endpoint was
abandoned, ostensibly due to procedural problems.** Preliminary results
had shown no statistically significant treatment effect. Results of a
well-conducted analysis of this data set could add importantly to the
knowledge base about infant pneumonia and may be useful in designing
future trials.

Labeling issues

The Indications and Usage section of the proposed label includes the
following language:

The vaccine is indicated for active immunization of infants and children
beginning as early as 6 weeks of age for:

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

Should Prevenar be licensed, the following points weigh against allowing
the proposed indication for prevention of clinical pneumonia with
abnormal chest X-ray:

1\) Pneumonia endpoints were tertiary outcomes in the efficacy trial.

2\) The efficacy trial was not designed to identify cases of clinical
pneumonia using prospectively defined diagnostic criteria.

3\) Investigators failed to demonstrate efficacy for the primary
pneumonia endpoint.

4\) The estimate of efficacy for the secondary pneumonia endpoint (35%),
while statistically significant, was relatively low for a preventive
vaccine; the lower bound of the 95% confidence interval was only 4% in
the per protocol analysis.

In favor of including a description of the pneumonia results in the
vaccine label

are the following points:

1\) Prevention of pneumonia due to pneumococcus may be greater than was
demonstrated for the secondary endpoint, which encompasses pneumonia due
to all etiologies.

2\) The secondary endpoint reflects normal clinical practice. As such,
this endpoint provides a crude, but "real world" estimate of vaccine
efficacy against pneumonia.

3\) The preventive effects of Prevenar on pneumonia endpoints may enter
into the risk/benefit assessment when considering use of the vaccine.

**FDA clinical and statistical review of the pneumonia efficacy data is
ongoing.**