FDA Briefing Document for the Vaccines and Related Biological Products
Advisory Committee (VRBPAC)

May 21, 2002

Prevnar™, Pneumococcal Conjugate Vaccine 7-valent, for the Prevention of
Acute Otitis Media

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

**List of Abbreviations**

**7VPnC** 7-valent pneumococcal conjugate vaccine, manufactured by
Wyeth-Lederle; Pre-licensure notation for Prevnar, used in the Northern
California Kaiser Permanente study report.

**AOM** Acute otitis media

**BLA** Biologics license application

**CI** Confidence interval

**DTP** Diphtheria, tetanus, pertussis vaccine

**GMC** Geometric mean concentration

**HBV** Hepatitis B vaccine

**Hib** Hemophilus influenza type b vaccine

**ITT** Intent-to-treat

**MEF** Middle ear fluid

**MnCC** Meningococcal conjugate type C vaccine, investigational
vaccine, manufactured by Wyeth-Lederle; control vaccine in Northern
California Kaiser Permanente study

**NCKP** Northern California Kaiser Permanente

**PCR** Polymerase chain reaction

**PncCRM** 7-valent pneumococcal conjugate vaccine, manufactured by
Wyeth-Lederle; Pre-licensure notation for Prevnar, used in the Finnish
otitis media study report.

**PncOMPC** 7-valent pneumococcal conjugate vaccine, investigational
vaccine manufactured by Merck & Co., used in the Finnish otitis media
study

**PP** Per protocol

**VRBPAC** Vaccines and Related Biologic Products Advisory Committee

**1.0 Scope of Discussion**

Prevnar, pneumococcal 7-valent conjugate vaccine, was licensed in the
U.S. on February 17, 2000, for active immunization of infants and
toddlers against invasive disease caused by the 7 pneumococcal serotypes
represented in the vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, 23F).
With the present supplement to the product license application,
Wyeth-Lederle now seeks to extend the approved indication to include
prevention of acute otitis media. Specifically, regulatory approval has
been requested to market Prevnar:

> "**For active immunization of infants and toddlers against invasive
> disease [and otitis media]{.underline} caused by *Streptococcus
> pneumoniae* due to capsular serotypes included in the vaccine (4, 6B,
> 9V, 14, 18C, 19F, 23F)."**

Data intended to support this additional indication have been provided
from two well-controlled clinical trials: 1) Northern California Kaiser
Permanente Efficacy Trial, and 2) Finnish Acute Otitis Media trial.

This FDA briefing document will focus largely on the additional efficacy
data from these 2 clinical trials and the specific indication these data
may support. Discussion of safety data will be limited to clinical trial
data not provided or addressed in the original Prevnar^TM^ license
application. No issues related to vaccine production or product
characterization of this licensed vaccine are discussed in this
document.

Prevnar is currently the only licensed pneumococcal conjugate vaccine.
Prevnar is recommended by the Advisory Committee on Immunization
Practices (ACIP), the American Academy of Pediatrics (AAP), and the
American Academy of Family Physicians (AAFP) for all children under 2
years of age, and for older children in some groups at high-risk for
invasive pneumococcal disease. Extending the licensed indication to
prevention of acute otitis media may not impact use of the vaccine in
the U.S. in the near future. However, FDA views consideration and
discussion of this application by VRBPAC appropriate for the following
reasons:

1)  As will be discussed, the efficacy estimates for otitis media
    outcomes are comparatively low for preventive vaccines.

2)  Data from the Finnish study suggest that there may be increased risk
    of AOM (negative efficacy) due to pneumococcal serotypes not
    included in Prevnar. Consequently, the reduction in overall AOM may
    be less due to serotype replacement in the population.

3)  Concern has been expressed in the medical community about the
    potential for unrealistic public expectations regarding the benefit
    of the vaccine in preventing otitis media.

> Following publication of the Finnish otitis media study, (Eskola J et
> al., 2001), a number of letters to the editor regarding that article
> were submitted to the New England Journal of Medicine (N Engl J Med
> 2001;344:1719-20). Correspondents questioned the overall clinical
> significance of the treatment effect (Lavin A; Damoiseaux R; Cantekin
> E; Sauder K). Concerns that the limited benefit of Prevnar in
> preventing otitis media may be misunderstood by the public (Sauder K)
> or would lessen the credibility of the existing recommendations for
> its use, were also expressed. One letter (Cantekin, E) incorrectly
> stated that FDA rejected the use of Prevnar for prevention of otitis
> media due to a clinically and statistically insignificant difference.

**2.0 Regulatory Background**

Licensure of Prevnar in the U.S. followed a priority review by FDA.
Priority status had been granted to the application and an expedited
review was conducted, based on: 1) the severity of disease for which the
vaccine would be indicated, i.e., invasive pneumococcal disease
(meningitis and bacteremia),

2\) lack of alternative licensed vaccines for use among infants and
small children, and 3) preliminary results indicating substantial
evidence of efficacy. Specifically, estimates of vaccine efficacy for
prevention of invasive disease due to vaccine serotypes in the large
efficacy trial conducted at NCKP were high \[100% in the per protocol
analysis (95%CI: 75.4, 100), and 90% in the intent-to-treat analysis
(95%CI: 81.7, 100)\].

Efficacy of Prevnar in preventing acute otitis media was examined among
the secondary endpoints in the NCKP efficacy study, and analyses of
endpoints relating to AOM were included in the initial license
application. However, prevention of AOM was not the focus of the initial
license application review, in part because the disease severity did not
satisfy requirements of a priority review. Moreover, it was recognized
by Wyeth-Lederle and FDA that results from the Finnish otitis media
study, which were only preliminary at the time the original license
application was submitted, would be critical to the regulatory
assessment of the specific indication of prevention of AOM. Thus, AOM
efficacy results from the NCKP trial were only briefly discussed in the
sponsor's presentation at the November 1999 VRBPAC, and the committee
was not asked to consider or discuss data relating to AOM.

Regulatory approval to market Prevenar (Prevnar^TM^) in Europe for
prevention of invasive disease was granted by the European Agency for
the Evaluation of Medicinal Products (EMEA) in October 2000. An
indication for prevention of otitis media was also considered in that
review, but not granted. Results of both the Finnish otitis media study
and the Kaiser efficacy study were available and evaluated by European
regulators. As stated in the scientific discussion of the review
committee, "...the overall impact of the vaccine on total number of
otitis media episodes was small, approximately 6%. Even if otitis media
is a very common disease in children, this extent of vaccine efficacy
does not support an indication" (European Public Assessment Report
(EPAR) for the Marketing Authorization for Prevenar, 2000, Scientific
Discussion, page 28).

No FDA regulations or published guidance specifically address the
minimum level of efficacy required for licensure of a preventive
vaccine. Approvals of most drugs and other therapeutic biological
products are based on substantial evidence of efficacy from at least 2
well-controlled clinical studies. Substantial evidence for therapeutic
products is commonly determined by hypothesis testing using an
acceptable level of statistical significance (e.g., p\< 0.05). For
preventive vaccines, more emphasis is placed on efficacy estimates with
95% confidence limits.

Approval of an otitis media indication for Prevnar could set a level of
evidence adequate for licensure of other pneumococcal conjugate vaccines
for the same indication, independent of whether or not license
applications for these other vaccines include evidence of efficacy for
prevention of invasive disease.

**3.0** **Pathogenesis, Epidemiology, and Treatment of Acute Otitis
Media**

Acute otitis media occurs when pathogenic bacteria within the
nasopharynx traverse the Eustachian tube into the middle ear space,
multiply to some threshold number, and provoke an inflammatory response.
Bacteria consistently documented to be associated with AOM include *S.
pneumoniae, H. influenzae, Moraxella catarrhalis*, and *Group A
Streptococcus* (Bluestone CD, et al., 1992). A preceding upper
respiratory viral infection appears to be a precipitating factor in much
of AOM of early childhood (Heikkinen T, 2001). Viral infections could
predispose to AOM by increasing bacterial adherence to epithelial cells
in the nasopharynx (Tuomanen EI, 2001). Viral infections may also result
in impaired Eustachian tube dysfunction by destroying ciliated
epithelium leading to increased mucous and cellular debris within the
tubal lumen, which can result in development of negative middle ear
pressure. Fluid may remain in the middle ear for weeks to months after
an episode of AOM (Klein JO, 2001). Recurrent AOM has been associated
with an earlier age at first episode of AOM (Kvaerner KJ, et al., 1997).
Among children with onset of AOM before age 9 months, approximately 25%
went on to develop recurrent AOM by age 2 years.

Bacteria ascending into the middle ear may be newly acquired, but most
are probably carried asymptomatically in the nasopharynx. Pneumococcal
serotypes are carried in the nasopharynx of approximately 1/2 of healthy
preschool age children in developed countries (Lopez B et al., 1999),
and in nearly 100% of young children in some developing countries
(Montgomery JM et al.,1990).

Otitis media caused by pneumococci may be more severe than AOM caused by
other common bacteria such as nontypeable *Hemophilus influenza* and
*Moraxalla catarrhalis*, as evidenced by higher rates of fever and less
frequent spontaneous resolution of episodes (Klein JO, 1994). Acute
otitis media due to pneumococcus is characterized by profound
inflammation. Pneumococcal cell wall fragments (peptidoglycan-teichoic
acid) activate the alternative pathway of the complement cascade,
leading to migration of neutrophils into the middle ear.

In the U.S., AOM is diagnosed in more than 60% of children during the
first year of life, and in more than 90% of children by age 5 years. The
peak incidence falls between 6 and 18 months of age. A 1990 surveillance
report by the Center for Disease Control and Prevention (CDC) comparing
reports in the years 1975 and 1990 identified otitis media as the most
frequently reported morbidity-related diagnosis among visits made by
children under age 10 years, for both years. The 7 serotypes included in
Prevnar were shown to account for 60% of AOM due to *S. pneumoniae*
(12-24% of all AOM) among pre-school children in the U.S.

The bacteriology of AOM among a cohort of 329 Finnish children age 2 to
24 months was investigated prior to the Finnish AOM vaccine efficacy
study (Kilpi T 2001). *S. pneumoniae, Moraxella catarrhalis,* and
*Hemophilus influenzae* were isolated from 26%, 23% and 23%,
respectively, of middle ear fluid isolates from 772 AOM events. Vaccine
serotypes accounted for 68% of all pneumococcal AOM events. The most
common pneumococcal serotypes isolated were types 19F (25%), 23F (20%),
6A (11%), 6B (9%), and 14 (7%).

The prevalence of pneumococci resistant to penicillin has been
increasing worldwide over the past 30 years. In the U.S., surveys
conducted in 1980 and 1987 showed that 96% of pneumococcal isolates in a
multi-laboratory survey were penicillin susceptible. Similar surveys in
1996-97 showed that 17% of isolates were resistant to penicillin, and
another 14% were of intermediate penicillin susceptibility (Barry AL,
1999). Penicillin-resistant strains are often resistant to multiple
antimicrobial agents, including trimethoprim-sulfmethoxazole,
erythromycin, tetracycline, and chloramphenicol (McDougal LK et al.,
1992).

Pneumococcal serotypes included in Prevnar are responsible for much of
the antibiotic resistance among circulating pneumococcal strains. In a
cross-sectional study of over 500 pneumococcal isolates from middle ear
fluids collected from children with AOM throughout the U.S. from
1996-1999, 57% showed decreased susceptibility to penicillin, and 32%
showed multiple-drug (penicillin, azithromycin, trimethoprim-sulfa)
resistance (Joloba ML et al., 2001). Serotypes included in Prevnar
accounted for 78% of the penicillin-nonsusceptible strains and nearly
all of the multiply-resistant pneumococci.

# 

# Injudicious use of antibiotics for the treatment of common upper respiratory symptoms in children, including otitis media, likely contributes to the increasing prevalence of antibiotic resistance. Rates of antimicrobial drug use are highest in children. Children treated with antimicrobial medications have a greater risk of becoming carriers of nonsusceptible pneumococci as a result of that treatment. Current treatment guidelines (Dowell SF, 1998) are intended to avoid unnecessary prescriptions for antibiotics by 1) distinguishing acute otitis media from otitis media with effusion (OME); 2) discouraging early antibiotic treatment of OME; 3) prescribing short courses (5-7 days) of antimicrobials in children over age 2 years; 4) reserving prophylactic use of antimicrobials for recurrent AOM, as defined by 3 episodes/6 months, or 4 episodes/12 months. 

# 

# Surgical placement of tympanostomy tubes has also been proposed as a rational alternative to long-term prophylactic antibiotics for recurrent AOM, and for children with chronic otitis media with effusion (Bluestone CD, 1998). 

# 

# 

# 4.0 Clinical Studies Reviewed[^1]

The clinical section of this application contains study reports for 2
studies:

1)  Finnish Acute Otitis Media study;

2)  Northern California Kaiser Permanente large efficacy and safety
    study.

Key characteristics of these trials are compared in the tables below:

**Characteristics of clinical studies in the**

######### Biologic License Application (BLA) Supplement

+-----+-------+-------+------+-----+-------------+-------------------+
| ##  | N     | Sch   | Con  | New | Case        | Regulatory        |
| ### | umber | edule | trol | E   | Definition  | Objective/        |
| ### |       |       |      | pis |             |                   |
|  St | of    | (Mo   | Vac  | ode |             | Other Information |
| udy | chi   | nths) | cine | In  |             |                   |
|     | ldren |       |      | ter |             |                   |
|     | enr   |       |      | val |             |                   |
|     | olled |       |      |     |             |                   |
+-----+-------+-------+------+-----+-------------+-------------------+
| F   | 1,6   | 2, 4, | HBV  | 30  | > Bacterial | > Demonstrate     |
| inn | 62^†^ | 6,    |      | d   | > cultures  | > efficacy for    |
| ish |       |       |      | ays |             | > prevention of   |
|     |       | 12-15 |      |     | (m          | > AOM;            |
|     |       |       |      |     | yringotomy) |                   |
+-----+-------+-------+------+-----+-------------+-------------------+
| Kai | 34,1  | 2, 4, | MnCC | 21  | > Automated | > Demonstrate     |
| ser | 46^‡^ | 6,    |      | d   | > database  | > efficacy for    |
|     |       |       |      | ays | > search    | > prevention of   |
| (NC |       | 12-15 |      |     | > for AOM   | > invasive        |
| KP) |       |       |      |     | > visits    | > disease, AOM,   |
|     |       |       |      |     |             | > and pneumonia;  |
|     |       |       |      |     |             | >                 |
|     |       |       |      |     |             | > Large safety    |
|     |       |       |      |     |             | > data base for   |
|     |       |       |      |     |             | > assessing rates |
|     |       |       |      |     |             | > of adverse      |
|     |       |       |      |     |             | > events;         |
+-----+-------+-------+------+-----+-------------+-------------------+

† Subjects distributed equally to PncCRM and HBV control vaccine; entire
study was randomized 1:1:1, PncCRM:PncOMP:HBV.

‡ Subjects randomized 1:1, 7VPnC:MnCC control vaccine

# 

# The Finnish otitis media study used a specific case definition based on culture of bacterial pathogens and serotyping of pneumococcal isolates collected from middle ear fluid by means of myringotomy in the context of a clinical episode of AOM. 

#  

# The NCKP study identified cases of AOM from searches of automated databases. No prospectively defined case definition was used. Rather, cases of AOM were diagnosed and recorded in the NCKP database in the course of routine practice of medicine at Kaiser clinics. Tympanocentesis with cultures of middle ear fluid was [not]{.underline} routinely performed in the Kaiser study, and, thus, the presence of pneumococcus in middle ear fluid was not confirmed for most cases. Also, follow-up visits for AOM could not be clearly differentiated from initial encounters for new episodes. 

# The clinical study designs, analysis plans, and results are described in greater detail in the sections that follow. 

# 

#  Finnish otitis media study

# 

# 4.1.1 Finnish otitis media study description 

> **Title: Efficacy Trial in Finnish Children of Pneumococcal Conjugate
> Vaccine (PncCRM) for Prevention of Acute Otitis Media Due to
> Pneumococcal Serotypes in the Vaccine**
>
> The study was randomized, double-blind, multi-center cohort study
> conducted in Finland. Children were enrolled and received the first
> doses of study vaccines at age 2 months, and were followed for
> efficacy and safety until 24 months of age.
>
> The study was conducted by the National Public Health Institute of
> Finland (Kansanterveyslaitos Flkhalsoinstitutet, KTL).
>
> As originally designed, the 3-arm study was to evaluate the efficacy
> of two 7-valent pneumococcal conjugate vaccines (PncCRM, Wyeth-Lederle
> and PncOMPC, Merck & Co.) compared to the same control vaccine
> (Hepatitis B vaccine, HBV, Merck & Co.). The submitted study report
> described results of the study only for the PncCRM and HBV groups.

The study was initiated in December 1995; enrollment ceased April, 1997.
The clinical phase of the study ended March 16, 1999.

> **Objectives**
>
> The primary objective was to determine the protective efficacy of the
> pneumococcal conjugate vaccine against culture-confirmed pneumococcal
> acute otitis media due to vaccine serotypes, compared to a control
> vaccine.
>
> Secondary objectives included assessments of the vaccine effect on:

-   efficacy using different levels of etiologic diagnosis,

-   efficacy in preventing nasopharyngeal carriage of pneumococci
    compared to control vaccine,

-   magnitude and persistence of antibody response, and to correlate
    serological data with clinical protection,

-   safety and tolerability of pneumococcal conjugate vaccine when
    administered concurrently with other vaccines relevant for age.

> **Schedule of Study Vaccines and Concurrently Administered Vaccines**
>
> Subjects received 0.5 mL intramuscular injections of either PncCRM or
> HBV vaccine at 2, 4, 6 and 12-15 months of age.
>
> Half the children received DTP-HbOC (Tetramune) and half received
> DTP-PRP-T concurrently at 2, 4, 6, and 24 months.
>
> Inactivated polio vaccine (IPV, IMOVAX) and MMR were also administered
> to children as per the schedule below:

Vaccination schedule\--Finnish study

  ---------------- ---------- ------- ------- ------- ------- ------- -------
  Vaccines         Age of                                             
  Administered     child                                              
                   (months)                                           

                   2          4       6       7       12      18      24

  Study vaccine    \+         \+      \+              \+              

  DTP-Hib          \+         \+      \+                              \+

  IPV                                         \+      \+              

  MMR                                                         \+      
  ---------------- ---------- ------- ------- ------- ------- ------- -------

Adapted from Table 9.1.1, page 39 of study report.

Allowable time frames for study vaccine administration---Finnish study

+---------------+---------------------+--------------------------------+
| Scheduled     | Time window,        | Time window,                   |
| visit         |                     |                                |
|               | Age of Child        | Interval after Preceding Study |
| (Months)      |                     | Vaccination                    |
+---------------+---------------------+--------------------------------+
| 2             | 6-13 weeks          |                                |
+---------------+---------------------+--------------------------------+
| 4             | 14-21 weeks         | 6-11 weeks                     |
+---------------+---------------------+--------------------------------+
| 6             | 22-29 weeks         | 6-11 weeks                     |
+---------------+---------------------+--------------------------------+
| 12            | 11-14.9 months      |                                |
+---------------+---------------------+--------------------------------+

Adapted from Table 10.2.2 of the study report.

###  Randomization and Blinding

> Subjects were equally randomized in blocks of twelve into one of six
> treatment groups (groups A-G), and two letter codes were assigned to
> each vaccine (PncCRM, PncOMP, HBV). Clinics received treatment codes
> in blocks of 12 to assure balanced allocation; treatment codes were
> assigned sequentially within each block to subjects at enrollment.
>
> Blinding was maintained through the study period for parents,
> investigators, or to study personnel, except for those administering
> the vaccines. Vaccinators, who were not blinded, were public health
> nurses, not involved in the diagnosis or treatment of AOM.
>
> **Study population**
>
> Children born between August 26, 1995 through March 19, 1997 in 3
> municipalities in southern Finland (Tampere, Nokia, and Kangasala)
> could participate. The total birth cohort in the area was
> approximately 3000 per year. Well baby clinics administer all routine
> childhood vaccination with coverage approaching 100%.
>
> Eligible subjects were in good health as determined by medical
> history, physical examination and clinical judgment. Children were
> excluded from study participation for known or suspected impairment of
> immunologic function, history of invasive pneumococcal disease, prior
> receipt of vaccine for hepatitis B, or any pneumococcal vaccine.
>
> **Note:** Premature infants could be enrolled according to chronologic
> age if they were judged to be in good health.
>
> **Case surveillance and ascertainment**
>
> Parents were encouraged to bring their children to the study clinics
> if the child had respiratory infections or symptoms suggesting AOM.
> Children had free access to the study clinics, which provided both
> well-child care as well as follow-up for AOM. Clinics were open every
> day of the week.
>
> Myringotomy with aspiration of middle ear fluid for culture was done
> if AOM was diagnosed at the visit. If pneumococcus was found, the
> serotype was determined.
>
> **Note:** Guidelines for antibiotic treatment in use in Finland during
> the study were provided upon FDA request. Recommendations for
> prophylactic antibiotics were said to be similar in Finland and in the
> US, as outlined in the 2000 Red Book: Report of the Committee on
> Infectious Diseases American Academy of Pediatrics (Pickering LK, ed.
> 2000 Red Book:*Report of the Committee on Infectious Disease*).
>
> **Definitions of efficacy outcome variables**
>
> **Acute Otitis Media**
>
> Acute otitis media was defined as a visually abnormal tympanic
> membrane (in regard to color, position, and/or mobility) suggesting
> effusion in the middle ear cavity, concomitantly with at least one of
> the following: fever, ear pain, irritability, diarrhea, vomiting,
> acute otorrhea not caused by external otitis, or other symptoms of
> respiratory infection.
>
> **AOM episode**
>
> An episode begins on the day of the clinic visit when the clinical
> diagnosis of AOM is made. A new episode was considered to start if at
> least 30 days had elapsed since the beginning of the previous episode.
>
> **AOM episode due to vaccine serotypes**
>
> AOM due to vaccine serotypes was defined as culture-confirmed
> pneumococcal AOM due to any of the serotypes included in the
> pneumococcal conjugate vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F,
> 24F). A new episode was considered to start if at least 30 days had
> elapsed since the beginning of the previous AOM due to the same
> serotype, or any interval for different vaccine serotypes.
>
> **Note:** If two or more vaccine serotypes were present at the
> beginning of an episode, this was considered to be a single episode
> for this outcome.

####  Culture-confirmed pneumococcal AOM episode

> Culture-confirmed pneumococcal AOM episode was an AOM episode in which
> any pneumococcal serotype was isolated. A new episode began if at
> least 30 days had elapsed since the beginning of the previous
> pneumococcal AOM, irrespective of serotype.
>
> **AOM episode with MEF regardless of etiology**
>
> AOM with MEF was AOM in which at least one MEF sample had been
> obtained. A new episode began if at least 30 days had elapsed since
> the beginning of the previous AOM with MEF, irrespective of findings
> in culture or PCR.
>
> **AOM episode regardless of etiology**
>
> A new episode was considered to start if at least 30 days had elapsed
> since the beginning of the previous AOM, irrespective of existence or
> non-existence of MEF sample.
>
> **Child with recurrent AOM**
>
> A child was considered to have recurrent AOM if he/she was diagnosed
> with 3 or more episodes of AOM in 6 months, or 4 or more episodes in
> 12 months at any time during the follow-up.
>
> **Note:** The definition of recurrent AOM is based on clinical AOM;
> the AOM episodes need not be associated with a middle ear fluid
> isolate of pneumococcus or any bacterial pathogen, but clinical
> episodes must be separated by at least 30 days to contribute to a
> recurrent AOM diagnosis.
>
> **Pneumococcal carriage**
>
> Pneumococcal carriage was assessed for all subjects at 12 and 18
> months based on bacterial culture results from nasopharyngeal swabs,
> and recorded as either present or absent for vaccine serotypes.
>
> **Definition of follow-up periods**
>
> **Per protocol** follow-up started 14 days after the 3^rd^ injection
> of the study vaccine and ended on the day of discontinuation as per
> protocol, or on the day of the close-out visit or the 2^nd^ birthday.
>
> **Intention-to-treat** (sponsor defined) follow-up began on the day
> that the first dose of study vaccine was administered, and ended on
> the day of permanent discontinuation or the 2^nd^ birthday.
>
> **Efficacy outcomes assessed**
>
> **Primary endpoint: All episodes of AOM due to vaccine serotypes**
>
> AOM episodes due to vaccine serotypes was the prospectively defined
> primary endpoint.

**Secondary endpoints: First and subsequent episodes**

> Secondary efficacy endpoints specified in the protocol included first
> and subsequent episodes of AOM.
>
> **Other prospectively defined otitis media endpoints**

-   All episodes AOM by vaccine dose

-   All pneumococcal AOM, regardless of pneumococcal serotype (culture
    and/or PCR confirmed)

-   All AOM episodes with MEF, regardless of etiology

-   All AOM episodes regardless of etiology

-   Children with recurrent AOM

-   Efficacy for all specified AOM endpoints under intent-to-treat

-   Pneumococcal carriage

-   Antibody response to pneumococcal conjugate vaccine;

> Geometric mean concentration (GMC) of serum antibodies as determined
> by ELISA, and percent of subjects exceeding antibody concentration
> cut-off levels of 0.3 mcg/mL, 0.5 mcg/mL, and 1.0 mcg/mL were
> provided.

##### Analysis plan

> Intent-to-treat analyses were provided in the study report only for
> the primary analysis (episodes due to vaccine serotypes), and for the
> analysis of efficacy by dose. It was expected that per protocol and
> intent-to-treat analyses would yield similar results because it was
> anticipated that few subjects would be lost to follow-up.
> Intent-to-treat analyses for other endpoints were provided upon FDA
> request during the review period.
>
> No interim analyses were planned or conducted.

**Primary endpoint: AOM episodes due to vaccine serotypes**

Vaccine efficacy for the primary endpoint was estimated by a generalized
Cox regression model (Anderson and Gill,1982), as was specified
prospectively in the analysis plan. As it was applied here, this model
provides an average vaccine effect on all AOM episodes (first and
subsequent) where treatment (vaccinated, unvaccinated) is the only
covariate. An underlying assumption of this model is that relative
hazard of episodes be proportional over time for two treatment groups.
Vaccine efficacy was calculated as 1- R, where R is the hazards ratio
estimated from the Cox model.

That repeated episodes of AOM within the same individual would not be
independent events was recognized in the analysis plan. The risk of AOM
was therefore estimated "piecewise", i.e., from event to event. The
analysis plan also states that dependence due to recurrences was taken
into account by estimating robust standard errors for the hazard
regression parameters. The proportionality of hazards over time was
checked by graphing cumulative hazard over time for each treatment
group.

> **Secondary endpoints: First and subsequent episodes**
>
> If the vaccine effect on all episodes is significant, the time to
> first AOM episode due to vaccine serotype is also expected to be
> significant. To distinguish between the effect of vaccination on first
> and subsequent episodes, a recurrent event proportional hazards model
> (Eerola M,1989) was used. The increasing or decreasing effect of
> vaccination on subsequent episodes compared to the first episodes is
> given by an interaction parameter between an indicator of the time of
> the first AOM episode and the treatment covariate.
>
> **Other prospectively defined AOM outcomes**
>
> The Anderson-Gill model was also used for other endpoints where the
> hazard of all episodes is considered regardless of the episodes being
> first or subsequent.
>
> **Recurrent otitis media**
>
> The number of children with recurrent AOM was compared between
> treatment groups by chi-square test.
>
> **Dose timing and follow-up**
>
> The vaccine effect for the period after each dose until the next dose
> in the series was estimated using a person-time nonparametric relative
> risk estimator.
>
> **Immunogenicity**
>
> A special serology cohort comprised all children enrolled at one
> (Kangasala) clinic. Follow-up started on the day of enrollment.
>
> Geometric mean concentrations (GMC) of serum antibody were presented
> with 95% confidence intervals. Reverse cumulative distributions of
> antibody concentrations at each time point were also presented.
>
> No adjustments for covariates were made. The immunogenicity
> evaluations were considered exploratory.
>
> **Carriage of pneumococci in the nasopharynx**
>
> The difference in relative frequencies of carriers of vaccine
> serotypes between treatment groups as measured at 12 and 18 months
> were tested by the chi square test.

# 4.1.2 Finnish otitis media study efficacy results

> Efficacy results from the Finnish study as presented in the initial
> BLA amendment submission, some of which were published (Eskola et al.,
> 2001), are shown in the tables that follow immediately below.
> Supplementary analyses performed in response to issues raised during
> the FDA review are presented and discussed subsequently.
>
> **Population characteristics**
>
> Information was collected for demographic variables and some
> characteristics associated with increased risk of AOM.

Small imbalances between treatment groups at study entry are apparent
for premature gestational age (\< 37 weeks), low birth weight (\<2500
grams), and history of AOM episodes prior to first vaccine dose. Each of
these characteristics are risk factors for AOM that, due to the observed
imbalance, would be expected to increase the risk for AOM in the control
group, and thus could be a source of potential bias toward a PncCRM
treatment effect.

Information about breastfeeding and cigarette smoking in the households
was collected during the course of the study. Little difference between
rates of breastfeeding and household smoking between treatment groups
was observed.

Population characteristics---Finnish study

  ------------------ ------------ --------- ---------- --------- ----------
                                  HBV       (%)        PncCRM    (%)

  Gender             Female       403       (48.5)     396       (47.7)

                     Male         428       (51.5)     435       (52.3)

  Gestational Age    \< 37 weeks  53        (6.4)      41        (4.9)

                     ≥ 37 weeks   778       (93.6)     790       (95.1)

  Birth weight       \< 2.5 kg    42        (5.1)      25        (3.0)

                     ≥ 2.5 kg     789       (94.9)     806       (97.0)

  No. of siblings    Mean         0.7                  0.7       

  Subjects with                   39        (4.7)      27        (3.2)
  prior episodes of                                              
  AOM                                                            

  Middle ear         None         804       (96.8)     804       (96.8)
  effusion at                                                    
  enrollment                                                     

                     Unilateral   16        (1.9)      22        (2.6)

                     Bilateral    10        (1.2)      3         (0.4)

                     No           1         (0.1)      2         (0.2)
                     visibility                                  

                     Total        831       \(100\)    831       \(100\)

  Breast Feeding at               441       (53.1)     444       (53.4)
  least 6 months                                                 

  Smoking within                  16        (1.9)      18        (2.2)
  Family reported at                                             
  least once                                                     
  ------------------ ------------ --------- ---------- --------- ----------

Adapted from Tables 11.1.1 and 11.1.3, Volume 2 of BLA.

**Primary analysis: AOM episodes caused by vaccine serotypes**

In the protocol defined primary analysis, AOM episodes due to vaccine
serotypes observed during per protocol follow-up, the vaccine efficacy
estimate was 57% (95%CI: 44%-67%). Results of the intent-to-treat
analysis were consistent with results of the per protocol analysis.

# Primary analysis, AOM episodes due to vaccine serotypes---Finnish study

+---------+--------+-----+------+-------+-------+--------+---------+
|         | Fol    | Num |      | R     |       | V      |         |
|         | low-up | ber |      | ate/p |       | accine |         |
|         | Period | of  |      | erson |       | Ef     |         |
|         |        | Ep  |      | year  |       | ficacy |         |
|         |        | iso |      |       |       |        |         |
|         |        | des |      |       |       |        |         |
+=========+========+=====+======+=======+=======+========+=========+
|         |        | HBV | #    | ####  | P     | ####   | (95%    |
|         |        |     | #### | # HBV | ncCRM | ### Es | CI)     |
|         |        |     | # Pn |       |       | timate |         |
|         |        |     | cCRM |       |       |        |         |
+---------+--------+-----+------+-------+-------+--------+---------+
| AOM due | ##     | 250 | 107  | 0.21  | 0.09  | 0.57   | (0.44,  |
| to      | Per Pr |     |      |       |       |        | 0.67)   |
| vaccine | otocol |     |      |       |       |        |         |
| se      |        |     |      |       |       |        |         |
| rotypes |        |     |      |       |       |        |         |
+---------+--------+-----+------+-------+-------+--------+---------+
|         | Int    | 292 | 135  | 0.20  | 0.09  | 0.54   | (0.41,  |
|         | ent-to |     |      |       |       |        | 0.64)   |
|         | -treat |     |      |       |       |        |         |
+---------+--------+-----+------+-------+-------+--------+---------+

#### Adapted from Table 11.1.5, p 83, Volume 2 of BLA.

# 

# Secondary analyses

> The table below summarizes results of analyses of secondary and other
> prospectively defined study endpoints.

Secondary analyses---Finnish study

+-----------+------+-----+------+------+-------+--------+---------+
|           | F    | Num |      | Rat  |       | V      |         |
|           | ollo | ber |      | e/pe |       | accine |         |
|           | w-up | of  |      | rson |       | Ef     |         |
|           | Pe   | Ep  |      | year |       | ficacy |         |
|           | riod | iso |      |      |       |        |         |
|           |      | des |      |      |       |        |         |
+===========+======+=====+======+======+=======+========+=========+
|           |      | HBV | #    | #    | P     | ####   | (95%    |
|           |      |     | #### | #### | ncCRM | ### Es | CI)     |
|           |      |     | # Pn |  HBV |       | timate |         |
|           |      |     | cCRM |      |       |        |         |
+-----------+------+-----+------+------+-------+--------+---------+
| First AOM | #    | 177 | 89   | 0    | 0.081 | 0.52   | (0.39,  |
| Episode   | # PP |     |      | .171 |       |        | 0.63)   |
| due to    |      |     |      |      |       |        |         |
| Vaccine   |      |     |      |      |       |        |         |
| Serotype  |      |     |      |      |       |        |         |
+-----------+------+-----+------+------+-------+--------+---------+
|           | ITT  | 196 | 109  | 0    | 0.079 | 0.48   | (0.34,  |
|           |      |     |      | .152 |       |        | 0.59)   |
+-----------+------+-----+------+------+-------+--------+---------+
| S         | #    | 73  | 18   | 0    | 0.249 | 0.45   | (0.05,  |
| ubsequent | # PP |     |      | .467 |       |        | 0.69)   |
| AOM       |      |     |      |      |       |        |         |
| Episode   |      |     |      |      |       |        |         |
| due to    |      |     |      |      |       |        |         |
| Vaccine   |      |     |      |      |       |        |         |
| Serotype  |      |     |      |      |       |        |         |
+-----------+------+-----+------+------+-------+--------+---------+
|           | ITT  | 96  | 26   | 0    | 0.250 | 0.49   | (0.20,  |
|           |      |     |      | .491 |       |        | 0.67)   |
+-----------+------+-----+------+------+-------+--------+---------+

Adpated from Table 11.1.6, page 85, Volume 2 of BLA, and Table Q1.1 of
January 10, 2002 submission to BLA.

> In the primary analysis of efficacy for vaccine serotypes, most of the
> vaccine serotype AOM episodes were observed as first episodes. First
> AOM episode due to vaccine serotypes accounted for 83% (89/107) of AOM
> episodes in the PncCRM group, and 71% (177/250) of all vaccine type
> AOM episodes in the HBV group.
>
> Efficacy estimates for prevention of both first (52%) and subsequent
> (45%) AOM episodes were statistical significance in the per protocol
> analysis. Results of the intent-to-treat analyses, provided upon FDA
> request during the review period, were consistent with the per
> protocol analysis.

**Other prospectively specified analyses**

> The efficacy estimate for culture-confirmed pneumococcal AOM,
> regardless of serotype, was 34% in the per protocol analysis; this was
> statistically significant. Efficacy estimates for prevention of AOM
> with middle ear effusion, and all cause AOM episodes did not attain
> statistical significance (95% confidence interval includes 0).
>
> Intent-to-treat analyses were large consistent with the per protocol
> analyses for these outcomes.

Other prospectively specified analyses---Finnish study

+-----------+------+-----+------+------+-------+--------+---------+
|           | F    | Num |      | Rat  |       | V      |         |
|           | ollo | ber |      | e/pe |       | accine |         |
|           | w-up | of  |      | rson |       | Ef     |         |
|           | Pe   | Ep  |      | year |       | ficacy |         |
|           | riod | iso |      |      |       |        |         |
|           |      | des |      |      |       |        |         |
+===========+======+=====+======+======+=======+========+=========+
|           |      | HBV | #    | #    | P     | ####   | (95%    |
|           |      |     | #### | #### | ncCRM | ### Es | CI)     |
|           |      |     | # Pn |  HBV |       | timate |         |
|           |      |     | cCRM |      |       |        |         |
+-----------+------+-----+------+------+-------+--------+---------+
| Culture-  | #    | 414 | 271  | 0.36 | 0.23  | 0.34   | (0.21,  |
| confirmed | # PP |     |      |      |       |        | 0.45)   |
| pne       |      |     |      |      |       |        |         |
| umococcal |      |     |      |      |       |        |         |
| AOM       |      |     |      |      |       |        |         |
+-----------+------+-----+------+------+-------+--------+---------+
|           | ITT  | 467 | 322  | 0.32 | 0.22  | 0.32   | (0.19,  |
|           |      |     |      |      |       |        | 0.42)   |
+-----------+------+-----+------+------+-------+--------+---------+
| ####      | #    | 1   | 1177 | 1.16 | 1.09  | 0.07   | (-0.05, |
| #### AOM  | # PP | 267 |      |      |       |        | 0.17)   |
| with MEF  |      |     |      |      |       |        |         |
+-----------+------+-----+------+------+-------+--------+---------+
|           | ITT  | 1   | 1390 | 1.06 | 1.01  | 0.04   | (-0.07, |
|           |      | 445 |      |      |       |        | 0.14)   |
+-----------+------+-----+------+------+-------+--------+---------+
| AOM       | #    | 1   | 1251 | 1.24 | 1.16  | 0.06   | (-0.04, |
| r         | # PP | 345 |      |      |       |        | 0.16)   |
| egardless |      |     |      |      |       |        |         |
| of        |      |     |      |      |       |        |         |
| etiology  |      |     |      |      |       |        |         |
+-----------+------+-----+------+------+-------+--------+---------+
|           | ITT  | 1   | 1474 | 1.13 | 1.08  | 0.04   | (-0.07, |
|           |      | 532 |      |      |       |        | 0.14)   |
+-----------+------+-----+------+------+-------+--------+---------+

Adapted from Table 11.1.5, page 83, Volume 2 of BLA, and Table Q1.1 of
January 10, 2002 submission to BLA.

> **Note:** Analysis of all pneumococcal AOM as determined by culture or
> PCR analyses of middle ear fluids was also prospectively specified in
> the analysis plan. However, the PCR data were not available at the
> time of the initial amendment submission. These supplemental analyses
> were provided upon FDA request during the review period (see below).

**Efficacy by dose**

> Vaccine efficacy by dose was also analyzed for AOM episodes due to
> vaccine serotypes under a modified intent-to-treat analysis. Efficacy
> estimates after dose 3 (57%) and after dose 4 (55%) were of similar
> magnitude, and both were statistically significant.

Vaccine efficacy by dose against AOM episodes due to vaccine serotypes
(ITT)---Finnish study

+--------------+-------+-------+-------+-------+---------+---------+
|              | N     |       | R     |       | Vaccine |         |
|              | umber |       | ate/p |       | E       |         |
|              | of    |       | erson |       | fficacy |         |
|              | Epi   |       | year  |       |         |         |
|              | sodes |       |       |       |         |         |
+==============+=======+=======+=======+=======+=========+=========+
|              | HBV   | ###   | ####  | P     | ##      | 95% CI  |
|              |       | ### P | # HBV | ncCRM | ##### E |         |
|              |       | ncCRM |       |       | stimate |         |
+--------------+-------+-------+-------+-------+---------+---------+
| ## Dose 1    | 14    | ####  | ##### | 0.11  | #####   | -0.74,  |
|              |       | ## 11 |  0.09 |       | ## 0.22 | 0.65    |
| (2 to 4      |       |       |       |       |         |         |
| months)      |       |       |       |       |         |         |
+--------------+-------+-------+-------+-------+---------+---------+
| ## Dose 2    | 24    | ####  | ##### | 0.10  | #####   | -0.04,  |
|              |       | ## 13 |  0.19 |       | ## 0.46 | 0.72    |
| (4 to 6      |       |       |       |       |         |         |
| months)      |       |       |       |       |         |         |
+--------------+-------+-------+-------+-------+---------+---------+
| ## Dose 3    | 93    | ####  | ##### | 0.10  | #####   | 0.36,   |
|              |       | ## 40 |  0.24 |       | ## 0.57 | 0.71    |
| (6 to 12     |       |       |       |       |         |         |
| months)      |       |       |       |       |         |         |
+--------------+-------+-------+-------+-------+---------+---------+
| ## Dose 4    | 159   | ####  | ##### | 0.09  | #####   | 0.39,   |
|              |       | ## 71 |  0.20 |       | ## 0.55 | 0.67    |
| (12 to 24    |       |       |       |       |         |         |
| months)      |       |       |       |       |         |         |
+--------------+-------+-------+-------+-------+---------+---------+

Reproduced from Table 11.1.7, Volume 2 of BLA.

**Vaccine efficacy by serotype**

> The contribution of each vaccine serotype to efficacy as measured by
> the primary endpoint is shown in the table below. Results of the
> intent-to-treat analyses were provided upon FDA request during the
> review period.

Efficacy Results of Individual Vaccine Serotypes---Finnish study

+--------+-------+------+-------+-------+-------+-------+----------+
| ## AOM | Foll  | Nu   |       | Rat   |       | Va    |          |
|  Episo | ow-up | mber |       | e/100 |       | ccine |          |
| de due | P     | of   |       | p     |       | Eff   |          |
|  to Se | eriod | Epis |       | erson |       | icacy |          |
| rotype |       | odes |       | year  |       |       |          |
+========+=======+======+=======+=======+=======+=======+==========+
|        |       | HBV  | ###   | ####  | P     | #     | 95%CI    |
|        |       |      | ### P | # HBV | ncCRM | ##### |          |
|        |       |      | ncCRM |       |       | # Est |          |
|        |       |      |       |       |       | imate |          |
+--------+-------+------+-------+-------+-------+-------+----------+
| 4      | ## PP | 4    | 2     | 0.34  | 0.17  | 0.49  | (-1.76,  |
|        |       |      |       |       |       |       | 0.91)    |
+--------+-------+------+-------+-------+-------+-------+----------+
|        | ITT   | 4    | 2     | 0.27  | 0.13  | 0.50  | (-1.72,  |
|        |       |      |       |       |       |       | 0.91)    |
+--------+-------+------+-------+-------+-------+-------+----------+
| 6B     | ## PP | 56   | 9     | 4.71  | 0.76  | 0.84  | (0.62,   |
|        |       |      |       |       |       |       | 0.93)    |
+--------+-------+------+-------+-------+-------+-------+----------+
|        | ITT   | 61   | 12    | 4.12  | 0.81  | 0.80  | (0.60,   |
|        |       |      |       |       |       |       | 0.90)    |
+--------+-------+------+-------+-------+-------+-------+----------+
| #####  | ## PP | 11   | 5     | 0.92  | 0.42  | 0.54  | (-0.48,  |
| ### 9V |       |      |       |       |       |       | 0.86)    |
+--------+-------+------+-------+-------+-------+-------+----------+
|        | ITT   | 11   | 6     | 0.74  | 0.40  | 0.45  | (-0.66,  |
|        |       |      |       |       |       |       | 0.82)    |
+--------+-------+------+-------+-------+-------+-------+----------+
| 14     | ## PP | 26   | 8     | 2.18  | 0.68  | 0.69  | (0.20,   |
|        |       |      |       |       |       |       | 0.88)    |
+--------+-------+------+-------+-------+-------+-------+----------+
|        | ITT   | 31   | 8     | 2.09  | 0.54  | 0.74  | (0.34,   |
|        |       |      |       |       |       |       | 0.90)    |
+--------+-------+------+-------+-------+-------+-------+----------+
| 18C    | ## PP | 17   | 7     | 1.43  | 0.59  | 0.58  | (-0.04,  |
|        |       |      |       |       |       |       | 0.83)    |
+--------+-------+------+-------+-------+-------+-------+----------+
|        | ITT   | 18   | 7     | 1.21  | 0.47  | 0.61  | (0.02,   |
|        |       |      |       |       |       |       | 0.85)    |
+--------+-------+------+-------+-------+-------+-------+----------+
| 19F    | ## PP | 58   | 43    | 4.88  | 3.66  | 0.25  | (-0.14,  |
|        |       |      |       |       |       |       | 0.51)    |
+--------+-------+------+-------+-------+-------+-------+----------+
|        | ITT   | 67   | 60    | 4.53  | 4.06  | 0.10  | (-0.32,  |
|        |       |      |       |       |       |       | 0.39)    |
+--------+-------+------+-------+-------+-------+-------+----------+
| 23F    | ## PP | 82   | 33    | 6.91  | 2.81  | 0.59  | (0.35,   |
|        |       |      |       |       |       |       | 0.75)    |
+--------+-------+------+-------+-------+-------+-------+----------+
|        | ITT   | 104  | 40    | 7.04  | 2.70  | 0.62  | (0.41,   |
|        |       |      |       |       |       |       | 0.75)    |
+--------+-------+------+-------+-------+-------+-------+----------+

Adapted from Table 11.1.10, page 90, Volume 2 of BLA, and Table Q1.2 of
January 10, 2002 submission to BLA.

> The 3 most common vaccine serotypes associated with AOM were serotypes
> 23F, 19F, 6B, and 14. Vaccine efficacy estimates under the per
> protocol analysis ranged from 84% for serotype 6B, to 25% for serotype
> 19F. Statistical significance for vaccine efficacy was demonstrated
> for individual serotypes 6B, 14, and 23F. Efficacy estimates under
> intent-to-treat and per protocol analyses were largely consistent,
> with higher estimates for some of the serotypes under intent-to-treat.
> The greatest difference between PP and ITT analyses was for type 19F
> (25% vs. 10%).
>
> Efficacy of PncCRM in preventing episodes of pneumococcal serotypes
> belonging to the same serogroups as vaccine serotypes was also
> analyzed. Results of analyses of efficacy for these vaccine related
> serotypes are shown below.

Efficacy for serotypes related to vaccine serotypes---Finnish study

+--------+-------+------+-------+-------+-------+-------+----------+
| ## AOM | Foll  | Nu   |       | Rat   |       | Va    |          |
|  Episo | ow-up | mber |       | e/100 |       | ccine |          |
| de due | P     | of   |       | p     |       | Eff   |          |
|  to Se | eriod | Epis |       | erson |       | icacy |          |
| rotype |       | odes |       | year  |       |       |          |
+========+=======+======+=======+=======+=======+=======+==========+
|        |       | HBV  | ###   | ####  | P     | #     | 95%CI    |
|        |       |      | ### P | # HBV | ncCRM | ##### |          |
|        |       |      | ncCRM |       |       | # Est |          |
|        |       |      |       |       |       | imate |          |
+--------+-------+------+-------+-------+-------+-------+----------+
| #####  | ## PP | 45   | 19    | 3.78  | 1.61  | 0.57  | (0.24,   |
| ### 6A |       |      |       |       |       |       | 0.76)    |
+--------+-------+------+-------+-------+-------+-------+----------+
|        | ITT   | 48   | 23    | 3.24  | 1.55  | 0.52  | (0.17,   |
|        |       |      |       |       |       |       | 0.72)    |
+--------+-------+------+-------+-------+-------+-------+----------+
| 9N     | ## PP | 8    | 2     | 0.67  | 0.17  | 0.75  | (-0.24,  |
|        |       |      |       |       |       |       | 0.95)    |
+--------+-------+------+-------+-------+-------+-------+----------+
|        | ITT   | 9    | 2     | 0.61  | 0.13  | 0.78  | (-0.06,  |
|        |       |      |       |       |       |       | 0.95)    |
+--------+-------+------+-------+-------+-------+-------+----------+
| 18B    | ## PP | 1    | 2     | 0.08  | 0.17  | -1.03 | (-21.30, |
|        |       |      |       |       |       |       | 0.82)    |
+--------+-------+------+-------+-------+-------+-------+----------+
|        | ITT   | 1    | 2     | 0.07  | 0.13  | -1.01 | (-21.08, |
|        |       |      |       |       |       |       | 0.82)    |
+--------+-------+------+-------+-------+-------+-------+----------+
| 19A    | ## PP | 26   | 17    | 2.18  | 1.44  | 0.34  | (-0.26,  |
|        |       |      |       |       |       |       | 0.65)    |
+--------+-------+------+-------+-------+-------+-------+----------+
|        | ITT   | 28   | 22    | 1.89  | 1.48  | 0.21  | (-0.40,  |
|        |       |      |       |       |       |       | 0.56)    |
+--------+-------+------+-------+-------+-------+-------+----------+
| 23A    | ## PP | 4    | 1     | 0.34  | 0.08  | 0.75  | (-1.51,  |
|        |       |      |       |       |       |       | 0.97)    |
+--------+-------+------+-------+-------+-------+-------+----------+
|        | ITT   | 4    | 1     | 0.27  | 0.07  | 0.75  | (-1.49,  |
|        |       |      |       |       |       |       | 0.97)    |
+--------+-------+------+-------+-------+-------+-------+----------+

Adapted from Table 11.1.10 of BLA and Table Q1.2 of January 10, 2002
submission to BLA.

> Serotype 6A, although not a vaccine serotype, was associated with a
> substantial number of cases, and the efficacy estimate for type 6A was
> statistically significant. Statistically significant demonstration of
> efficacy was not observed for any of the other individual
> vaccine-related serotypes, but few episodes of AOM due to the vaccine
> associated serotypes 9N, 18B, and 23A were observed.
>
> Interestingly, the efficacy estimates for the related serotype 19A,
> although not statistically significant, exceeded that of the vaccine
> serotype 19F.
>
> Taken together, the vaccine-related serotypes contributed to a
> significant treatment effect, as shown in the table below.

**AOM caused by non-vaccine, but vaccine-related serotypes---Finnish
study**

+---------+--------+-----+------+-------+-------+--------+---------+
|         | Fol    | Num |      | R     |       | V      |         |
|         | low-up | ber |      | ate/p |       | accine |         |
|         | Period | of  |      | erson |       | Ef     |         |
|         |        | Ep  |      | year  |       | ficacy |         |
|         |        | iso |      |       |       |        |         |
|         |        | des |      |       |       |        |         |
+=========+========+=====+======+=======+=======+========+=========+
|         |        | HBV | #    | ####  | P     | ####   | (95%    |
|         |        |     | #### | # HBV | ncCRM | ### Es | CI)     |
|         |        |     | # Pn |       |       | timate |         |
|         |        |     | cCRM |       |       |        |         |
+---------+--------+-----+------+-------+-------+--------+---------+
| ## A    | ## PP  | 84  | 41   | 0.070 | 0.035 | 0.51   | (0.27,  |
| OM due  |        |     |      |       |       |        | 0.67)   |
| to vacc |        |     |      |       |       |        |         |
| ine-rel |        |     |      |       |       |        |         |
| ated se |        |     |      |       |       |        |         |
| rotypes |        |     |      |       |       |        |         |
+---------+--------+-----+------+-------+-------+--------+---------+
|         | ITT    | 90  | 50   | 0.061 | 0.034 | 0.44   | (0.20,  |
|         |        |     |      |       |       |        | 0.62)   |
+---------+--------+-----+------+-------+-------+--------+---------+

Adapted from Table Q1.1 of January 10, 2002 submission to BLA.

> As was shown above, the efficacy estimate for all pneumococcal AOM
> episodes regardless of serotype was 34% (95%CI 21, 45) in the per
> protocol analysis. As would be expected, this estimate is lower than
> the efficacy estimates for vaccine serotypes, and vaccine-related
> serotypes; one would not anticipate comparable or added efficacy by
> inclusion of the unrelated pneumococcal serotypes in the analysis.
> When analyzed together, the pneumococcal serotypes unrelated to
> vaccine serotypes actually contributed to statistically significant
> negative vaccine efficacy estimates in both the per protocol \[-0.34,
> (95%CI --0.81, 0.0) and ITT \[-0.39 (95%CI: -0.86, -0.03)\] analyses.

**AOM caused by pneumococcal serotypes other than vaccine or
vaccine-related serotypes---Finnish study**

+-----------+-------+-----+------+-------+-------+--------+---------+
|           | Foll  | Num |      | R     |       | V      |         |
|           | ow-up | ber |      | ate/p |       | accine |         |
|           | P     | of  |      | erson |       | Ef     |         |
|           | eriod | Ep  |      | year  |       | ficacy |         |
|           |       | iso |      |       |       |        |         |
|           |       | des |      |       |       |        |         |
+===========+=======+=====+======+=======+=======+========+=========+
|           |       | HBV | #    | ####  | P     | ####   | (95%    |
|           |       |     | #### | # HBV | ncCRM | ### Es | CI)     |
|           |       |     | # Pn |       |       | timate |         |
|           |       |     | cCRM |       |       |        |         |
+-----------+-------+-----+------+-------+-------+--------+---------+
| ## AO     | ## PP | 95  | 126  | 0.080 | 0.107 | -0.34  | (-0.81, |
| M due to  |       |     |      |       |       |        | 0.00)   |
| other tha |       |     |      |       |       |        |         |
| n vaccine |       |     |      |       |       |        |         |
|  related  |       |     |      |       |       |        |         |
| serotypes |       |     |      |       |       |        |         |
+-----------+-------+-----+------+-------+-------+--------+---------+
|           | ITT   | 101 | 140  | 0.068 | 0.094 | -0.39  | (-0.86, |
|           |       |     |      |       |       |        | -0.03)  |
+-----------+-------+-----+------+-------+-------+--------+---------+

Adapted from Table Q1.1 of January 10, 2002 submission to BLA.

The most common vaccine-unrelated pneumococcal serotypes isolated from
middle ear fluids were from serogroups 3, 11, 15, and 35. All 7 isolates
of serogroup 33 were from the PncCRM group. Efficacy estimates for the
individual vaccine-unrelated serotypes are summarized below:

AOM due to vaccine-unrelated serotypes---Finnish study

+---------------------+-----------+-----------+-----------+-----------+
| Serotype/Serogroup  | Number of |           | Rate/100  |           |
|                     | Episodes  |           | person    |           |
|                     |           |           | year      |           |
+=====================+===========+===========+===========+===========+
|                     | HBV       | ####      | ##### HBV | PncCRM    |
|                     |           | ## PncCRM |           |           |
+---------------------+-----------+-----------+-----------+-----------+
| ## 3                | 15        | 17        | 1.01      | 1.15      |
+---------------------+-----------+-----------+-----------+-----------+
| ## 7^∗^             | 3         | 4         | 0.20      | 0.27      |
+---------------------+-----------+-----------+-----------+-----------+
| ## 10^∗^            | 6         | 3         | 0.40      | 0.20      |
+---------------------+-----------+-----------+-----------+-----------+
| ## 11^∗^            | 25        | 34        | 1.68      | 2.29      |
+---------------------+-----------+-----------+-----------+-----------+
| ## 12^∗^            | 0         | 1         | 0.00      | 0.07      |
+---------------------+-----------+-----------+-----------+-----------+
| ## 15^∗^            | 25        | 28        | 1.68      | 1.89      |
+---------------------+-----------+-----------+-----------+-----------+
| ## 16^∗^            | 3         | 5         | 0.20      | 0.34      |
+---------------------+-----------+-----------+-----------+-----------+
| ## 22^∗^            | 7         | 8         | 0.47      | 0.54      |
+---------------------+-----------+-----------+-----------+-----------+
| ## 28^∗^            | 0         | 1         | 0.00      | 0.07      |
+---------------------+-----------+-----------+-----------+-----------+
| ## 33^∗^            | 0         | 7         | 0.00      | 0.47      |
+---------------------+-----------+-----------+-----------+-----------+
| ## 34               | 2         | 0         | 0.13      | 0.00      |
+---------------------+-----------+-----------+-----------+-----------+
| ## 35^∗^            | 10        | 15        | 0.67      | 1.01      |
+---------------------+-----------+-----------+-----------+-----------+
| ## 38               | 3         | 7         | 0.20      | 0.47      |
+---------------------+-----------+-----------+-----------+-----------+
| ## Pool G^∗∗^       | 1         | 2         | 0.07      | 0.13      |
+---------------------+-----------+-----------+-----------+-----------+
| ## Rough            | 2         | 7         | 0.13      | 0.47      |
+---------------------+-----------+-----------+-----------+-----------+

Adapted from table 14.2.2, page 124, Volume 2 of BLA.

^∗^ Typing to serogroup level only;

^∗∗^ Pool G consists of serogroups/types 29, 34, 35, 42, 47

**Children with recurrent AOM**

> The efficacy estimate for percent reduction in the number of children
> who met a definition of recurrent AOM (3 episodes/6 months or 4
> episodes/12 months) was 16% in the per protocol analysis, and 9% in
> the intent-to-treat analysis. Neither estimate was statistically
> significant.

# Children with Recurrent Acute Otitis Media (all causes)--- Finnish study 

+---------+--------+-----+------+-------+-------+--------+---------+
|         | Fol    | Num |      | R     |       | V      |         |
|         | low-up | ber |      | ate/p |       | accine |         |
|         | Period | of  |      | erson |       | Ef     |         |
|         |        | Ep  |      | year  |       | ficacy |         |
|         |        | iso |      |       |       |        |         |
|         |        | des |      |       |       |        |         |
+=========+========+=====+======+=======+=======+========+=========+
|         |        | HBV | #    | ####  | P     | ####   | (95%    |
|         |        |     | #### | # HBV | ncCRM | ### Es | CI)     |
|         |        |     | # Pn |       |       | timate |         |
|         |        |     | cCRM |       |       |        |         |
+---------+--------+-----+------+-------+-------+--------+---------+
| ##      | PP     | 149 | ##   | #     | 0.104 | ###### | (-0.06, |
|  Childr |        |     | #### | ####  |       | # 0.16 | 0.35)   |
| en with |        |     |  123 | 0.125 |       |        |         |
|  Recurr |        |     |      |       |       |        |         |
| ent AOM |        |     |      |       |       |        |         |
+---------+--------+-----+------+-------+-------+--------+---------+
|         | ITT    | 174 | ##   | #     | 0.106 | ###### | (-0.12, |
|         |        |     | #### | ####  |       | # 0.09 | 0.27)   |
|         |        |     |  158 | 0.117 |       |        |         |
+---------+--------+-----+------+-------+-------+--------+---------+

Adapted from Table Q3.1 of January 10, 2002 submission to BLA.

**Nasopharyngeal carriage**

At 12 months of age, the carriage rate of vaccine serotype pneumococci
was 10% in the PncCRM group vs. 12% in the HBV group. This difference
was not statistically significant.

At 18 months, the carriage rate for vaccine serotypes was 10% in the
PncCRM group vs. 16% in the HBV group. This difference was statistically
significant.

Analyses of carriage by individual serotypes, and for carriage of
non-vaccine pneumococcal serotypes, were not provided with the
application.

**Nasopharyngeal carriage of vaccine serotypes, per protocol**

**---Finnish study**

  ------- ---------- -------- ---------- -------- ---------- -------- ------------ --------
          No.                 No.                 \%                  Difference   
          Children            Carriers            Carriage            of %         

          HBV        PncCRM   HBV        PncCRM   HBV        PncCRM   Estimate     95% CI

  12 mos  809        801      99         81       12.2       10.1     2.1          -1.1,
                                                                                   5.3

  18 mos  797        787      129        75       16.2       9.5      6.7          3.3,
                                                                                   10.1
  ------- ---------- -------- ---------- -------- ---------- -------- ------------ --------

Adapted from Table 11.1.9, page 89, Volume 2 of BLA.

# Serological responses

# 

> A special serology cohort was comprised of children enrolled at one of
> the 3 centers, the Kangasala clinic, and consisted of 115 children, 58
> in the HBV group and 57 in the PncCRM group. Of these children, 111
> (96.5%) completed the study, and 94 (81.7%) had a full series of blood
> samples drawn. All children in the immunogenicity study received
> DTP-HbOC as their DTP-Hib vaccine.
>
> The serology cohorts for the two treatment groups were well-balanced
> for gender, gestational age, birth weight, number of siblings, and
> maternal education.
>
> The geometric mean concentration (GMC) of serum antibody to
> type-specific pneumococcal polysaccharides as determined in ELISA
> assays are summarized below.

**Geometric mean concentration (mcg/mL) of pneumococcal antibodies
following the 3^rd^** dose---Finnish study

+--------+-------------+---------------+-------------+----------------+
| Se     | HBV         |               | PncCRM      |                |
| rotype |             |               |             |                |
|        | N=52        |               | N=54        |                |
+--------+-------------+---------------+-------------+----------------+
|        | GMC         | 95% CI        | GMC         | 95% CI         |
+--------+-------------+---------------+-------------+----------------+
| 4      | 0.05        | 0.04, 0.07    | 1.70        | 1.32, 2.20     |
+--------+-------------+---------------+-------------+----------------+
| 6B     | 0.09        | 0.07, 0.13    | 2.00        | 1.35, 2.96     |
+--------+-------------+---------------+-------------+----------------+
| 9V     | 0.10        | 0.07, 0.13    | 2.48        | 1.97, 3.11     |
+--------+-------------+---------------+-------------+----------------+
| 14     | 0.21        | 0.16, 0.27    | 6.28        | 4.78, 8.23     |
+--------+-------------+---------------+-------------+----------------+
| 18C    | 0.08        | 0.06, 0.11    | 3.55        | 2.80, 4.49     |
+--------+-------------+---------------+-------------+----------------+
| 19F    | 0.22        | 0.16, 0.29    | 3.28        | 2.57, 4.18     |
+--------+-------------+---------------+-------------+----------------+
| 23F    | 0.10        | 0.07, 0.12    | 2.51        | 1.84, 3.43     |
+--------+-------------+---------------+-------------+----------------+

Adapted from Tables 11.2.1 page 95, Volume 2 of BLA.

Geometric mean concentration (mcg/mL) of pneumococcal antibodies
following the 4th dose---Finnish study

+--------+-------------+---------------+-------------+----------------+
| Se     | HBV         |               | PncCRM      |                |
| rotype |             |               |             |                |
|        | N=54        |               | N=55        |                |
+--------+-------------+---------------+-------------+----------------+
|        | GMC         | 95% CI        | GMC         | 95% CI         |
+--------+-------------+---------------+-------------+----------------+
| 4      | 0.11        | 0.08, 0.14    | 2.56        | 2.00, 3.28     |
+--------+-------------+---------------+-------------+----------------+
| 6B     | 0.16        | 0.12, 0.20    | 9.05        | 6.50, 12.59    |
+--------+-------------+---------------+-------------+----------------+
| 9V     | 0.21        | 0.16, 0.27    | 3.97        | 3.20, 4.91     |
+--------+-------------+---------------+-------------+----------------+
| 14     | 0.21        | 0.17, 0.27    | 10.82       | 8.30, 14.09    |
+--------+-------------+---------------+-------------+----------------+
| 18C    | 0.10        | 0.08, 0.13    | 6.51        | 5.04, 8.41     |
+--------+-------------+---------------+-------------+----------------+
| 19F    | 0.41        | 0.31, 0.53    | 4.96        | 3.86, 6.37     |
+--------+-------------+---------------+-------------+----------------+
| 23F    | 0.15        | 0.12, 0.20    | 6.25        | 4.54, 8.61     |
+--------+-------------+---------------+-------------+----------------+

Adapted from Tables 11.2.3, page 97 Volume 2 of BLA.

> Pre-dose 1 GMC's were said to be similar between HBV and PncCRM
> groups; those data were not provided to CBER.
>
> Tables were also provided in the application showing percentages of
> subjects with antibody concentrations above defined levels (0.3
> mcg/mL, 0.5 mcg/mL, and 1.0 mcg/mL).

**Percentages of subjects achieving given antibody concentration after
the 3^rd^** dose---Finnish Study

  ----------------- -------- -------- -------- -------- -------- --------
  Serotype          \%                \%                \% \>    
                    \>0.30            \>0.50            1.0      
                    mcg/mL            mcg/mL            mcg/mL   

                    HBV      PncCRM   HBV      PncCRM   HBV      PncCRM

  4                 7.7      94.4     5.8      92.6     0        75.9

  6B                9.6      85.2     7.7      83.3     3.8      66.7

  9V                13.5     98.1     7.7      94.4     3.8      88.9

  14                34.6     100      19.2     96.3     7.7      94.4

  18C               15.4     100      7.7      100      1.9      94.4

  19F               38.5     100      25       100      5.8      90.7

  23F               9.6      94.4     3.8      92.6     1.9      77.8
  ----------------- -------- -------- -------- -------- -------- --------

Adapted from Tables 11.2.2a, b, and c, page 96, Volume 2 of BLA.

**Percentages of subjects achieving given antibody concentration after
the 4^th^** dose---Finnish Study

  ----------------- -------- -------- -------- -------- -------- --------
  Serotype          \%                \%                \% \>    
                    \>0.30            \>0.50            1.0      
                    mcg/mL            mcg/mL            mcg/mL   

                    HBV      PncCRM   HBV      PncCRM   HBV      PncCRM

  4                 18.5     98.2     3.7      94.5     0        90.9

  6B                24.1     98.2     14.8     96.4     0        92.7

  9V                37       100      27.8     100      5.6      96.4

  14                38.9     100      20.4     100      5.6      100

  18C               11.1     100      5.6      100      0        96.4

  19F               63       100      40.7     100      13       94.5

  23F               25.9     100      9.3      100      1.9      94.5
  ----------------- -------- -------- -------- -------- -------- --------

# Adapted from Tables 11.2.4a, b, and c, page 98, Volume 2 of BLA.

# 

# Invasive disease

Four cases of confirmed invasive pneumococcal disease were reported in
the Finnish study, 2 of which were due to vaccine serotypes (see table
below).

# 

# Invasive Disease due to Pneumococcus---Finnish study

+---------------+---------------+-----------------+-------------------+
| Study group   | Serotype      | Clinical        | Age               |
|               |               | syndrome        |                   |
+---------------+---------------+-----------------+-------------------+
| PncCRM        | 7^∗∗^         | Bacteremia      | 19 months         |
+---------------+---------------+-----------------+-------------------+
| HBV           | 15^∗∗^        | Meningitis      | 8 months          |
|               |               |                 |                   |
|               | 23F^∗^        | Meningitis      | 14 months         |
|               |               |                 |                   |
|               | 19F^∗^        | Bacteremia      | 9 months          |
+---------------+---------------+-----------------+-------------------+

Table compiled by FDA.

^∗^ Vaccine serotypes

^∗∗^ Non-vaccine serotype

# 4.2.3 Review issues and supplementary analyses for the Finnish trial

Early in FDA's review of the application, specific issues were
identified, and additional analyses were requested in order to better
understand the treatment effect of Prevnar on otitis media outcomes.
Some of these supplementary analyses are discussed below.

**Analysis of covariates in the Finnish study**

Despite randomization, some imbalances between treatment groups for
certain risk factors for otitis media were observed after unblinding. To
determine whether the vaccine efficacy estimates were robust against
imperfect distribution of risk factors between the two groups, covariate
adjusted analyses were performed by the sponsor upon FDA request. This
supplementary analysis was not part of the pre-unblinding analysis plan.

Andersen-Gill analyses that incorporated AOM history prior to enrollment
and other potential risk factors (gender, gestational age, birth weight,
daycare attendance, breast-feeding, and household smoking) as covariates
were conducted. The effect of gender, AOM history prior to enrollment,
and daycare attendance on the number of AOM episodes were highly
significant. However, the interaction between these variables and
vaccine effect was not significant at the 0.05 level in the sponsor's
analysis. Thus, in spite of a significant impact of these risk factors
on the overall incidence of episodes, no significant vaccine effect in
the populations defined by these factors was evident. Similarly, no
significant interactions were seen at the 0.05 level between vaccine
effect and gestational age, birth weight, breast-feeding or household
smoking.

Vaccine efficacy estimates adjusted for these covariates were derived
with these factors incorporated as main effects, since none of the
interactions were significant. All adjusted vaccine efficacy estimates
were similar to the un-adjusted estimates previously reported.

**Vaccine Efficacy Estimates Adjusted for Gender, AOM Prior to
Enrollment, Gestational Age, Birth Weight, Daycare Attendance,
Breast-feeding, and Household Smoking---Finnish study**

  --------------------- ------------- -------------- --------------- -------------
                        Vaccine                                      
                        Efficacy (95%                                
                        CI)                                          

                        Un-adjusted                  Adjusted for    
                        for                          Covariates      
                        Covariates                   (Covariates     
                                                     Included as     
                                                     Main Effects in 
                                                     Andersen-Gill   
                                                     Analysis)       

  AOM due to Vaccine                                                 
  Serotypes                                                          

  Per Protocol          0.57          (0.44, 0.67)   0.57            (0.45, 0.67)

  Intent-to-treat       0.54          (0.41, 0.64)   0.54            (0.41, 0.64)

  Culture-confirmed                                                  
  Pneumococcal AOM                                                   

  Per Protocol          0.34          (0.21, 0.45)   0.36            (0.23, 0.46)

  Intent-to-treat       0.32          (0.19, 0.42)   0.32            (0.20, 0.43)

  AOM with MEF                                                       

  Per Protocol          0.07          (-0.05, 0.17)  0.08            (-0.02, 0.18)

  Intent-to-treat       0.04          (-0.07, 0.14)  0.05            (-0.06, 0.14)

  AOM Regardless of                                                  
  Etiology                                                           

  Per Protocol          0.06          (-0.04, 0.16)  0.08            (-0.02, 0.18)

  Intent-to-treat       0.04          (-0.07, 0.14)  0.05            (-0.06, 0.14)
  --------------------- ------------- -------------- --------------- -------------

Adapted from Table Q13.3 of January 10, 2002 submission to BLA.

#  

# Efficacy by serotype, subsequent episodes of the same serotype excluded

According to the case definition used in the analysis of the primary
endpoint, if the same pneumococcal serotype were isolated from the same
child on multiple occasions, separated by at least 30 days, each episode
would be counted as a separate event and contribute to the efficacy
analysis.

In FDA's review it was noted that the same pneumococcal serotypes were
cultured repeatedly from middle ear fluid samples over extended periods
of time for some subjects. Repeated AOM episodes due to the same
serotype in the control group would tend to increase the efficacy
estimate. Repeated episodes due to the same vaccine serotype in the
PncCRM vaccine group would diminish the efficacy etimates.

FDA requested supplemental analyses, in which each pneumococcal serotype
is counted only once, at the first AOM episode due to that serotype. The
requested analyses for vaccine serotypes, by individual vaccine
serotypes, and by all pneumococcal serotypes, were provided during the
review period, and are shown in the tables below.

Serotype Efficacy, Subsequent AOM Episodes due to Same Serotypes
Included or Excluded---Finnish study

+-------+-----+---------------+----+------+----+------+-----+-------+
| ##    | Fol | > Inclus      | Nu |      | R  |      | V   |       |
| Type  | low | ion/Exclusion | mb |      | at |      | acc |       |
| of Ep | -up | > of Multiple | er |      | e/ |      | ine |       |
| isode | Per | > Episodes of | of |      |    |      | Ef  |       |
|       | iod | > Same        | Ep |      | pe |      | fic |       |
|       |     | > Serotype    | is |      | rs |      | acy |       |
|       |     |               | od |      | on |      |     |       |
|       |     |               | es |      | ye |      |     |       |
|       |     |               |    |      | ar |      |     |       |
+=======+=====+===============+====+======+====+======+=====+=======+
|       |     |               | H  | #    | #  | Pn   | ##  | 95%   |
|       |     |               | BV | #### | ## | cCRM | ### | CI    |
|       |     |               |    | # Pn | ## |      | ##  |       |
|       |     |               |    | cCRM |  H |      | Est |       |
|       |     |               |    |      | BV |      | im. |       |
+-------+-----+---------------+----+------+----+------+-----+-------+
| AOM   | ##  | ## Per        | 2  | 107  | 0. | 0.09 | 0   | 0.44, |
| due   |  PP | Analysis Plan | 50 |      | 21 |      | .57 | 0.67  |
| to    |     |               |    |      |    |      |     |       |
| va    |     |               |    |      |    |      |     |       |
| ccine |     |               |    |      |    |      |     |       |
| sero  |     |               |    |      |    |      |     |       |
| types |     |               |    |      |    |      |     |       |
+-------+-----+---------------+----+------+----+------+-----+-------+
|       |     | Exclude all   | 2  | 95   | 0. | 0.08 | 0   | 0.43, |
|       |     | subseq.       | 16 |      | 18 |      | .55 | 0.65  |
|       |     | episodes of   |    |      |    |      |     |       |
|       |     | same serotype |    |      |    |      |     |       |
+-------+-----+---------------+----+------+----+------+-----+-------+
|       | ITT | ## Per        | 2  | 135  | 0. | 0.09 | 0   | 0.41, |
|       |     | Analysis Plan | 92 |      | 20 |      | .54 | 0.64  |
+-------+-----+---------------+----+------+----+------+-----+-------+
|       |     | Exclude all   | 2  | 118  | 0. | 0.08 | 0   | 0.38, |
|       |     | subseq.       | 39 |      | 16 |      | .51 | 0.61  |
|       |     | episodes of   |    |      |    |      |     |       |
|       |     | same serotype |    |      |    |      |     |       |
+-------+-----+---------------+----+------+----+------+-----+-------+
| All   | ##  | ## Per        | 4  | 271  | 0. | 0.23 | 0   | 0.21, |
| cu    |  PP | Analysis Plan | 14 |      | 36 |      | .34 | 0.45  |
| lture |     |               |    |      |    |      |     |       |
| -conf |     |               |    |      |    |      |     |       |
| irmed |     |               |    |      |    |      |     |       |
| pne   |     |               |    |      |    |      |     |       |
| umo-c |     |               |    |      |    |      |     |       |
| occal |     |               |    |      |    |      |     |       |
| AOM   |     |               |    |      |    |      |     |       |
+-------+-----+---------------+----+------+----+------+-----+-------+
|       |     | Exclude all   | 3  | 245  | 0. | 0.21 | 0   | 0.21, |
|       |     | subseq.       | 74 |      | 31 |      | .34 | 0.44  |
|       |     | episodes of   |    |      |    |      |     |       |
|       |     | same serotype |    |      |    |      |     |       |
+-------+-----+---------------+----+------+----+------+-----+-------+
|       | ITT | ## Per        | 4  | 322  | 0. | 0.22 | 0   | 0.19, |
|       |     | Analysis Plan | 67 |      | 32 |      | .32 | 0.42  |
+-------+-----+---------------+----+------+----+------+-----+-------+
|       |     | Exclude all   | 4  | 288  | 0. | 0.19 | 0   | 0.16, |
|       |     | subseq.       | 05 |      | 27 |      | .29 | 0.40  |
|       |     | episodes of   |    |      |    |      |     |       |
|       |     | same serotype |    |      |    |      |     |       |
+-------+-----+---------------+----+------+----+------+-----+-------+

Adapted from Table Q2.1 of January 10, 2002 submission to BLA.

Individual Serotype Efficacy Results with Subsequent AOM Episodes due to
Same Serotypes Included or Excluded, Per Protocol Follow-up---Finnish
study

+--------+--------------+-----+-----+-------+------+-------+-------+
| AOM    | Inclusi      | Num |     | Rat   |      | Va    |       |
| due to | on/Exclusion | ber |     | e/100 |      | ccine |       |
| ser    | of Multiple  | of  |     | p     |      | Eff   |       |
| otypes | Episodes of  | Ep  |     | erson |      | icacy |       |
|        | Same         | iso |     | year  |      |       |       |
|        | Serotype     | des |     |       |      |       |       |
+========+==============+=====+=====+=======+======+=======+=======+
|        |              | HBV | #   | ####  | Pn   | #     | 95%CI |
|        |              |     | ### | # HBV | cCRM | ##### |       |
|        |              |     | ##  |       |      | # Est |       |
|        |              |     | Pnc |       |      | imate |       |
|        |              |     | CRM |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 4      | ## Per A     | 4   | 2   | 0.34  | 0.17 | 0.49  | (-    |
|        | nalysis Plan |     |     |       |      |       | 1.76, |
|        |              |     |     |       |      |       | 0.91) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 4   | 2   | 0.34  | 0.17 | 0.49  | (-    |
|        | subsequent   |     |     |       |      |       | 1.76, |
|        | episodes of  |     |     |       |      |       | 0.91) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 6B     | ## Per A     | 56  | 9   | 4.71  | 0.76 | 0.84  | (     |
|        | nalysis Plan |     |     |       |      |       | 0.62, |
|        |              |     |     |       |      |       | 0.93) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 46  | 7   | 3.98  | 0.60 | 0.85  | (     |
|        | subsequent   |     |     |       |      |       | 0.67, |
|        | episodes of  |     |     |       |      |       | 0.93) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 9V     | ## Per A     | 11  | 5   | 0.92  | 0.42 | 0.54  | (-    |
|        | nalysis Plan |     |     |       |      |       | 0.48, |
|        |              |     |     |       |      |       | 0.86) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 8   | 5   | 0.67  | 0.43 | 0.37  | (-    |
|        | subsequent   |     |     |       |      |       | 0.93, |
|        | episodes of  |     |     |       |      |       | 0.79) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 14     | ## Per A     | 26  | 8   | 2.18  | 0.68 | 0.69  | (     |
|        | nalysis Plan |     |     |       |      |       | 0.20, |
|        |              |     |     |       |      |       | 0.88) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 24  | 6   | 2.04  | 0.51 | 0.75  | (     |
|        | subsequent   |     |     |       |      |       | 0.39, |
|        | episodes of  |     |     |       |      |       | 0.90) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 18C    | ## Per A     | 17  | 7   | 1.43  | 0.59 | 0.58  | (-    |
|        | nalysis Plan |     |     |       |      |       | 0.04, |
|        |              |     |     |       |      |       | 0.83) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 14  | 7   | 1.18  | 0.60 | 0.50  | (-    |
|        | subsequent   |     |     |       |      |       | 0.25, |
|        | episodes of  |     |     |       |      |       | 0.80) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 19F    | ## Per A     | 58  | 43  | 4.88  | 3.66 | 0.25  | (-    |
|        | nalysis Plan |     |     |       |      |       | 0.14, |
|        |              |     |     |       |      |       | 0.51) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 51  | 41  | 4.45  | 3.58 | 0.20  | (-    |
|        | subsequent   |     |     |       |      |       | 0.21, |
|        | episodes of  |     |     |       |      |       | 0.47) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 23F    | ## Per A     | 82  | 33  | 6.91  | 2.81 | 0.59  | (     |
|        | nalysis Plan |     |     |       |      |       | 0.35, |
|        |              |     |     |       |      |       | 0.75) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 73  | 27  | 6.43  | 2.34 | 0.63  | (     |
|        | subsequent   |     |     |       |      |       | 0.43, |
|        | episodes of  |     |     |       |      |       | 0.77) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+

Adapted from Table Q2.2 of January 10, 2002 submission to BLA.

Individual Serotype Efficacy Results with Subsequent AOM Episodes due to
Same Serotypes Included or Excluded, Intent-to-treat Follow-up---Finnish
study

+--------+--------------+-----+-----+-------+------+-------+-------+
| AOM    | Inclusi      | Num |     | Rat   |      | Va    |       |
| due to | on/Exclusion | ber |     | e/100 |      | ccine |       |
| ser    | of Multiple  | of  |     | p     |      | Eff   |       |
| otypes | Episodes of  | Ep  |     | erson |      | icacy |       |
|        | Same         | iso |     | year  |      |       |       |
|        | Serotype     | des |     |       |      |       |       |
+========+==============+=====+=====+=======+======+=======+=======+
|        |              | HBV | #   | ####  | Pn   | #     | 95%CI |
|        |              |     | ### | # HBV | cCRM | ##### |       |
|        |              |     | ##  |       |      | # Est |       |
|        |              |     | Pnc |       |      | imate |       |
|        |              |     | CRM |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 4      | ## Per A     | 4   | 2   | 0.27  | 0.13 | 0.50  | (-    |
|        | nalysis Plan |     |     |       |      |       | 1.72, |
|        |              |     |     |       |      |       | 0.91) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 4   | 2   | 0.27  | 0.13 | 0.50  | (-    |
|        | subsequent   |     |     |       |      |       | 1.73, |
|        | episodes of  |     |     |       |      |       | 0.91) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 6B     | ## Per A     | 61  | 12  | 4.12  | 0.81 | 0.80  | (     |
|        | nalysis Plan |     |     |       |      |       | 0.60, |
|        |              |     |     |       |      |       | 0.90) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 48  | 10  | 3.33  | 0.68 | 0.80  | (     |
|        | subsequent   |     |     |       |      |       | 0.60, |
|        | episodes of  |     |     |       |      |       | 0.90) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 9V     | ## Per A     | 11  | 6   | 0.74  | 0.40 | 0.45  | (-    |
|        | nalysis Plan |     |     |       |      |       | 0.66, |
|        |              |     |     |       |      |       | 0.82) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 8   | 6   | 0.54  | 0.41 | 0.25  | (-    |
|        | subsequent   |     |     |       |      |       | 1.16, |
|        | episodes of  |     |     |       |      |       | 0.74) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 14     | ## Per A     | 31  | 8   | 2.09  | 0.54 | 0.74  | (     |
|        | nalysis Plan |     |     |       |      |       | 0.34, |
|        |              |     |     |       |      |       | 0.90) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 26  | 6   | 1.78  | 0.41 | 0.77  | (     |
|        | subsequent   |     |     |       |      |       | 0.45, |
|        | episodes of  |     |     |       |      |       | 0.91) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 18C    | ## Per A     | 18  | 7   | 1.21  | 0.47 | 0.61  | (     |
|        | nalysis Plan |     |     |       |      |       | 0.02, |
|        |              |     |     |       |      |       | 0.85) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 14  | 7   | 0.95  | 0.47 | 0.50  | (-    |
|        | subsequent   |     |     |       |      |       | 0.23, |
|        | episodes of  |     |     |       |      |       | 0.80) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 19F    | ## Per A     | 67  | 60  | 4.53  | 4.06 | 0.10  | (-    |
|        | nalysis Plan |     |     |       |      |       | 0.32, |
|        |              |     |     |       |      |       | 0.39) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 56  | 55  | 3.92  | 3.84 | 0.02  | (-    |
|        | subsequent   |     |     |       |      |       | 0.42, |
|        | episodes of  |     |     |       |      |       | 0.32) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+
| 23F    | ## Per A     | 104 | 40  | 7.04  | 2.70 | 0.62  | (     |
|        | nalysis Plan |     |     |       |      |       | 0.41, |
|        |              |     |     |       |      |       | 0.75) |
+--------+--------------+-----+-----+-------+------+-------+-------+
|        | Exclude all  | 87  | 32  | 6.21  | 2.20 | 0.64  | (     |
|        | subsequent   |     |     |       |      |       | 0.47, |
|        | episodes of  |     |     |       |      |       | 0.76) |
|        | same         |     |     |       |      |       |       |
|        | serotype     |     |     |       |      |       |       |
+--------+--------------+-----+-----+-------+------+-------+-------+

Adapted from Table Q2.2 of January 10, 2002 submission to BLA.

In general, these supplemental analyses in which episodes subsequent to
the first episode of AOM due to the same serotype are excluded, yielded
efficacy estimates similar to those calculated in accordance with the
original analysis plan. Exceptions include serotypes 9V and 19F for
which the efficacy estimates were substantially reduced in the
supplementary analysis. However, in neither analysis were the efficacy
estimates statistically significant for these two serotypes.

**PCR confirmed pneumococcal AOM episodes**

Analyses of AOM episodes using a case definition that included
identification of pneumococci in middle ear fluid by PCR were specified
in the study protocol, but were not available at the time of the study
report was written, and were not provided with the initial BLA
submission. The PCR assay detects pneumolysin gene, a gene common to all
*S. pneumoniae*, but does not distinguish among serotypes. Potential
advantages of using PCR to detect pneumococci in middle ear fluids were
cited in the study protocol, and have been described in the literature
(Virolainen A, 1994). Results of the analyses of pneumococcal AOM
episodes based on PCR were provided during the review period upon FDA
request.

A moderate concordance between pneumococcal AOM episodes based on PCR
and culture results was observed (kappa \< 0.6). A substantial number of
samples were positive for *S. pneumoniae* by PCR, but culture negative
(532 and 486 in the PncCRM and HBV groups, respectively).

**Comparison of Culture and PCR Results---Finnish study**

+-------------+-------------+---------+---------+---------------------+
|             |             | PCR     |         | Kappa (95% CI)      |
+-------------+-------------+---------+---------+---------------------+
|             | #           | Pnc-    | Pnc+    |                     |
|             | ### Culture |         |         |                     |
+-------------+-------------+---------+---------+---------------------+
| HBV         | #### Pnc-   | 1353    | 532     | 0.56 (0.53, 0.59)   |
+-------------+-------------+---------+---------+---------------------+
|             | Pnc+        | 24      | 684     |                     |
+-------------+-------------+---------+---------+---------------------+
| PncCRM      | Pnc-        | 1563    | 486     | 0.52 (0.48, 0.55)   |
+-------------+-------------+---------+---------+---------------------+
|             | Pnc+        | 13      | 432     |                     |
+-------------+-------------+---------+---------+---------------------+

# Reproduced from Table Q6.2, of January 10, 2002 submission to BLA.

In the per protocol analysis, the vaccine efficacy estimate for AOM
episodes due to pneumococci regardless of serotype was lower (20%) if
based on PCR or culture confirmed episodes, than efficacy estimate based
solely on culture methods (34%).

In the intent-to-treat analysis for the same outcomes, the efficacy
estimate was 18% for pneumococcal AOM episodes confirmed by PCR or
culture, versus 32% for episodes confirmed by culture alone.

Efficacy for all pneumococcal AOM episodes, by culture and PCR---Finnish
Study

+-----+----------------+-----+-------+-----+-------+-------+--------+
| Fol | ## Metho       | Num |       | Ra  |       | Va    |        |
| low | d of Diagnosis | ber |       | te/ |       | ccine |        |
| -up |                | of  |       | per |       | Eff   |        |
| Per |                | Ep  |       | son |       | icacy |        |
| iod |                | iso |       | y   |       |       |        |
|     |                | des |       | ear |       |       |        |
+=====+================+=====+=======+=====+=======+=======+========+
|     |                | HBV | ###   | ### | P     | #     | 95%CI  |
|     |                |     | ### P | ##  | ncCRM | ##### |        |
|     |                |     | ncCRM | HBV |       | # Est |        |
|     |                |     |       |     |       | imate |        |
+-----+----------------+-----+-------+-----+-------+-------+--------+
| ##  | ##             | 414 | 271   | 0   | 0.23  | 0.34  | (0.21, |
| ### | ###### Determi |     |       | .36 |       |       | 0.45)  |
| ### | ned by culture |     |       |     |       |       |        |
|  PP |                |     |       |     |       |       |        |
+-----+----------------+-----+-------+-----+-------+-------+--------+
|     | Determined by  | 678 | 541   | 0   | 0.48  | 0.20  | (0.07, |
|     | PCR            |     |       | .60 |       |       | 0.31)  |
+-----+----------------+-----+-------+-----+-------+-------+--------+
|     | Determined by  | 687 | 548   | 0   | 0.48  | 0.20  | (0.07, |
|     | culture or PCR |     |       | .60 |       |       | 0.31)  |
+-----+----------------+-----+-------+-----+-------+-------+--------+
|     | Determined by  | 459 | 321   | 0   | 0.28  | 0.30  | (0.17, |
|     | PCR/ excluding |     |       | .40 |       |       | 0.41)  |
|     | Culture        |     |       |     |       |       |        |
|     | Confirmed *H.  |     |       |     |       |       |        |
|     | flu, M.cat,    |     |       |     |       |       |        |
|     | and S. pyo*    |     |       |     |       |       |        |
+-----+----------------+-----+-------+-----+-------+-------+--------+
|     | Determined by  | 466 | 325   | 0   | 0.28  | 0.30  | (0.17, |
|     | PCR or Culture |     |       | .40 |       |       | 0.41)  |
|     | / excluding    |     |       |     |       |       |        |
|     | Culture        |     |       |     |       |       |        |
|     | Confirmed *H.  |     |       |     |       |       |        |
|     | flu, M.cat,    |     |       |     |       |       |        |
|     | and S. pyo*    |     |       |     |       |       |        |
+-----+----------------+-----+-------+-----+-------+-------+--------+
| ITT | ##             | 467 | 322   | 0   | 0.22  | 0.32  | (0.19, |
|     | ###### Determi |     |       | .32 |       |       | 0.42)  |
|     | ned by culture |     |       |     |       |       |        |
+-----+----------------+-----+-------+-----+-------+-------+--------+
|     | Determined by  | 764 | 635   | 0   | 0.44  | 0.18  | (0.05, |
|     | PCR            |     |       | .54 |       |       | 0.29)  |
+-----+----------------+-----+-------+-----+-------+-------+--------+
|     | Determined by  | 775 | 642   | 0   | 0.45  | 0.18  | (0.05, |
|     | culture or PCR |     |       | .54 |       |       | 0.29)  |
+-----+----------------+-----+-------+-----+-------+-------+--------+
|     | Determined by  | 527 | 396   | 0   | 0.27  | 0.25  | (0.13, |
|     | PCR/ excluding |     |       | .37 |       |       | 0.36)  |
|     | Culture        |     |       |     |       |       |        |
|     | Confirmed *H.  |     |       |     |       |       |        |
|     | flu, M.cat,    |     |       |     |       |       |        |
|     | and S. pyo*    |     |       |     |       |       |        |
+-----+----------------+-----+-------+-----+-------+-------+--------+
|     | Determined by  | 536 | 400   | 0   | 0.28  | 0.26  | (0.13, |
|     | PCR or Culture |     |       | .37 |       |       | 0.37)  |
|     | / excluding    |     |       |     |       |       |        |
|     | Culture        |     |       |     |       |       |        |
|     | Confirmed *H.  |     |       |     |       |       |        |
|     | flu, M.cat,    |     |       |     |       |       |        |
|     | and S.pyo*     |     |       |     |       |       |        |
+-----+----------------+-----+-------+-----+-------+-------+--------+

Reproduced from Table Q6.1 of January 10, 2002 submission to BLA.

Other bacteria (*H. influenzae, M. catarrhalis, S. pyogenes)* were
detected by culture in 42.6% of the MEF samples for which the PCR was
positive and culture was negative for pneumococcus. The sponsor also
calculated efficacy estimates for pneumococcal AOM episodes confirmed by
either culture or PCR, but excluding episodes for which other bacteria
(*H. influenzae, M. catarrhalis and S. pyogenes*) were cultured; that
efficacy estimate was 30% in the per protocol analysis.

The clinical significance of an AOM episode with MEF that is PCR
positive and culture negative for *S. pneumoniae*, but culture positive
for other known otitis pathogens, is unknown. Some authors have
suggested that pneumolysin PCR is a sensitive and more accurate
diagnostic tool than culture, and that a positive PCR suggests
pneumococcal involvement, even if cultures are negative for pneumococcus
(Virolainen A, et al., 1994). The sponsor suggests that while PCR could
be a sensitive probe for actual pneumococcal otitis media, it may also
be detecting pneumococcal organisms present in small numbers but not
contributing to the pathogenesis of the acute event.

# Use of antibiotics in the Finnish study

As noted earlier, guidelines for antibiotic usage in the Finnish
population do not differ appreciably from practices in the U.S. Data
about antibiotic usage during the Finnish study were recorded onto case
report forms during the course of the study. However, antibiotic usage
was not included among the prospectively defined study outcomes, and no
analyses were provided with the initial BLA submission.

Clearly, patterns of antibiotic use could impact AOM outcomes. If use of
antibiotics were significantly greater in the PncCRM group than in the
control group, some of the apparent vaccine treatment effect might be
attributed to the differential use of antibiotics. Thus, FDA requested
that additional data and analyses relating to antibiotic usage be
provided.

As shown in the table below, the number of subjects receiving
antibiotics for the treatment of AOM was less in the vaccine group; this
difference approached statistical significance. The number of subjects
receiving antibiotics for prophylaxis, and for any purpose, was also
nominally smaller in the PncCRM group.

# Number of Subjects with Antimicrobial Prescriptions During ITT Follow-up---Finnish Study

+--------------+--------+----------+---------+---------+-------------+
|              | Number |          |         |         |             |
|              | (%) of |          |         |         |             |
|              | Su     |          |         |         |             |
|              | bjects |          |         |         |             |
|              | Who    |          |         |         |             |
|              | Had    |          |         |         |             |
|              | Antib  |          |         |         |             |
|              | iotics |          |         |         |             |
|              | P      |          |         |         |             |
|              | rescri |          |         |         |             |
|              | ptions |          |         |         |             |
|              |        |          |         |         |             |
|              | during |          |         |         |             |
|              | ITT    |          |         |         |             |
|              | Fol    |          |         |         |             |
|              | low-up |          |         |         |             |
+--------------+--------+----------+---------+---------+-------------+
|              | PncCRM |          | HBV     |         | P-Value^\*^ |
|              | (      |          | (N=831) |         |             |
|              | N=831) |          |         |         |             |
+--------------+--------+----------+---------+---------+-------------+
| AOM          | 551    | (66.3%)  | 589     | (70.9%) | 0.051       |
| Treatm       |        |          |         |         |             |
| ent**[^٭٭^]{ |        |          |         |         |             |
| dir="rtl"}** |        |          |         |         |             |
+--------------+--------+----------+---------+---------+-------------+
| AOM          | 132    | (15.9%)  | 143     | (17.2%) | 0.509       |
| Prevent      |        |          |         |         |             |
| ion**[^٭٭^]{ |        |          |         |         |             |
| dir="rtl"}** |        |          |         |         |             |
+--------------+--------+----------+---------+---------+-------------+
| Other        | 157    | (18.9%)  | 147     | (17.7%) | 0.568       |
| Purposes     |        |          |         |         |             |
+--------------+--------+----------+---------+---------+-------------+
| Regardless   | 578    | (69.6%)  | 605     | (72.8%) | 0.159       |
| of Purpose   |        |          |         |         |             |
+--------------+--------+----------+---------+---------+-------------+

Adapted from Table Q5.1 of January 10, 2002 submission to BLA.

P-value based on Fisher's exact test.

^[٭**٭**]{dir="rtl"}^ All etiologies of AOM

Similarly, when antibiotic usage was examined by the number of courses
prescribed for the treatment of AOM, usage in the PncCRM group was
nominally lower than in the control group.

**Number of Courses of Antibiotics Prescribed during ITT Follow-up---**

**Finnish Study**

  ------------------ ----------- -------- ----------------- ----------------- -------------
                     Total                Mean^†^                             P-Value^\*^
                     Number of            [+]{.underline}                     
                     Courses              SD Number of                        
                     during ITT           Courses Per                         
                     Follow-up            Subject during                      
                                          ITT Follow-up                       

                     PncCRM (N=  HBV (N=  PncCRM (N= 831)   HBV (N= 831)      
                     831)        831)                                         

  AOM                1940        2018     2.33              2.43              0.164
  Treatment^\*\*^                         [+]{.underline}   [+]{.underline}   
                                          2.65              2.60              

  AOM                299         300      0.36              0.36              0.531
  Prevention^\*\*^                        [+]{.underline}   [+]{.underline}   
                                          0.98              0.94              

  Other Purposes     195         177      0.23              0.21              0.471
                                          [+]{.underline}   [+]{.underline}   
                                          0.54              0.51              

  Regardless of      2277        2342     2.74              2.82              0.275
  Purpose                                 [+]{.underline}   [+]{.underline}   
                                          3.14              3.10              
  ------------------ ----------- -------- ----------------- ----------------- -------------

Adapted from Table Q5.2 of January 10, 2002 submission to the BLA.

^\*^P-value based on Wilcoxon rank sum test.

^\*\*^ All etiologies of AOM.

^†^ Mean and SD of the whole treatment group including children who did
not have any prescriptions.

Taken together, these data relating to antibiotic use during the Finnish
study are consistent with, and largely supportive of, a vaccine
treatment effect in the prevention of AOM in the study population.

**Tympanostomy tube placement in Finnish study**

Information about tympanostomy tube placement during the Finnish study
was recorded onto case report forms during the course of the study.
However, the study report did not provide group data summaries or
statistical analyses of these data. During the review period, FDA
requested that recommendations regarding ear tube placement in Finland
be provided and that available data relating to ear tube placement be
analyzed and submitted to the BLA.

Recommendations regarding ear tube placement during the Finnish study
were provided upon FDA request. Children who experience ≥ 3 to 5 AOM
episodes within 6 months or ≥ 4 to 6 AOM episodes within a year, or who
have asymptomatic bilateral otitis media with effusion (OME) persisting
for ≥ 3 months, or unilateral OME persisting for ≥ 6 months are referred
for consideration of adenoidectomy and/or insertion of tympanostomy
tubes.

The incidence of first ear tube placement in the Finnish study was
substantially higher than was consistent with standard practice in
Finland. The incidence of tympanostomy tube placement in children under
2 years of age in Finland was estimated to be 0.03 per child year in a
study of daycare attendees (Niemela et al., 1999), compared to an
incidence of 0.12 per child year observed in the Finnish AOM trial. The
ear tube placement incidence in the Finnish study was also substantially
higher than the rate observed in the NCKP trial (see below) and in a
region served by a large New England health insurer (Thompson et al.,
1999). The sponsor suggests that because of the close follow-up within
the trial framework, parents may have sought treatment at an earlier
phase of disease.

Little difference was observed between the treatment groups with respect
to patient characteristics or rate of tympanostomy tube placement, as
shown in the table below.

**Characteristics of Children Who Underwent Tympanostomy Procedure,**

Intent-to-treat Follow-Up---Finnish study

+----------------------------------+-----------------+-----------------+
|                                  | > PncCRM        | > HBV Control   |
+----------------------------------+-----------------+-----------------+
| > FinOM Trial                    |                 | ########        |
+----------------------------------+-----------------+-----------------+
| > No. of Randomized Subjects     | > 831           | > 831           |
+----------------------------------+-----------------+-----------------+
| > No. of Subjects Who Had ≥ 1    | > 548           | > 587           |
| > AOM Visit                      |                 |                 |
+----------------------------------+-----------------+-----------------+
| > No of Subjects Undergoing      | > 153           | > 161           |
| > Tympanostomy                   |                 |                 |
+----------------------------------+-----------------+-----------------+
| > Incidence of Tympanostomy (per | > 0.11          | > 0.12          |
| > person yr)                     |                 |                 |
+----------------------------------+-----------------+-----------------+
| > ≤ 12 mo. of age                | > 0.05          | > 0.05          |
+----------------------------------+-----------------+-----------------+
| > \> 12 mo. of age               | > 0.15          | > 0.16          |
+----------------------------------+-----------------+-----------------+
| > Mean Age (mo.) of Procedure    | > 15.9 (4, 24)  | > 15.7 (4, 24)  |
| >                                |                 |                 |
| > (interquartile range)          |                 |                 |
+----------------------------------+-----------------+-----------------+
| > Mean Number of Prior AOM       | > 3.21 (2, 4)   | > 3.13 (2, 4)   |
| > Episodes (interquartile range) |                 |                 |
+----------------------------------+-----------------+-----------------+
| > Mean Number of Prior AOM       | > 4.57 (4, 5)   | > 4.48 (3, 5)   |
| > Visits (interquartile range)   |                 |                 |
+----------------------------------+-----------------+-----------------+
| > Mean Number of Visits /        | > 1.42          | > 1.43          |
| > Episode Prior to Tympanostomy  |                 |                 |
| > Procedure                      |                 |                 |
+----------------------------------+-----------------+-----------------+

Adapted from Tables Q5.4 and Q5.5 of January 10, 2002 submission to BLA.

If the relatively frequent tympanostomy tube placement in the Finnish
AOM trial had prevented AOM episodes that would have been otherwise
observed, such undercounting would likely affect the two treatment
groups similarly, since the rate of tube placement was similar in the
tube groups. Thus, the direction of the treatment effect would not be
expected to change; the likely effect on the magnitude and confidence
limits of the efficacy estimates is less clear.

In discussing how the tympanostomy tube placement results from the
Finnish AOM trial may apply to a U.S. population, the sponsor suggests
that lower vaccine efficacy than what was observed in the Finnish OM
trial would be unlikely in a population with less frequent tympanostomy
tube placement, as more observable AOM episodes in unimmunized children
may be preventable by vaccine.

The sponsor also suggested (January 10, 2002 BLA submission) that
because of the increased rates of this procedure in the Finnish trial,
tympanostomy tube placement would not be an informative efficacy
endpoint for providing inferences that could be generalized to the U.S.
population.

Subsequently, a long-term follow-up study of the Finnish AOM cohort was
completed. In a February 12, 2002 submission, the sponsor proposed an
analysis plan of these data for submission to the BLA. All eligible
children were 4 to 5 years of age at the planned follow-up visit, which
took place between March and June 2001. The vaccination status of all
children was made known to parents and investigators following the
unblinding in August 1999. Nasopharyngeal sampling, serum for antibody
determinations, parental interview for otitis media history, and
pneumatic otoscopy were performed. Records of procedures were verified
through hospital or private physicians' records.

The primary analysis compared the risk of first ear tube placement
between treatment groups among children enrolled in the follow-up study,
counting events since enrollment at 2 months of age in the Finnish AOM
trial until 4 to 5 years of age. Relative risk was estimated based on a
generalized Cox regression model with vaccine group as a covariate.
Results are reported as vaccine efficacy (1- relative risk) with 95%
confidence intervals.

Results of the Finnish follow-up study relating to tympanostomy tube
placement were submitted to the license application late in the review
period (March 29, 2002). A total of 756 of the original 1662 randomized
children enrolled and completed assessments in the follow-up study. Of
the participants, 353 received HBV and 403 received PncCRM. Demographic
characteristics of children who participated did not differ markedly by
vaccine group. Likewise, characteristics for non-participants were
similar between the vaccine groups.

The efficacy estimate for tube placement during the efficacy trial among
the cohort participating in the long-term follow-up was 12%; however,
this was not as statistically significant result.

During the long-term follow-up in this cohort, ear tube placement was
reduced 39%; this was a statistically significant result.

# Tympanostomy tube placement among children enrolled in Finnish AOM follow-up study

+------------------------+---------+---------+------------+----------+
|                        | HBV     | PncCRM  | Efficacy   | 95% CI   |
|                        |         |         | estimate   |          |
+------------------------+---------+---------+------------+----------+
| Number enrolled        | 353     | 403     |            |          |
+------------------------+---------+---------+------------+----------+
| ITT follow-up, Finnish |         |         |            |          |
| AOM trial              |         |         |            |          |
|                        |         |         |            |          |
| (age 2 months to 2     |         |         |            |          |
| years)                 |         |         |            |          |
+------------------------+---------+---------+------------+----------+
| Number of subjects     | 84      | 82      |            |          |
| with events            |         |         |            |          |
+------------------------+---------+---------+------------+----------+
| Number of events       | 95      | 95      |            |          |
+------------------------+---------+---------+------------+----------+
| Rate of events (/100   | 14.8    | 12.9    | 0.12       | -0.17,   |
| child years)           |         |         |            | 0.34     |
+------------------------+---------+---------+------------+----------+
|                        |         |         |            |          |
+------------------------+---------+---------+------------+----------+
| Long-term follow-up    |         |         |            |          |
|                        |         |         |            |          |
| (age 2 years to 4-5    |         |         |            |          |
| years)                 |         |         |            |          |
+------------------------+---------+---------+------------+----------+
| Number of subjects     | 46^†^   | 33^‡^   |            |          |
| with events            |         |         |            |          |
+------------------------+---------+---------+------------+----------+
| Number of events       | 57      | 40      |            |          |
+------------------------+---------+---------+------------+----------+
| Rate of events (/100   | 5.7     | 3.5     | 0.39       | 0.04,    |
| child years)           |         |         |            | 0.61     |
+------------------------+---------+---------+------------+----------+

Adapted from Table 4 of March 29, 2002 submission to the BLA.

^†^ 23 subjects had tube placed during the efficacy trial

^‡^ 17 subjects had tube placed during the efficacy trial

A secondary analysis was performed in which data on ear tube placement
was collected

for the entire Finnish AOM study population using only available
hospital medical records. Children known to have discontinued study
participation in the AOM study or who moved from the area were excluded
from this analysis.

# Tympanostomy tube placement among all children enrolled in Finnish AOM study who were known to be at risk^§^--- Finnish Follow-up study

+------------------------+---------+---------+------------+----------+
|                        | HBV     | PncCRM  | Efficacy   | 95% CI   |
|                        |         |         | estimate   |          |
+------------------------+---------+---------+------------+----------+
| Number enrolled        | 831     | 831     |            |          |
+------------------------+---------+---------+------------+----------+
| ITT follow-up, Finnish |         |         |            |          |
| AOM trial              |         |         |            |          |
|                        |         |         |            |          |
| (age 2 months to 2     |         |         |            |          |
| years)                 |         |         |            |          |
+------------------------+---------+---------+------------+----------+
| Number of subjects     | 161     | 153     |            |          |
| with events            |         |         |            |          |
+------------------------+---------+---------+------------+----------+
| Number of events       | 189     | 178     |            |          |
+------------------------+---------+---------+------------+----------+
| Rate of events (/100   | 12.7    | 12.0    | 0.04       | -0.19,   |
| child years)           |         |         |            | 0.23     |
+------------------------+---------+---------+------------+----------+
|                        |         |         |            |          |
+------------------------+---------+---------+------------+----------+
| Long-term follow-up    |         |         |            |          |
|                        |         |         |            |          |
| (age 2 years to 4-5    |         |         |            |          |
| years)                 |         |         |            |          |
+------------------------+---------+---------+------------+----------+
| Number included^§^     | 744     | 746     |            |          |
+------------------------+---------+---------+------------+----------+
| Number of subjects     | 71^†^   | 46^‡^   |            |          |
| with events            |         |         |            |          |
+------------------------+---------+---------+------------+----------+
| Number of events       | 92      | 53      |            |          |
+------------------------+---------+---------+------------+----------+
| Rate of events (/100   | 4.1     | 2.4     | 0.44       | 0.19,    |
| child years)           |         |         |            | 0.62     |
+------------------------+---------+---------+------------+----------+

Adapted from Table 5 of March 29, 2002 submission to the BLA.

^§^ Subjects discontinued from Finnish AOM study or moved from study
area were excluded.

^†^ 38 subjects had tube placed during the efficacy trial.

^‡^ 19 subjects had tube placed during the efficacy trial.

The efficacy estimate for tympanostomy tube placement during the Finnish
AOM study was 4%; this was not statistically significant.

During the long-term follow-up of the original Finnish AOM study cohort,
excluding subjects known to have left the area, ear tube placement was
reduced 44%, based on available hospital records; this was a
statistically significant result.

1.  **Northern California Kaiser Permanente (NCKP) study**

    1.  **NCKP study description**

> **Title:** **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**
>
> This was a randomized, double-blind study conducted at multiple
> clinics within the Northern California Kaiser Permanente health care
> system.
>
> The study was initiated in October 1995; enrollment ceased August 24,
> 1998, after results of the planned interim analysis demonstrated
> substantial evidence of efficacy for the primary study outcome-
> prevention of invasive disease. The otitis media database had been
> locked on April 30, 1998. Follow-up of infants for invasive
> pneumococcal disease and serious adverse events continued through
> April 20, 1999.
>
> The study design of the NCKP study was discussed at the November 1999
> VRBPAC, and will not be presented again here in detail. Only efficacy
> data relating to otitis media were submitted with the application.
>
> Additional information about concurrent immunizations, vaccine
> schedules, eligibility criteria, randomization and blinding are
> provided in Attachment B of this document.
>
> **Objectives of the NCKP study**
>
> 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.
>
> One of the multiple secondary objectives of the NCKP study was to
> assess the effectiveness of 7VPnC on rates of acute otitis media.

**Case surveillance and ascertainment in the NCKP study**

> No special provisions were made for surveillance and ascertainment of
> otitis media cases. AOM cases were diagnosed by the child's health
> care provider within the Kaiser Health Care system and identified by a
> check in a box for "acute otitis media" or "otitis media" on a patient
> encounter form for data capture and entry into the Kaiser automated
> databases for emergency room and clinic visits.
>
> Tympanocentesis and bacterial culture of middle ear fluid from cases
> of AOM were not routinely performed. Fluid from spontaneous drainage
> of ears was cultured for pneumococcus in some cases. However, the
> presence of pneumococcus or other pathogens was not confirmed for most
> AOM cases.
>
> **Note:** Follow-up visits could not be clearly differentiated from
> initial encounters for new episodes using the automated databases.

**Definitions of outcome variables**

> **AOM** diagnoses were based on the clinical practices of the
> participating clinicians. No definition of AOM based on a set of
> clinical characteristics was uniformly applied across centers.
>
> **AOM episode** is a clinic visit at which AOM was diagnosed and at
> least 21 days had elapsed since any previous visit for AOM.
>
> **Note:** The period defining a new AOM episode in the NCKP and
> Finnish studies differs. The Finnish study uses a period of at least
> 30 days.
>
> **Recurrent otitis media** was defined prospectively by 3 otitis media
> episodes within 6 months, or 4 episodes within 12 months.

**Definition of follow-up periods**

> **Per protocol** **(PP)** follow-up started 14 days after the 3^rd^
> injection of the study vaccine and continued until the earliest of: 1)
> dropout from the NCKP health plan, 2) attainment of age 16 months
> without receipt of a 4^th^ dose, or 3) April 30, 1998.
>
> **Intention-to-treat** **(ITT)** follow-up began the day after
> randomization and continued until April 30, 1998, and included all
> subjects who were randomized into the study. For ITT follow-up,
> children were not censored when they disenrolled from the Kaiser
> health plan.

**Efficacy outcomes assessed**

> **Primary otitis media endpoint** was the overall reduction in the
> incidence of all otitis media episodes.
>
> **Secondary endpoints** prospectively identified included:

-   Risk of at least 1 episode of otitis media

-   Risk of frequent otitis media

-   Risk of tympanostomy tube placement

-   Overall incidence of clinic visits for otitis media

**Exploratory endpoints** included:

-   Incidence of spontaneously ruptured tympanic membranes that yielded
    a positive culture for vaccine-serotype pneumococcus.

-   Risk of frequent otitis media using other definitions

> **Analysis plan**
>
> The Anderson-Gill model was used to analyze recurrent event data,
> including the primary outcome, all otitis media episodes, and the
> secondary outcome, all clinic visits. Relative risk was assumed to be
> fixed over time. This assumption was checked graphically by plotting
> the relative risk over time. Robust estimates of variance were used.
>
> The Cox proportional hazard model was used for single event data,
> including first AOM episode, frequent otitis media, and tympanostomy
> tube placement.
>
> The exact binomial test was used to analyze cases of ruptured ear
> drums.

#  

A Poisson regression model was used to examine the effects of gender,
age, and season on overall incidence of otitis media.

# 

# 

# 4.2.2 NCKP study AOM efficacy results

> **Disposition of subjects**
>
> Enrollment into the study continued until the planned interim analysis
> of efficacy for invasive disease demonstrated substantial evidence of
> efficacy. At the time enrollment stopped, 37,868 infants had been
> randomized. However, the AOM data base was closed for the purpose of
> analysis and preparation of a study report on April 30, 1998, after
> 34,146 children had been enrolled. The table below provides the number
> of children included in the AOM analysis by study group and the number
> of children who had received each dose.

Number of subjects included in the AOM analysis who received each
dose---NCKP Study

+--------------------+----------------+----------------+--------------+
| > Dose (age in     | > 7VPnC        | > MnCC         | > Total      |
| > months)          |                |                |              |
+--------------------+----------------+----------------+--------------+
| > 1 (2 months)     | > 17,066       | > 17,080       | > 34,146     |
+--------------------+----------------+----------------+--------------+
| > 2 (4 months)     | > 15,427       | > 15,410       | > 30,837     |
+--------------------+----------------+----------------+--------------+
| > 3 (6 months)     | > 13,812       | > 13,775       | > 27,587     |
+--------------------+----------------+----------------+--------------+
| > 4 (12-15 months) | > 9,047        | > 9,122        | > 18,169     |
+--------------------+----------------+----------------+--------------+

Adapted from Table 2, page 42, Volume 5 of BLA.

# Demographic characteristics

> Information about gender and age at start of AOM follow-up was
> available for all subjects in the AOM analysis.

# 

# Characteristics of subjects included in the Otitis Media Analysis---NCKP Study

+----------------------------------+-----------------+-----------------+
|                                  | > 7VPnC         | > MnCC          |
+----------------------------------+-----------------+-----------------+
| Per-Protocol Analysis Population |                 |                 |
+----------------------------------+-----------------+-----------------+
| Number of Children               | > 11849         | > 11897         |
+----------------------------------+-----------------+-----------------+
| Male (%)                         | > 51.9          | > 51.5          |
+----------------------------------+-----------------+-----------------+
| Mean (±SD) Age at Start of       | > 207.8 ± 19.1  | > 207.7 ± 19.0  |
| Follow-up (days)                 |                 |                 |
+----------------------------------+-----------------+-----------------+
| Intent-to-Treat Analysis         |                 |                 |
| Population                       |                 |                 |
+----------------------------------+-----------------+-----------------+
| Number of Children\*             | > 17070         | > 17076         |
+----------------------------------+-----------------+-----------------+
| Male (%)                         | > 51.6          | > 51.1          |
+----------------------------------+-----------------+-----------------+
| Mean (±SD) Age at Start of       | > 64.5 ± 11.1   | > 64.3 ± 10.9   |
| Follow-up (days)                 |                 |                 |
+----------------------------------+-----------------+-----------------+

Adapted from Table 10, page 49, Volume 5 of BLA.

\* The number of children randomized to each treatment group and
included in the ITT analysis, as shown in this table, differs from the
number of children receiving the first dose, as shown in the previous
table, due to errors in administration of treatments as per assignments.

> A substantial proportion of AOM episodes among the randomized
> population were excluded from the per protocol analysis. The
> proportions excluded in each treatment group were similar, 37% (7VPnC)
> vs. 36% (MnCC). The most common reason for excluding children from the
> per protocol analysis was that subjects had not received 3 doses of
> vaccine at data cut-off.
>
> Additional information about demographics of the study population was
> collected on a subset of approximately 7500 randomly selected subjects
> by means of parental telephone interview.
>
> The proportion of the population subset identifying with specific
> race/ethnicity groups is shown below.

Race/Ethnicity As Reported at 48 Hour Interview After Dose 1\-- NCKP
study

+--------------+------+------+------+------+--------+-------+-------+
|              | A    | B    | Hisp | W    | Multi- | O     | p-va  |
|              | sian | lack | anic | hite | ethnic | ther/ | lue\* |
|              |      |      |      |      |        |       |       |
|              | \%   | \%   | \%   | \%   | \%     | Un    |       |
|              |      |      |      |      |        | known |       |
|              |      |      |      |      |        |       |       |
|              |      |      |      |      |        | \%    |       |
+--------------+------+------+------+------+--------+-------+-------+
| 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 7, page 46, Volume 5 of BLA

\*Chi-Square Test (sponsor's analysis)

The study groups appear to be well-balanced with respect to gender,
race/ethnicity, and age at onset of follow-up for AOM outcomes.

> Information about day-care attendance, household income, and mother's
> education was also collected by parental interview of the randomized
> subset. No important differences between study groups for these
> demographic characteristics were identified.

# Primary endpoint analysis: All AOM episodes

> A total of 16,124 AOM episodes were identified in the 11,849 children
> in the 7VPnC group as compared to 17,405 episodes in 11,897 children
> in the MnCC group, a reduction of 7% (95% CI 4.1%, 9.7%).
>
> Results of the intent-to-treat analysis were similar.

Primary endpoint analysis, all AOM episodes---NCKP study

+---------------+--------+--------+-------+--------+--------+--------+
| Outcome       | Ep     |        | Rate/ |        | V      |        |
|               | isodes |        | child |        | accine |        |
|               |        |        | year  |        | effic  |        |
|               |        |        |       |        | acy^1^ |        |
+---------------+--------+--------+-------+--------+--------+--------+
|               | 7VPnC  | MnCC   | 7VPnC | MnCC   | \%     | (95%   |
|               |        |        |       |        | Red    | CI)    |
|               |        |        |       |        | uction |        |
+---------------+--------+--------+-------+--------+--------+--------+
| All AOM       | 16,124 | 17,405 | 1.60  | 1.72   | 7.0%   | (4.1,  |
| Episodes,     |        |        |       |        |        | 9.7)   |
|               |        |        |       |        |        |        |
| Per protocol  |        |        |       |        |        |        |
+---------------+--------+--------+-------+--------+--------+--------+
| All AOM       | 25,590 | 27,199 | 1.29  | 1.37   | 6.4%   | (3.9,  |
| Episodes,     |        |        |       |        |        | 8.7)   |
|               |        |        |       |        |        |        |
| In            |        |        |       |        |        |        |
| tent-to-treat |        |        |       |        |        |        |
+---------------+--------+--------+-------+--------+--------+--------+

> ^1^ Estimates of relative risk based on Andersen-Gill counting process
> over time with treatment as the only covariate.
>
> **Secondary endpoints analyses**

# First AOM episode

> The risk of at least one AOM episode (or risk of first episode) counts
> no more than one AOM episode per subject. Vaccine efficacy estimates
> for the risk of at least one episode (or risk of first episode) were
> statistically significant in both per protocol and intent-to-treat
> analyses, 5.4% and 4.9%, respectively.
>
> In the per protocol analysis, first episodes of AOM accounted for
> approximately 44% and 43% of all AOM episodes in the 7VPnC and MnCC
> groups, respectively. In the intent-to-treat analysis, first episodes
> of AOM accounted for approximately 40% and 38% of all AOM episodes in
> the 7VPnC and MnCC groups, respectively.
>
> Risk of at least one episode---NCKP study

+---------------+--------+--------+--------+--------+--------+--------+
| Outcome       | Number |        | Rate   |        | V      |        |
|               | of     |        | /child |        | accine |        |
|               | Ch     |        | year   |        | ef     |        |
|               | ildren |        |        |        | ficacy |        |
|               | with ≥ |        |        |        |        |        |
|               | 1      |        |        |        |        |        |
|               | E      |        |        |        |        |        |
|               | pisode |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
|               | 7VPnC  | MnCC   | 7VPnC  | MnCC   | \%     | (95%   |
|               |        |        |        |        | Red    | CI)    |
|               |        |        |        |        | uction |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Risk of ≥ 1   | 7,126  | 7,411  | 0.651  | 0.669  | 5.4    | (2.3,  |
| Episode AOM   |        |        |        |        |        | 8.4)   |
|               |        |        |        |        |        |        |
| Per protocol  |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Risk of ≥ 1   | 10,112 | 10,394 | 0.474  | 0.488  | 4.9    | (2.3,  |
| Episode AOM   |        |        |        |        |        | 7.5)   |
|               |        |        |        |        |        |        |
| In            |        |        |        |        |        |        |
| tent-to-treat |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+

> Adapted from Table 12, page 58, Volume 5 of BLA.
>
> Estimates of relative risk and confidence intervals were based on
> Cox-regression model of hazard over time, with gender as covariate.
>
> Frequent otitis media
>
> The definition of frequent otitis media was specified as 3 episodes
> (new visits) within a 6-month period, 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 AOM, compared to 1,809 (15.2%)
> children in the MnCC group. The risk reduction for frequent AOM was
> 9.5% (95% CI: 3.2% to 15.3%). Results of the intent-to-treat analysis
> were similar.
>
> Children with frequent otitis media---NCKP study

+-------------+---------+---------+-------+------+---------+--------+
| Outcome     | Number  |         | Rat   |      | Vaccine |        |
|             | of      |         | e/100 |      | e       |        |
|             | C       |         | child |      | fficacy |        |
|             | hildren |         | years |      |         |        |
|             | with    |         |       |      |         |        |
|             | F       |         |       |      |         |        |
|             | requent |         |       |      |         |        |
|             | AOM     |         |       |      |         |        |
+-------------+---------+---------+-------+------+---------+--------+
|             | 7VPnC   | MnCC    | 7VPnC | MnCC | \%      | 95% CI |
|             |         |         |       |      | Re      |        |
|             |         |         |       |      | duction |        |
+-------------+---------+---------+-------+------+---------+--------+
| Frequent    | 1,647   | 1,809   | 16.4  | 17.9 | 9.5%    | (3.2,  |
| AOM         |         |         |       |      |         | 15.3)  |
|             |         |         |       |      |         |        |
| Per         |         |         |       |      |         |        |
| protocol    |         |         |       |      |         |        |
+-------------+---------+---------+-------+------+---------+--------+
| Frequent    | 2,612   | 2,839   | 12.3  | 13.3 | 9.2%    | (4.3,  |
| AOM         |         |         |       |      |         | 13.9)  |
|             |         |         |       |      |         |        |
| Inte        |         |         |       |      |         |        |
| nt-to-treat |         |         |       |      |         |        |
+-------------+---------+---------+-------+------+---------+--------+

> Adapted from Table 13, page 62, Volume 5 of BLA.
>
> Estimates of relative risk and confidence intervals were based on Cox
> regression model over time with gender as a covariate.

# 

# Tympanostomy tube placement

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

# 

# Tympanostomy tube placement---NCKP study

+---------------+--------+--------+--------+-------+--------+--------+
| Outcome       | Number |        | Ra     |       | V      |        |
|               | of     |        | te/100 |       | accine |        |
|               | Ch     |        | child  |       | ef     |        |
|               | ildren |        | years  |       | ficacy |        |
|               | with   |        |        |       |        |        |
|               | Tube   |        |        |       |        |        |
|               | Pla    |        |        |       |        |        |
|               | cement |        |        |       |        |        |
+---------------+--------+--------+--------+-------+--------+--------+
|               | 7VPnC  | MnCC   | 7VPnC  | MnCC  | \%     | (95%   |
|               |        |        |        |       | Red    | CI)    |
|               |        |        |        |       | uction |        |
+---------------+--------+--------+--------+-------+--------+--------+
| Tube          | 157    | 198    | 1.43   | 1.79  | 20.3%  | (1.8,  |
| Placement     |        |        |        |       |        | 35.4)  |
|               |        |        |        |       |        |        |
| Per protocol  |        |        |        |       |        |        |
+---------------+--------+--------+--------+-------+--------+--------+
| Tube          | 192    | 240    | 0.90   | 1.13  | 20.6%  | (4.0,  |
| Placement     |        |        |        |       |        | 34.3)  |
|               |        |        |        |       |        |        |
| In            |        |        |        |       |        |        |
| tent-to-treat |        |        |        |       |        |        |
+---------------+--------+--------+--------+-------+--------+--------+

> Adapted from Table 14, page 66, Volume 5 of BLA.
>
> Estimates of relative risk and confidence intervals were based on Cox
> regression model of hazard over time.

# Clinic visits for otitis media

# 

# A total of 22,478 clinic visits for AOM were recorded in the 7VPnC group during the per protocol follow-up period, compared to 24,914 visits in the MnCC group. The overall incidence of AOM visits was reduced from 2.25 visits per child-year in the MnCC group, to 2.05 visits per child-year in the 7VPnC group, an 8.9% (95% CI: 5.8% to 11.8%) reduction. Results of the intent-to-treat analysis were consistent with per protocol.

# 

# Overall incidence of all otitis media visits---NCKP study

+---------------+--------+--------+--------+------+--------+---------+
| Outcome       | Number |        | Ra     |      | V      |         |
|               | of     |        | te/100 |      | accine |         |
|               | Ch     |        | child  |      | ef     |         |
|               | ildren |        | years  |      | ficacy |         |
|               | with   |        |        |      |        |         |
|               | Tube   |        |        |      |        |         |
|               | Pla    |        |        |      |        |         |
|               | cement |        |        |      |        |         |
+---------------+--------+--------+--------+------+--------+---------+
|               | 7VPnC  | MnCC   | 7VPnC  | MnCC | \%     | (95%    |
|               |        |        |        |      | Red    | CI)     |
|               |        |        |        |      | uction |         |
+---------------+--------+--------+--------+------+--------+---------+
| All AOM       | 22,478 | 24,914 | 2.05   | 2.25 | 8.9%   | (5.8,   |
| visits        |        |        |        |      |        | 11.8)   |
|               |        |        |        |      |        |         |
| Per protocol  |        |        |        |      |        |         |
+---------------+--------+--------+--------+------+--------+---------+
| All AOM       | 38,010 | 38,010 | 1.64   | 1.78 | 7.8%   | (5.2,   |
| visits        |        |        |        |      |        | 10.5)   |
|               |        |        |        |      |        |         |
| In            |        |        |        |      |        |         |
| tent-to-treat |        |        |        |      |        |         |
+---------------+--------+--------+--------+------+--------+---------+

Adapted from Table 15, page 69, Volume 5 of BLA.

Estimates of relative riskwere based on Andersen-Gill counting process
over time with treatment as the only covariate.

> **Exploratory 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 November 6, 1998. The number of ruptured eardrums
> in the dataset locked in April 1998 was too small for meaningful
> analysis. The later data cut-off for this endpoint was chosen so that
> the additional cases accrued could be included in the analysis. This
> analysis took place prior to unblinding of the otitis media dataset,
> however, the timing of this analysis was not pre-specified in the
> analysis plan.
>
> Of the 13 cases of ruptured eardrums with a bacterial culture positive
> for vaccine serotype pneumococcus during per protocol follow-up, 4
> were in the 7VPnC group and 9 were in the control group. The vaccine
> efficacy estimate, 55.6%, was not statistically significant .
> Likewise, the efficacy estimate of vaccine serotypes during
> intent-to-treat follow-up was 57%; this result was not statistically
> significant.
>
> The efficacy estimate for ruptured eardrums with a positive culture
> for any pneumococci, regardless of serotype, was 61% in the
> intent-to-treat analysis; this result was statistically significant.

Ruptured eardrums with pneumococcus isolated---NCKP study

+---------------+------------+------------+-------------+-------------+
| Ruptured      | Number of  |            | Vaccine     |             |
| Eardrum       | Cases      |            | Efficacy    |             |
|               |            |            |             |             |
| (Cases        |            |            |             |             |
| through       |            |            |             |             |
| November 6,   |            |            |             |             |
| 1998)         |            |            |             |             |
+---------------+------------+------------+-------------+-------------+
|               | 7VPnC      | MnCC       | \%          | (95% CI)    |
|               |            |            | Reduction   |             |
+---------------+------------+------------+-------------+-------------+
| Vaccine       |            |            |             |             |
| Serotypes     |            |            |             |             |
+---------------+------------+------------+-------------+-------------+
| Per Protocol  | 4          | 9          | 55.6%       | (-59.3, 90) |
+---------------+------------+------------+-------------+-------------+
| In            | 6          | 14         | 57.1%       | (-18.7,     |
| tent-to-treat |            |            |             | 86.5)       |
+---------------+------------+------------+-------------+-------------+
| All           |            |            |             |             |
| pneumococcal  |            |            |             |             |
| serotypes     |            |            |             |             |
+---------------+------------+------------+-------------+-------------+
| Per Protocol  | 5          | 13         | 61.5%       | (-15.0,     |
|               |            |            |             | 89.3)       |
+---------------+------------+------------+-------------+-------------+
| In            | 7          | 18         | 61.1%       | (2.4, 86.3) |
| tent-to-treat |            |            |             |             |
+---------------+------------+------------+-------------+-------------+

Adapted from Table 19, Volume 1 of PLA.

Confidence limits were determined based on exact binomial distributions.

Vaccine sertoype 19F and related serotype 19A accounted for all isolates
from ruptured tympanic membranes in the 7VPnC group. Serotype 19F
accounted for 39% of all isolates from the MnCC group. Vaccine serotypes
accounted for 78% (14/18) of all isolates from the control group, and
80% (20/35) of all isolates in both groups.

# Serotype distribution of isolates from ruptured ear drums due to pneumococcus, intent-to-treat analysis\--NCKP study

+------------------------+--------------------+------------------------+
| > Serotype             | Number of cases    |                        |
|                        | (%) due to each    |                        |
|                        | serotype           |                        |
+------------------------+--------------------+------------------------+
|                        | > 7VPnC            | > MnCC                 |
+------------------------+--------------------+------------------------+
| > 19F                  | > 6                | > 7 (38.9%)            |
+------------------------+--------------------+------------------------+
| > 14                   | > 0                | > 4 (22.2%)            |
+------------------------+--------------------+------------------------+
| > 9V                   | > 0                | > 1 (5.6%)             |
+------------------------+--------------------+------------------------+
| > 23F                  | > 0                | > 2 (11.1%)            |
+------------------------+--------------------+------------------------+
| > Total of vaccine     | > 6                | > 14 (77.8%)           |
| > serotypes            |                    |                        |
+------------------------+--------------------+------------------------+
| > 19A                  | > 1                | > 1 (5.6%)             |
+------------------------+--------------------+------------------------+
| > 6A                   | > 0                | > 1 (5.6%)             |
+------------------------+--------------------+------------------------+
| > 3                    | > 0                | > 1 (5.6%)             |
+------------------------+--------------------+------------------------+
| > 29 & 35              | > 0                | > 1 (5.6%)             |
+------------------------+--------------------+------------------------+
| > Total of non-vaccine | > 1                | > 4 (22.2%)            |
| > serotypes            |                    |                        |
+------------------------+--------------------+------------------------+
| > Total of all         | > 7                | > 18                   |
| > serotypes            |                    |                        |
+------------------------+--------------------+------------------------+

Adapted from Table 17, page 73, Volume 5 of BLA.

> Follow-up analyses
>
> The data cut-off for the AOM efficacy analysis was April 30, 1998.
> However, children continued to enroll in the study until August 24,
> 1998, when the data were unblinded for the efficacy analysis for
> invasive disease. All enrolled children were followed within NCKP
> using the computerized patient data for AOM outcomes until April 20,
> 1999, at which time parents and participating clinicians were made
> aware of treatment assignments. AOM efficacy data through the extended
> follow-up are shown below.

Efficacy Analysis for AOM During Intent-to-treat Follow-up,

All Data of NCKP Trial through April 20, 1999---NCKP study

+------------+-------+-------+------+-------+-----------+-----------+
|            | ##    |       |      |       |           |           |
|            | ##### |       |      |       |           |           |
|            | # ITT |       |      |       |           |           |
|            |  Foll |       |      |       |           |           |
|            | ow-up |       |      |       |           |           |
+------------+-------+-------+------+-------+-----------+-----------+
|            | N     |       | Nu   |       | Risk      |           |
|            | umber |       | mber |       | Reduction |           |
|            | of    |       | of   |       | Estimate  |           |
|            | Sub   |       | Ev   |       |           |           |
|            | jects |       | ents |       |           |           |
+------------+-------+-------+------+-------+-----------+-----------+
|            | April | April | A    | April | April 30, | April 20, |
|            | 30,   | 20,   | pril | 20,   | 1998      | 1999      |
|            | 1998  | 1999  | 30,  | 1999  |           |           |
|            |       |       | 1998 |       |           |           |
+------------+-------+-------+------+-------+-----------+-----------+
| All AOM    | 3414  | 378   | 5    | 84978 | 6.4%      | 5.9%      |
| Episodes   | 6^\*^ | 66^†^ | 2789 |       | (3.9%,    | (3.8%,    |
|            |       |       |      |       | 8.7%)     | 7.9%)     |
+------------+-------+-------+------+-------+-----------+-----------+
| First AOM  | 34146 | 37866 | 2    | 27343 | 4.9%      | 4.4%      |
| Episode    |       |       | 0506 |       | (2.3%,    | (2.1%,    |
|            |       |       |      |       | 7.5%)     | 6.7%)     |
+------------+-------+-------+------+-------+-----------+-----------+
| First Tube | 34146 | 37866 | 432  | 751   | 20.6%     | 23.2%     |
| Placement  |       |       |      |       | (4.0%,    |           |
|            |       |       |      |       | 34.3%)    | (11.3%,   |
|            |       |       |      |       |           | 33.5%)    |
+------------+-------+-------+------+-------+-----------+-----------+
| All AOM    | 34146 | 37866 | 7    | 1     | 7.8%      | 7.0%      |
| Clinic     |       |       | 3041 | 16636 | (5.2%,    | (4.8%,    |
| Visit      |       |       |      |       | 10.5%)    | 9.2%)     |
+------------+-------+-------+------+-------+-----------+-----------+
| Frequent   | 34146 | 37866 | 5451 | 12252 | 9.2%      | 10.9%     |
| AOM        |       |       |      |       |           |           |
|            |       |       |      |       | (4.3%,    | (7.7%,    |
|            |       |       |      |       | 13.9%)    | 14.0%)    |
+------------+-------+-------+------+-------+-----------+-----------+
| Ruptured   | 34146 | 37866 | 20   | 24    | 57.1%     | 66.7%     |
| Ear        |       |       |      |       |           |           |
|            |       |       |      |       | (-18.7%,  | (12.3%,   |
| Drum due   |       |       |      |       | 86.5%)    | 89.2%)    |
| to Vaccine |       |       |      |       |           |           |
| Serotype   |       |       |      |       |           |           |
+------------+-------+-------+------+-------+-----------+-----------+

Adapted from Table Q17.1 of BLA submission of April 15, 2002.

^\*^ 7VPnC: 17070; MnCC: 17076

^†^ 7VPnC: 18925; MnCC: 18941

# 

# Efficacy results for all outcomes in the extended follow-up period are consistent with results of the planned AOM analyses. Efficacy estimates are similar and confidence intervals are generally narrower with the additional follow-up data. 

**5.0 FDA discussion of review issues related to acute otitis media**

###### In deliberations on new product approvals, risks and benefits are evaluated, and a determination is made whether or not a product is safe and effective for the indication being sought. The safety of Prevnar was carefully examined in several studies at the time of licensure for prevention of invasive disease, including the large safety and efficacy study conducted at NCKP. Safety data from the Finnish AOM study were reviewed with this submission, and are discussed in Attachment A of this document. However, product labels can be updated with important safety findings at any time. Discussion of the proposed indication for prevention of AOM will focus on describing additional benefits of Prevnar, i.e., prevention of AOM. Should the indication be approved, description of the treatment effect of Prevnar in prevention of AOM in approved labeling could then be used in the manufacturer's promotional materials. 

###### 

**Finnish AOM study**

The Finnish study provided serotype specific, direct causal evidence of
prevention of AOM due to *S. pneumoniae*, as the bacteria were isolated
from the middle ears of subjects presenting with AOM. This type of trial
would be quite difficult to conduct in the U.S. since tympanocentesis
and culture of middle ear fluid are not the standard of care for the
management of AOM in most communities.

An important anomalous finding from the Finnish study was the increased
risk of AOM due to pneumococci from serogroups not represented in
Prevnar. This "negative efficacy" for non vaccine serotypes has been
referred to as "serotype replacement". These AOM episodes due to
non-vaccine serotypes are clearly of clinical significance, as affected
subjects suffered symptoms sufficient to bring them to medical attention
and subsequent myringotomy. Thus, consideration of this finding is
essential to the evaluation and description of the overall benefit
afforded by Prevnar. However, to the extent that the replacing
pneumococcal serotypes are more susceptible to commonly used
antimicrobials, which is likely based on the known association of
antibiotic resistance with vaccine serotypes, the replacement of
antibiotic-resistant pneumococci by antibiotic-susceptible organisms
might be interpreted as a favorable outcome.

Although the overall vaccine effect on all cause AOM was not
statistically significant in the Finnish study, the trial was not
designed or powered to detect an effect on this outcome. The efficacy
point estimate (6%) was nevertheless comparable to what was observed in
the NCKP study for a similar endpoint.

The repeated isolation of the same serotype from middle ear fluids over
extended periods (several months) of some subjects observed in the
Finnish study may simply reflect nasopharyngeal carriage of those
serotypes. However, as was pointed out in a letter to the editor
following publication of study results (Cantekin, 2001), an implication
for the analysis of counting multiple AOM episodes per subject is that
the true treatment effect can be inflated. In the sponsor's planned
secondary analysis of first AOM episodes due to vaccine serotypes,
(i.e., one AOM episode per subject), the efficacy estimates were similar
to those of the primary analysis and were statistically significant (52%
per protocol, 48% intent-to-treat). Supplemental analyses requested by
FDA to examine alternative estimates of the treatment effect, in which
only one episode per serotype per subject contributes to the analysis,
showed that the efficacy estimates for vaccine serotypes and for all
pneumococcal serotypes were statistically significant and not markedly
changed from those of the planned analyses, which included multiple
episodes per subject.

Examination of characteristics of the subject population revealed some
differences between the study groups for AOM risk factors. The
supplemental covariate analyses conducted by the sponsor provided some
assurance that results for the primary endpoints would not be
significantly affected by these differences.

Other supplementary analyses requested by FDA, such as analyses of the
use of antibiotics and the placement of ear tubes, provided results
largely consistent with a positive treatment effect of Prevnar on AOM.
Analysis of AOM episodes based on the identification of pneumococcus
using PCR did yield efficacy estimates slightly lower than efficacy
estimates based on bacterial culture. Some authors have suggested that
PCR provides a sensitive indicator of pneumococcal involvement in AOM
(Virolainen A, et al., 1994). Culture will identify viable organisms,
while PCR can detect non-viable organisms or fragments of residual DNA
in middle ear fluid. The most appropriate interpretation of efficacy
results based on PCR is not readily apparent.

**NCKP study**

The NCKP study was limited by the lack of common uniform diagnostic
criteria for AOM, and the lack of culture confirmation for most cases of
AOM. Strengths of the NCKP study for AOM outcomes included the great
power to detect small differences in overall benefit, and the "real
world" approximation of the diagnosis and management of AOM, which may
be generalizable to a wider US population. Also, the randomization of
such a large study population practically assures good balance between
the study groups at baseline of subjects with AOM risk factors.

The efficacy estimate for the primary endpoint, all AOM episodes, of
7.0% (95%CI: 4.1%, 9.7%) in the per protocol analysis, is comparable to
the efficacy estimate from the Finnish trial for the similar endpoint.
It is worth emphasizing that the outcome of "all AOM episodes" included
AOM episodes due to viral pathogens, *M. catarrhalis, H. influenzae, S.
pyogenes*, and non-vaccine serotype pneumococci. Nevertheless, the NCKP
study had sufficient power to demonstrate statistical significance for
this outcome.

The 21-day period between "AOM episodes" used in the NCKP AOM
definitions, differs from the 30-day period used to define new episodes
in the Finnish study. The most appropriate period for defining a new AOM
episode is uncertain. However, it is likely that shorter period defining
new episodes will lead to inclusion of more new episodes in the
analysis, some of which may be the same slowly resolving AOM episodes,
or simply follow-up visits encoded as clinic visits for AOM on the
patient encounter forms.

One check on the possibility that the definition used in the NCKP study
for "all AOM episodes" may overcount cases or otherwise inflate the
treatment effect is the secondary outcome of "at least one AOM episode".
This outcome counts no more than one AOM episode per subject. The
efficacy estimate for "at least one AOM episode" in the per protocol
analysis was 5.4% (95%CI: 2.3, 8.4), slightly lower than the efficacy
estimate for the primary analysis, but nevertheless a statistically
significant result.

The highest statistically significant efficacy estimate among the
secondary AOM endpoints in the NCKP study was for prevention of ear tube
placement, 20.6% in the intent-to-treat analysis; however, the 95%
confidence intervals for this estimate were wide (95% CI: 4.0, 34.3).
After an additional year of extended follow-up, the efficacy estimate
for prevention of ear tube placement was 23.2%, and the confidence
intervals had narrowed with the additional follow-up data (11.3%,
33.5%).

# Analysis issues

The efficacy estimates for the primary endpoints in both the Finnish and
NCKP studies use analytic methods for repeated measures over time. This
type of analysis is not typical for most vaccine studies, in which each
study participant contributes no more than one case to the analysis.

The Anderson-Gill model of proportional hazards that was chosen for the
analysis of repeated episodes of AOM is said to analyze risk periods
"piecewise" with "robust standard errors". These statistical methods may
be the best available for the analysis of repeated episodes of AOM
following vaccination as a means to measure efficacy using all available
outcome data. Nevertheless, the methods are likely not intuitive to most
clinicians, and applicability of these methods in a vaccine trial may
not be readily apparent.

Sequential episodes of AOM within subjects will be dependent to some
extent based on inherent risk or resistance factors. Episodes of AOM may
not be entirely resolved by the end of 21 days (NCKP) or 30 days
(Finnish study), in which case a new episode may be counted that is in
fact an extension of the same episode. Based on what is known about the
pathogenesis of AOM, persistence of edema around the Eustachian tube and
persistence of middle ear fluid after an episode of AOM resolves may
contribute to conditions favorable to a repeated episodes. Carriage of a
serotype in the nasopharynx likely impacts on repeated isolation of that
serotype on repeated samplings of middle ear fluid during AOM episodes.
The risks of AOM episodes might also be expected to increase
disproportionately between groups over time if early episodes predispose
to later episodes.

One check on the repeated measures data that was included among
secondary endpoints in both trials, was the analysis of "risk of first
episode". If only first episodes are considered, much of the AOM outcome
data would be discarded, but uncertainty related to carry over effects
of previous episodes beyond the 21-day or 30-day periods would be
avoided. FDA also requested additional analyses to check the robustness
of the original analysis and to elucidate the effects of baseline
imbalances for risk factors, which may also carry forward. Other
analyses from the Finnish study based "one episode per pneumococcal
serotype per subject" were requested in order to better understand
whether counting multiple episodes of the same serotype in individuals
inflates efficacy estimates. While the efficacy estimates from these
supplementary and secondary analyses vary, they remain statistically
significant, and, therefore, provide confirmatory evidence of a positive
treatment effect of Prevnar on prevention of AOM.

**Level of evidence sufficient for an approved indication**

Approvals of most drugs and other therapeutic biological products are
based on substantial evidence of efficacy from at least 2
well-controlled clinical studies. This follows from the Code of Federal
Regulations (CFR), Section 505 \[21 CFR 355\] (d), defining substantial
evidence as "consisting of adequate and well controlled investigations".
As modified under the Food and Drug Modernization Act (FADMA) of 1997, a
single well-controlled clinical investigation may be deemed sufficient
to meet a level of substantial evidence if confirmatory data from other
studies are also available. For many vaccines, a single study has been
deemed sufficient for providing evidence of efficacy; however, vaccine
efficacy studies are typically quite large, multi-center, and
demonstrate a high level of efficacy.

The Finnish study and the NCKP study provide efficacy data using
complementary study designs. The Finnish study was designed to provide
direct causal evidence of efficacy, by isolation and identification of
pneumococci from the middle ears fluids of subjects. The Kaiser study
was a large trial that provided empirical evidence of a small treatment
effect in preventing all cause AOM in infants and small children. In
each study, statistical significance was demonstrated for the primary
endpoints. Evidence from secondary endpoints was supportive and
consistent with the expected treatment effects.

Arguably, the sponsor has provided efficacy data from two adequate and
well-controlled studies demonstrating a level of evidence that is
sufficient by FDA regulations for an approved indication.

The lowest level of efficacy acceptable for approval of a vaccine
indication has not been set by FDA regulation or CBER policy. For most
preventive vaccines, vaccine efficacy estimates are high (\>80%) and are
associated with a high level of statistical significance. Examples of
licensed vaccines associated with relatively low efficacy estimates for
the primary outcome measures in studies include cholera (\~50%) (MMWR,
1988), typhoid (50-79%) (MMWR, 1994), and influenza (20-80%) (Patriarca
P et al., 1987).

# Description of the treatment effect

If one accepts that substantial evidence of efficacy in preventing AOM
has been demonstrated, then a new indication that describes the
treatment effect of Prevnar regarding AOM will be included in the label
indication. The sponsor proposes an indication for prevention of AOM
limited to serotypes represented in Prevnar. Such an indication would
reflect the primary endpoint of the Finnish AOM study, but not the
primary AOM endpoint in the NCKP study. Focusing on vaccine
serotype-specific efficacy would not capture the treatment effect for
vaccine-related serotypes, nor the increased risk of AOM due to other,
non-vaccine- related pneumococcal serotypes observed in the Finnish
study.

Preventing as much otitis media as possible is clearly the goal of a
vaccine to prevent otitis media. While it may not be realistic to expect
a large preventive effect on otitis media caused by pneumococcal
serotypes not covered by Prevnar, the potential for serotype replacement
appears to be a real possibility. An indication for prevention of all
pneumococcal AOM, regardless of serotypes would be based on a lower
efficacy estimate (34%) from the Finnish study, but it appears to
capture the effect on vaccine-related serotypes, serotype replacement,
and would provide a standard of efficacy that could be reasonably
applied to other pneumococcal vaccines that may be active against
additional serotypes. If serotype specific efficacy serves as the basis
for the AOM indication, then information about overall efficacy for
pneumococcal AOM disease (vaccine and non-vaccine combined) as well as
unrelated serotypes should also be included in the label.

Approval of Prevnar for prevention of invasive disease was for an
indication limited to vaccine serotypes. However, vaccine serotypes
accounted for over 80% of all invasive disease isolates. Moreover,
replacement of vaccine serotypes by non-vaccine serotypes was not
observed during the large efficacy study, and has not been observed,
even after prolonged follow-up at NCKP (Black SB, et al., 2001).

**Implications for licensure of other pneumococcal vaccines**

At the March 2001 VRBPAC, the committee was asked to consider pathways
to licensure of future pneumococcal vaccines. Specifically, the
committee was asked to comment on whether efficacy data demonstrating a
significant treatment effect in preventing AOM would provide a basis for
licensure of a pneumococcal vaccine for an indication of invasive
disease. The predominant opinion expressed by committee members was that
demonstration of efficacy for AOM alone would not provide sufficient
support for an invasive disease indication. It was noted that while
prevention of otitis media may be a stringent test of vaccine efficacy,
other variables such as the level of preventive efficacy for AOM, and
the relative distribution of important serotypes for the two disease
conditions, complicate the translation of efficacy for AOM to efficacy
against invasive disease.

To date, Prevnar is the only licensed pneumococcal conjugate vaccine for
any indication. No correlation between a serological parameter and
efficacy for any indication has been clearly demonstrated or generally
accepted. With the availability of Prevnar, efficacy trials using
invasive disease endpoints could be difficult to conduct in any setting.

In the future, FDA may be asked to consider license applications for
other pneumococcal vaccines for prevention of acute otitis media. The
approval of an indication for Prevnar for prevention of AOM, would
likely set a precedent for the type of data and level of efficacy
sufficient for approval of future pneumococcal vaccines for this
indication, independent of whether or not the license applications for
these new vaccines include evidence of efficacy for prevention of
invasive disease. The description of the treatment effect could
influence the type of data used as a basis for approval of other
pneumococcal vaccines for prevention of AOM. One can envision a scenario
where a vaccine might have a lower efficacy estimate than Prevnar for
serotypes included in the vaccine, yet prevent more cases of AOM as a
result of greater coverage of pneumococcal serotypes, either due to
increased number of serotypes represented in the vaccine, or by some
other mechanism.

**Clinical benefit vs. economic benefit as basis of regulatory
approval**

In the risk/benefit assessment of product approvals by FDA, substantial
evidence of clinical benefit must be provided from well-controlled
studies. A decrease in office visits for AOM and potential cost savings
of medical care related to AOM have been cited by the sponsor and in the
literature among the benefits of Prevnar. To the extent that office
visits reflect patient disease, they may be considered in the assessment
of clinical benefit for the basis of a regulatory decision. However,
economic benefit to individuals or society cannot provide the basis of
efficacy for a product approval.

###### Antibody responses in Finnish study

Serum antibody concentrations (GMC) from the Finnish study based on
standardized ELISA assays, appear to be consistent with antibody levels
observed among 7VPnC recipients in other pre-licensure studies. However,
the antibody levels do not provide any insight regarding observed
differences in efficacy by serotype. For example, the estimate of
vaccine efficacy against type 6B was greatest among the serotypes, yet
the GMC after the first 3 doses was 2^nd^ lowest. Little efficacy was
observed for serotype 19F, yet GMCs after the 3^rd^ and 4^th^ doses were
similar to those of other serotypes. Likewise, using percent of subjects
responding above defined antibody cutoff levels, 100% of subjects in the
serology cohort had antibody levels to serotype 19F above 0.3 mcg/mL and
0.5 mcg/mL, and 91% had antibody levels above 1.0 mcg/mL after 3 doses.
For serotype 6B, 85%, 83% and 67% of subjects had antibody levels above
0.3 mcg/mL, 0.5 mcg/mL, and 1.0 mcg/mL, respectively.

It may be informative to determine the presence of opsonophagocytic
antibody (OPA) by serotype and to examine its predictive value for
protection against AOM. It would also be of interest to examine ELISA
and GMCs for related vaccine serotypes. These data were not provided in
the application. However, the sponsor does not propose any specific
claims regarding the relationship of immune response parameters with
efficacy for otitis media.

Results from the Finnish and NCKP studies regarding serotype 19F deserve
additional comment. In the Finnish study, statistical significance for
serotype specific efficacy for 19F was not observed, despite a
substantial number of AOM episodes due to serotype 19F. In the
supplemental analysis in which each serotype contributes no more than
one episode of AOM to the analysis, the efficacy estimate for 19F was
only 2% in the ITT analysis. Moreover, in the NCKP study, 6 of the 7
isolates from ruptured tympanic membranes in the 7VPnC group were due to
serotype 19F (and the remaining isolate was the related type 19A). Taken
together, these data suggest that the pathogenesis of AOM due to
serotype 19F, or the immune response to serotype 19F induced by Prevnar,
may be fundamentally different for this serotype.

# Marketing implications of an AOM indication

###### 

Approval of an indication for prevention of otitis media would normally
allow the manufacturer to distribute marketing materials promoting use
of the product based on information included in the approved labeling.
The potential for misleading public expectations in marketing materials
would exist for Prevnar, as for any product and approved indication.
However, FDA is empowered to restrict unrealistic marketing claims.
Regulations for post-marketing reporting requires applicants to submit
advertisements and promotional labeling to CBER for review.
Advertisements that are judged false, lacking in fair balance, or are
otherwise misleading (defined in CFR 202.1) can result in a product
being misbranded. If a company fails to correct such violations, CBER is
empowered to suspend or revoke an approved license (21 CFR 601.6 and
601.5).

**Summary remarks**

Results from two, randomized, well-controlled clinical studies
demonstrated statistically significant reduction in acute otitis media
outcomes. In each study, the primary analysis demonstrated a
statistically significant effect on the prospectively chosen outcome of
interest. Results of secondary and ancillary outcome measures in both
trials, as well as supplementary analyses requested by FDA, were largely
consistent with a positive treatment effect afforded by Prevnar. The
magnitude of the efficacy estimates for the primary outcomes were
relatively low compared to efficacy results of most preventive vaccines.
Whether the impact of Prevnar on acute otitis media represents
substantial evidence of efficacy for this new indication, and if so, the
most appropriate description of the treatment effect, merit discussion
in a public forum by a panel of experts.

**References**

American Academy of Pediatrics. Antimicrobial Agents and Related
Therapy.In:Pickering LK,ed. 2000 Red Book:*Report of the Committee on
Infectious Disease*.25^th^ ed. Elk Grove Village, IL. American Academy
of Pediatrics:2000:648.

Anderson PK, Gill RD. Cox's regression model for counting processes: A
large sample study. Annals of Statistics, 1982; 10:1100-1120.

Barry AL. Antimicrobial Resistance among Clinical Isolates of
Streptococcus pneumoniae in North America; Am J Med 1999; 107:28S-34S.

Black SB, Shinefield HR, Hansen J, Elvin L, Laufer D, Malinoski F.
Postlicensure evaluation of the effectiveness of seven valent
pneumococcal conjugate vaccine. Pediatr Infect Dis J 2001 20:1105-7.

Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, Elvin L,
Ensor KM, Hackell J, Siber G, Malinoski F, Madore D, Chang I, Kohberger
R, Watson W, Austrian R, Edwards K. Efficacy, safety and immunogenicity
of heptavalent pneumococcal conjugate vaccine in children. Northern
California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect
Dis J 2000; 19:187-95

Bluestone CD, Stephenson JS, Martin LM. Ten year review of otitis media
pathogens. Pediatr Infec Dis J 1992; 11:S7-S11.

Bluestone CD. Role of surgery for otitis media in the era of resistant
bacteria. Pediatr Infect Dis J 1998; 17:1090-8.

Cantekin E. Letter to the editor, N Engl J Med 2001;344:1719-20.

Center for Disease Control and Prevention. Recommendations of the
immunization practices advisory committee (ACIP): Cholera vaccine. MMWR
1988; 37:617-624.

Center for Disease Control and Prevention. Typhoid immunization
recommendations of the advisory committee on immunization practices
(ACIP). MMWR 1994;431-7.

Damoiseaux R. Letter to the editor, N Engl J Med 2001;344:1719-20.

Dowell SF, Marcy SM, Phillips WR, Gerber MA, Schwartz B. Otitis
Media\--Principles of Judicious Use of Antimicrobial Agents. Pediatrics
1998;101(Suppl):165-6.

Eerola M. Repeatable events in life-history analysis; the effect of
childhood separation on future mental health. Bull. Int. Stat. Inst.
1989;LIII:213-225.

[Eskola J, Kilpi T, Palmu A, Jokinen J, Haapakoski J, Herva E, Takala A,
Kayhty H, Karma P, Kohberger R, Siber G, Makela
PH](http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11172176&dopt=Abstract).
Efficacy of a pneumococcal conjugate vaccine against acute otitis media.
N Engl J Med 2001; 344:403-9.

European Public Assessment Report (EPAR) for the Marketing Authorization
for Prevenar, October 19, 2000, Scientific Discussion, page 28.

Heikkinen T. The role of respiratory viruses in otitis media. Vaccine
2000;19 Suppl 1:S51-5.

Jero J, Virolainen A, Salo P, Leinonen M, Eskola J, Karma P. PCR Assay
for detecting *Streptococcus pneumoniae* in the Middle Ear Fluid of
Children with Otitis Media with Effusion. Acta Otolaryngol 1996;
116:288-292.

Joloba ML, Windau A, Bajaksouzian s, Appelbaum PC, Hausdorff WP, Jacobs
MR. Pneumococcal conjugate vaccine serotypes of Streptococcus pneumoniae
isolates and the antimicrobial susceptibility of such isolates in
children with otitis media. Clin Infect Dis 2001; 33:1489-1494

Kilpi T, Herva E, Kaijalainen T, Syrjanen R, Takala AK. Bacteriology of
acute otitis media in a cohort of Finnish children followed for the
first two years of life. Pediatr Inf Dis J 2001; 20:654-662

Klein JO. The burden of otitis media. Vaccine 2000; 19:S2-8.

Klein JO. Otitis media. Clin Infect Dis 1994; 19:823-33

Kvaerner KJ, et al., Recurrent acute otitis media: the significance of
age at onset. Acta Otolaryngol 1997; 117:578-84.

Lavin A. Letter to the editor, N Engl J Med 2001; 344:1719-20.

Lopez B et al., Epidemiological Study of *Streptococcus pneumoniae*
Carriers in Healthy Primary School Children 1999; 18:771-776

McDougal LK et al., Analyses of multiply antimicrobial-resitant isolates
of Streptococcus pneumoniae from the United States. Antimicrobial Agents
Chemother 1992; 36:2176-2184.

Montgomery JM et al., Bacterial colonization of the upper respiratory
tract and its association with acute lower respiratory tract infections
in highland children of Papua New Guinea. Rev Infect Dis 1990;
12S1006-16

Niemela M, Uhari M, Mottonen M, Pokka T. Costs arising from otitis
media. Acta Paediatr 1999; 88:553-6.

Patriarca PA, Arden NH, Kolan JP, et al., Prevention and control of type
A influenza infections in nursing homes: Benefits and costs of four
approaches using vaccinationa and amantadine. Ann Intern Med 1987;
107:732-740.

Sauder K. Letter to the editor, N Engl J Med 2001; 344:1719-20.

Thompson D, Oster G, McGarry LJ, Klein JO. Management of otitis media
among children in a large health insurance plan. Pediatr Infect Dis J
1999; 18:239-44

Tuomanen EI, Pathogenesis of pneumococcal inflammation: otitis media.
Vaccine 2001; 19:S38-40.

Virolainen A, Salo P, Jero J, Karma P, Eskola, J, Leinonen M. Comparison
of PCR Assay with Bacterial Culture for Detecting Streptococcus
pneumoniae in Middle Ear Fluid of Children with Acute Otitis Media. J
Clin Microbiol 1994; 32:2667-70.

**Attachment A: Review of safety from Finnish study**

No questions regarding safety data are being asked of VRBPAC at the May
2002 meeting. Safety data from the Kaiser efficacy study were reviewed
at the November 1999 VRBPAC, in the context of consideration of the
invasive disease indication. Safety data from the Finnish study were
reviewed with the BLA for prevention of AOM. A discussion of these data
follows.

# Description of Finnish safety data

Safety follow-up for each participant began at the time of enrollment (2
months of age), and ended at 24 months of age.

Local and systemic reactions were monitored in all children for 3 days
after each vaccine dose using a 3-day diary card completed by parents.
Presence or absence and severity of local tenderness, redness, swelling,
fever, and crying were recorded. Rectal temperatures were to be measured
and recorded at 24, 48, and 72 hours after inoculations. The diameter of
redness and swelling was to be measured and recorded by parents.

Parent compliance with reporting of vaccine reactions was nearly
complete. Data on vaccine reactions were available for 6523 cards
(98.9%) after 6597 inoculations.

Local and systemic reaction rates are summarized in the following
tables:

# Vaccine Reactions Reported within 72 Hours of HBV and PncCRM vaccines, 

# First 3 doses---Finnish study

<table style="width:100%;">
<colgroup>
<col style="width: 15%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 10%" />
<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>PncCRM</p>
<p>N=825<sup>a</sup></p>
<p>%</p></td>
<td><p>HBV</p>
<p>N=825<sup>a</sup></p>
<p>%</p></td>
<td>p-value<sup>1</sup></td>
<td><p>PncCRM</p>
<p>N=818 <sup>a</sup></p>
<p>%</p></td>
<td><p>HBV</p>
<p>N=826 <sup>a</sup></p>
<p>%</p></td>
<td>p-value<sup>1</sup></td>
<td><p>PncCRM</p>
<p>N=817 <sup>a</sup></p>
<p>%</p></td>
<td><p>HBV</p>
<p>N=816 <sup>a</sup></p>
<p>%</p></td>
<td>p-value<sup>1</sup></td>
</tr>
<tr class="odd">
<td>Fever ≥38°C</td>
<td>14.3</td>
<td>9.3</td>
<td>0.01</td>
<td>18.4</td>
<td>12.7</td>
<td>&lt;0.01</td>
<td>23.5</td>
<td>13.3</td>
<td>&lt;0.01</td>
</tr>
<tr class="even">
<td>Fever &gt;39°C</td>
<td>0.4</td>
<td>0.2</td>
<td>1</td>
<td>1.0</td>
<td>0.5</td>
<td>0.38</td>
<td>2.0</td>
<td>0.5</td>
<td>0.01</td>
</tr>
<tr class="odd">
<td>Crying increased</td>
<td>41.6</td>
<td>36.4</td>
<td>0.03</td>
<td>42.0</td>
<td>32.9</td>
<td>&lt;0.01</td>
<td>39.6</td>
<td>30.6</td>
<td>&lt;0.01</td>
</tr>
<tr class="even">
<td>Crying &gt; 4 hrs</td>
<td>0.6</td>
<td>0.4</td>
<td>0.72</td>
<td>0.5</td>
<td>0.1</td>
<td>0.37</td>
<td>0.4</td>
<td>0.1</td>
<td>0.62</td>
</tr>
<tr class="odd">
<td>Pain</td>
<td>3.4</td>
<td>1.9</td>
<td>0.09</td>
<td>3.7</td>
<td>0.7</td>
<td>0.02</td>
<td>5.1</td>
<td>2.8</td>
<td>0.02</td>
</tr>
<tr class="even">
<td>Redness (Any)</td>
<td>14.2</td>
<td>9.3</td>
<td>&lt;0.01</td>
<td>16.0</td>
<td>12.6</td>
<td>0.06</td>
<td>20.0</td>
<td>15.9</td>
<td>0.02</td>
</tr>
<tr class="odd">
<td>≥ 2.5 cm</td>
<td>0</td>
<td>0.1</td>
<td>1</td>
<td>0.2</td>
<td>0.2</td>
<td>0.62</td>
<td>0.4</td>
<td>0.0</td>
<td>0.25</td>
</tr>
<tr class="even">
<td>Swelling (Any)</td>
<td>4.7</td>
<td>1.7</td>
<td>&lt;0.01</td>
<td>4.0</td>
<td>3.0</td>
<td>0.16</td>
<td>4.8</td>
<td>3.6</td>
<td>0.19</td>
</tr>
<tr class="odd">
<td>≥ 2.5 cm</td>
<td>1.0</td>
<td>0.1</td>
<td>1</td>
<td>0.9</td>
<td>0.4</td>
<td>0.33</td>
<td>0.5</td>
<td>0.2</td>
<td>0.68</td>
</tr>
</tbody>
</table>

Adapted from Tables 13 and 14, pages 21and 22, Volume 1 of PLA
(Sponsor's analysis).

**Vaccine Reactions Reported within 72 Hours of HBV and PncCRM
vaccines,**

**4^th^ dose---Finnish study**

+-----------------+-----------------+-----------------+-----------------+
| Systemic        | Dose 4 (12      |                 |                 |
| Reaction        | months)         |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
|                 | PncCRM          | HBV             | p-value^1^      |
|                 |                 |                 |                 |
|                 | N=798^a^        | N=798 ^a^       |                 |
|                 |                 |                 |                 |
|                 | \%              | \%              |                 |
+-----------------+-----------------+-----------------+-----------------+
| Fever ≥38°C     | 11.5            | 6.9             | \<0.01          |
+-----------------+-----------------+-----------------+-----------------+
| Fever \>39°C    | 1.6             | 1.7             | 0.97            |
+-----------------+-----------------+-----------------+-----------------+
| Crying          | 28.2            | 19.3            | \<0.01          |
| increased       |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Crying \> 4     | 0               | 0               | NA              |
| hours           |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Pain            | 7.5             | 2.3             | \<0.01          |
+-----------------+-----------------+-----------------+-----------------+
| Redness (Any)   | 14.7            | 14.4            | 0.60            |
+-----------------+-----------------+-----------------+-----------------+
| ≥ 2.5 cm        | 0.8             | 0.0             | 0.04            |
+-----------------+-----------------+-----------------+-----------------+
| Swelling (Any)  | 4.9             | 5.4             | 0.83            |
+-----------------+-----------------+-----------------+-----------------+
| ≥ 2.5 cm        | 1.3             | 0.4             | 0.09            |
+-----------------+-----------------+-----------------+-----------------+

^a^ Total number monitored varied from 771-798, depending on number of
completed reports received.

^1^ p-valus derived from Ch-square tests; for comparisons of mild or
any, each variable dichotomized by combining severity classes mild and
moderate/severe. For comparisons of more severe reactions, each variable
dichotomized by combining classes none and mild (Sponsor's analysis).

#########  Systemic reactions

> Rectal temperatures were to be measured at 24, 48, and 72 hours after
> inoculations. Other than fever and increased crying, no other common
> vaccine reactions were actively monitored in this study.
>
> Fever (≥38°C) was reported more commonly in the PncCRM group than in
> the HBV group after each of the 4 doses. Fever rates in the PncCrm7
> group were 14.7%, 19.3%, 25.5% and 13.1% following doses 1-4
> respectively. Higher grade fever (\>39°C) was reported by no more than
> 2% after any dose. The difference in rates of higher grade fever was
> statistically significant after the 3^rd^ dose.
>
> **Note:** Whole cell pertussis vaccine (DTP-Hib) was administered
> concurrently with doses 1-3, and IPV was co-administered with dose 4.
> These concurrently administered vaccines likely contributed to the
> observed systemic vaccine reactions.
>
> Increased crying was also reported significantly more often by
> recipients of PncCRM after all 4 doses (41.6%, 42%, 39.6% and 28.2%
> after doses 1-4, respectively). Prolonged crying (\>4 hours) was
> reported by no more than 1% of PncCRM7 recipients after any dose, and
> no significant differences between groups were observed for any dose.

#########  Local reactions

In general, rates of induration (swelling), erythema (redness), and
tenderness (pain) were greater at PncCRM injections sites than at HBV
inoculation sites. Compared to local reactions at DTP-Hib injection
sites within the same individuals, local reactions at PncCRM sites were
significantly less frequent for all comparisons (data not shown above).
Local reactions were more common at the PncCRM injection sites than at
IPV injection sites with the 4^th^ dose.

> **Adverse events**

**Deaths**

One death occurred during follow-up, in an 8-month old child, 85 days
after the 3^rd^ dose of PncCRM. The cause of death was a congenitally
anomalous mesentery leading to obstruction and necrosis of the bowel.

**Serious and unexpected adverse events**

Serious adverse reactions (hospitalizations, fatal or life-threatening
event, disabling event) and unexpected events were tabulated and
analyzed together. A total of 354 SAEs cases were reported---348 were
serious adverse events and 6 were cases of unexpected events deemed
possibly related to study vaccines.

> Of the 354 SAEs cases, 160 serious adverse events were reported in the
> PncCRM7 group, and 194 in the HBV group. These are summarized in the
> following table:
>
> Cases of serious or unexpected adverse events by primary diagnosis,
> intent-to-treat follow-up

+------------------------+----------+---------+----------+-----------+
| SAE Diagnosis          | Number   |         | Hazard   |           |
|                        | of Cases |         | Ratio    |           |
+------------------------+----------+---------+----------+-----------+
|                        | HBV      | PncCRM7 | Estimate | 95% CI    |
+------------------------+----------+---------+----------+-----------+
| HHE                    | 1        | 0       | 0        | NA        |
+------------------------+----------+---------+----------+-----------+
| Invasive bacterial     | 4        | 1       | 0.25     | > (0.03,  |
| infection              |          |         |          | > 2.21)   |
+------------------------+----------+---------+----------+-----------+
| Wheezy bronchiolitis   | 43       | 39      | 0.91     | > (0.50,  |
|                        |          |         |          | > 1.66)   |
+------------------------+----------+---------+----------+-----------+
| Upper respiratory      | 9        | 7       | 0.78     | > (0.29,  |
| infection              |          |         |          | > 2.05)   |
+------------------------+----------+---------+----------+-----------+
| Laryngitis             | 7        | 7       | 1.00     | > (0.34,  |
|                        |          |         |          | > 2.93)   |
+------------------------+----------+---------+----------+-----------+
| Pneumonia              | 8        | 4       | 0.50     | > (0.15,  |
|                        |          |         |          | > 1.64)   |
+------------------------+----------+---------+----------+-----------+
| Gastroenteritis        | 15       | 19      | 1.27     | > (0.63,  |
|                        |          |         |          | > 2.55)   |
+------------------------+----------+---------+----------+-----------+
| Urinary Tract          | 13       | 6       | 0.46     | > (0.17,  |
| Infection              |          |         |          | > 1.24)   |
+------------------------+----------+---------+----------+-----------+
| Exanthema subitum      | 1        | 1       | 1.00     | > (0.06,  |
|                        |          |         |          | > 15.97)  |
+------------------------+----------+---------+----------+-----------+
| Indefinite viral       | 4        | 2       | 0.50     | > (0.09,  |
| infection              |          |         |          | > 2.70)   |
+------------------------+----------+---------+----------+-----------+
| Suspected infection    | 13       | 4       | 0.31     | > (0.10,  |
|                        |          |         |          | > 0.95)   |
+------------------------+----------+---------+----------+-----------+
| Skin infection         | 2        | 4       | 2.00     | > (0.33,  |
|                        |          |         |          | > 12.17)  |
+------------------------+----------+---------+----------+-----------+
| Other infections with  | 2        | 1       | 0.50     | > (0.05,  |
| etiology               |          |         |          | > 5.46)   |
+------------------------+----------+---------+----------+-----------+
| Febrile seizure        | 14       | 12      | 0.86     | > (0.37,  |
|                        |          |         |          | > 1.99)   |
+------------------------+----------+---------+----------+-----------+
| Indefinite neurologic  | 0        | 3       | Inf.     | > NA      |
| symptoms               |          |         |          |           |
+------------------------+----------+---------+----------+-----------+
| Urticaria              | 3        | 4       | 1.33     | > (0.09,  |
|                        |          |         |          | > 20.53)  |
+------------------------+----------+---------+----------+-----------+
| Rash/other skin        | 1        | 3       | 3.00     | > (0.32,  |
| reactions              |          |         |          | > 28.15)  |
+------------------------+----------+---------+----------+-----------+
| Elective procedure     | 13       | 8       | 0.62     | > (0.24,  |
|                        |          |         |          | > 1.60)   |
+------------------------+----------+---------+----------+-----------+
| Social reasons         | 1        | 1       | 1.00     | > (0.06,  |
|                        |          |         |          | > 15.64)  |
+------------------------+----------+---------+----------+-----------+
| Other reasons          | 40       | 34      | 0.85     | > (0.49,  |
|                        |          |         |          | > 1.48)   |
+------------------------+----------+---------+----------+-----------+
| Total                  | 194      | 160     |          |           |
+------------------------+----------+---------+----------+-----------+

> Adapted from Table 12.3.1, Volume 2, Page 107 of PLA.
>
> Most primary hospitalization diagnoses were more common in the HBV
> group, although statistical significance was reached only for
> "suspected infection". Hospitalizations for gastroenteritis were
> notably increased in the PncCRM group. However, only 2 of the 19 cases
> of gastroenteritis occurred within 30 days of a vaccine dose.
>
> Line listings of "other reasons" for serious adverse event reports
> were included in an appendix to the study report.
>
> One case of diabetes mellitus with ketoacidosis occurred in PncCRM
> recipient, onset 43 days after the 4^th^ vaccine dose.
>
> Also in the PncCRM group were: 1 case of neutropenia (subject 1650,
> see below), and 1 case of transient erythrocytic aplasia, with onset
> of uncertain date, but likely greater than 1 year after the 4^th^
> dose.
>
> In the HBV group were: 1 case of transient erythroblasopenia (subject
> 1031), onset 131 days after the 4^th^ dose, 1 case of transient anemia
> (subject 3193), onset 105 days after the 4^th^ dose, and one case of
> Kawasaki's disease (subject 3549), onset 77 days after the 3^rd^
> vaccine dose.
>
> Also noted were 10 hospitalizations for afebrile
> convulsions/seizures/attacks (see discussion below).
>
> Two hospitalizations were considered at least possibly related to
> receipt of PncCRM7. Narratives of each case were provided:
>
> Subject 1343 was hospitalized for excessive crying at age 3 months, 1
> day after the first dose of PncCRM7. He had fever and local reaction
> at the DTP-Hib site. Additional doses of pertussis vaccine were
> omitted. No reactions were observed with subsequent doses of PncCRM7.
>
> Subject 1650 was hospitalized 62 days after the 2^nd^ dose of PncCRM7
> at age 6 months for fever, acute otitis media, viral respiratory
> infection. Granulocytopenia was noted on hospitalization. No obvious
> reason for granulocytopenia was found. He was hospitalized again 5
> days after the 3^rd^ vaccine dose for fever and restlessness.
> Granulocytopenia was still marked. The condition remitted
> spontaneously over 11 months. The second hospitalization was
> considered possibly related to vaccine because of fever.
>
> **Adverse events leading to discontinuation from study**

Two subjects in the PncCRM7 group discontinued study participation due
to urticarial reactions (see below), thought by investigators to be at
least possibly related to study vaccines.

Two subjects in the HBV control group also discontinued study
participation due to adverse events thought by investigators to be
possibly related to study vaccines, one for a hypotonic episode, and
another for an urticarial reaction.

> **Adverse events with special surveillance diagnoses**

Some diagnoses were designated for special surveillance in the Finnish
study. These included:

-   Sudden infant death (SIDS)

-   Invasive bacterial infection

-   Aseptic meningitis

-   Acute encephalopathy

-   Shock or shock-like state

-   Anaphylaxis

Nine cases with a diagnosis under special surveillance were noted---8 in
the HBV control group and 1 in the PncCRM7 group.

**Seizure events**

**Febrile seizures**

Febrile seizures accounted for 12 hospitalizations in the PncCRM7 group
vs. 14 in the HBV control group. In the PncCRM7 group, the shortest
interval between a vaccine dose and a febrile seizure was 28 days. One
subject in the HBV control group experienced a febrile seizure 4 days
after a vaccine dose. All other febrile seizures in the control group
occurred at least 34 days after a dose of HBV.

**Afebrile convulsions/seizures/attacks**

> A total of 6 children accounted for 10 hospitalizations for afebrile
> seizures in the PncCRM7 group vs. 2 hospitalizations for 1 child in
> the HBV group. Case narratives were provided for each child.

Despite the increased number of subjects with reports of afebrile
seizures in the PncCRM7 group, the case narratives provide no reason to
suspect a relationship of afebrile seizures with pneumococcal conjugate
vaccine. Onset of symptoms showed no clear temporal relationship to
vaccinations. Questionable or alternative diagnoses (e.g. GE reflux,
cervical spasms) accounted for most cases. Among the 6 PncCRM recipients
with reported afebrile seizures, work-up for neurological abnormalities
(electroencephalograms and MRIs) were normal in 5, and not reported for
one. Long-term outcomes appear to be favorable in all cases.

#########  Urticarial reactions

> In the Finnish study, urticarial reactions were reported as a reason
> for hospitalization, as an unexpected adverse event, and as a reason
> for discontinuation from the study.
>
> Number of subjects with reports of urticarial reactions---Finnish
> study

+---------------------+-----------------------+------------------------+
| Data Source         | PncCRM                | HBV                    |
+---------------------+-----------------------+------------------------+
| Reason for          | 2236, 1 day post      | 1256, 1 day post 2^nd^ |
| discontinuation     | 2^nd^ dose, 2705, 0   | dose                   |
|                     | days after 3^rd^ dose |                        |
+---------------------+-----------------------+------------------------+
| Hospitalization     | 1295, 1 day post      | 1256 (as above)        |
|                     | 4^th^ dose            |                        |
| diagnosis           |                       | 3445, 2 days post      |
|                     | 1670, 29 days post    | 4^th^ dose             |
|                     | 2^nd^ dose            |                        |
|                     |                       |                        |
|                     | 2705 (as above)       |                        |
+---------------------+-----------------------+------------------------+
| Among "other"       | 2360, 30 days post    | 1562, 80 days post     |
| adverse events      | 3^rd^ dose,           | 4^th^ dose,            |
|                     |                       |                        |
|                     | 1 day post 4^th^ dose | 3560, 389 days post    |
|                     |                       | 4^th^ dose             |
+---------------------+-----------------------+------------------------+

Table compiled by FDA review of all data sources for urticarial
reactions.

Considering only urticarial reactions occurring within 14 days after a
vaccine dose as a criterion for plausible relationship to study
vaccines, there were 4 cases in the PncCRM group vs. 2 in the control
group.

> **Sponsor's conclusions regarding safety data from the Finnish study**
>
> The sponsor acknowledges that PncCRM was more reactogenic than HBV,
> but less reactogenic than DTP-Hib. For systemic events, PncCRM
> resulted in increased rate of fever (≥38°C) within 3 days than did HBV
> administered with the same concurrent vaccines.
>
> The overall rate of serious or unexpected adverse events tended to be
> less in the PncCRM group compared to the HBV group.
>
> The sponsor concluded that based on safety data from the Finnish
> study, PncCRM7 was safe when administered in a 3 doses schedule in
> infancy followed by a 4^th^ dose at 12 months of age.
>
> **FDA comments regarding safety data in the application**

Relevance of vaccine reaction data from the Finnish AOM study to the US
population is limited, given that current practice in the U.S. makes use
of less reactogenic co-administered acellular pertussis vaccines, and
possibly due to differences in populations. Also, the safety database in
the Finnish study is substantially smaller and thus, of more limited
power to detect less common adverse reactions than was the NCKP study.
However, parent compliance with reporting of vaccine reactions appears
to have been nearly complete in the Finnish study, thus likely enhancing
the reliability of the reported data. These data do confirm an
incremental increased rate of fever attributable to Prevnar, as was also
observed in the NCKP study and other pre-licensure studies.

Complications of fever can include febrile seizures. In the Finnish
study, occurrences of febrile seizures occurred with greater frequency
in the control group. Furthermore, no temporal association with PncCRM
was evident for any of the 12 reports of febrile seizures.

No hospitalizations for fever, or fever with irritability within 3 days
of a vaccine dose were reported. A diagnosis of suspected infection
accounted for 13 hospitalizations in the HBV control group, vs. 4 in the
PncCRM7 group during the course of the study. This difference was
statistically significant, and may indicate that some occult
pneumococcal infections were prevented in the PncCRM group. Regardless,
an increased risk of hospitalizations as a complication of fever related
to PncCRM was not observed.

Urticarial reactions were a cause for study discontinuation in 2 PncCRM
recipients, and when all datasources were combined a slight imbalance in
a small number urticarial episodes within 14 days of a vaccine dose was
observed in the PncCRM group.

In the NCKP study urticaria-like rash was reported in 0.4%-1.4% of
children within 48 hours following immunization with Prevnar
administered concurrently with other routine childhood vaccines.
Urticaria-like rash was reported in 1.3-6% of children in the period
from 3 to 14 days following immunization. Interpretation of the rates
rates of urticaria in the different periods post-vaccination must take
into account the length of the observation period. The 3-14 day window
is 4-5 times as long as the 48 hour post-vaccination period; higher
rates would be expected between 3-14 days if the background rate were
constant over the 14 days post-inoculation period. Little reassurance
can be taken from the lack of statistical differences in rates of
urticarial reactions between 7VPnC and MnCC in the NCKP study, since
both vaccines use the same protein carrier (CRM~197~).

Reports of urticarial reactions following use of Prevnar, both alone and
with concurrent vaccines, have been received by the sponsor through
their world-wide post-marketing safety reports, and also through the
Vaccine Adverse Event Reporting System (VAERS). The vaccine label has
been amended since initial licensure to include this safety information
from post-marketing reports.

An important question regarding post-vaccination urticaria is whether
one occurrence predicts future occurrences on re-exposure, and whether
repeat occurrences are of increasing severity. Supplementary analyses
from the NCKP study, provided on FDA request during the AOM review
period, appear to show that urticaria is most often reported following
the fourth dose when it was administered concurrently with MMR vaccine.
Also, based on limited data, it appears that children with
urticaria-like rash after a dose of Prevnar may be more likely to report
urticaria-like rash following a subsequent dose of Prevnar. However,
there have been no reports from clinical studies or available post
marketing reports of possible serious complications of allergic
reactions, such as anaphylaxis or Stevens-Johnson syndrome, following
rechallenge with Prevnar after a previous episode of urticaria after a
dose of Prevnar.

Overall, safety data from the Finnish otitis media study are consistent
with earlier observations regarding the safety of Prevnar. No new safety
concerns were identified in the Finnish study. As had been previously
observed, Prevnar was associated with an increased rate of low-grade
fever, but complications of post-vaccination fever were uncommon.

**Attachment B: Additional Details Regarding NCKP Trial Design and
Description**

**Timetable of Study Events**

The study was initiated in October 1995; enrollment ceased August 24,
1998, and data regarding invasive disease outcomes was unblinded by the
DSMB to conduct the planned interim analysis, which demonstrated
substantial evidence of efficacy. The AOM database had been locked on
April 30, 1998. 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.

**Schedule of study vaccines and concurrently administered vaccines**

Subjects received 0.5 mL intramuscular injections of either PncCRM7 or
MnCC vaccine at 2, 4, 6 and 12-15 months of age.

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).

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. An amendment implemented in August 1996 allowed for the
substitution of DTaP and HbOC for DTP-HbOC, and for the substitution of
inactivated poliovirus vaccine (IPV) for OPV for immunization of infants
at 2, 4, and 6 months of age.

Allowable time frames for study vaccine administration were:

-   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.

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

Study vaccines were given in the left thigh. Other concurrently
administered injectable vaccines were to be inoculated into the right
thigh or deltoid, as appropriate.

**Study Design and Conduct**

This was a randomized, double-blind, controlled, multi-center trial.

### Randomization and Blinding

> Healthy infants were randomly assigned to receive PncCRM7 or MnCC,
> identified by A, B, C, or D; 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.
>
> 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.

**Study population**

> Healthy male and female infants age 2 months (range 42-120 days)
> enrolled in the NCKP health care system were eligible to participate.

**Exclusion criteria** included:

-   Known or suspected disease of the immune system including HIV
    infection, or those receiving immunosuppressive therapy

-   Progressive neurological disease

-   Uncontrolled epilepsy/infantile spasms or history of seizures

-   Any serious chronic disease (such as signs of cardiac or renal
    failure, or failure to thrive

-   Sickle cell disease, functional or anatomic asplenia, Down syndrome,
    or nephrotic syndrome

-   Known hypersensitivity to any of the components of the vaccines used
    in the study

-   History of invasive pneumococcal disease

-   History of idiopathic thrombocytopenic purpura

-   Prior receipt of any vaccine other than vaccine for hepatitis B

-   History of meningococcal disease (defined as a positive culture of
    *N. meningitidis* from a normally sterile body site).

> **Note:** Infants born prematurely could be enrolled if they were
> judged to be in good health.

**Demographic information**

A randomly selected subset of about 7500 subjects provided demographic
information collected via telephone interview with the subjects'
parents. The subset was selected based on the last digit of the
subject's medical record number.

[^1]: In the tables and summaries of studies conducted pre-licensure,
    Prevnar, 7-valent pneumococcal conjugate vaccine, is referred to as
    7VPnC in the NCKP study, and as PncCRM in the Finnish study;
    meningococcal group C conjugate vaccine was abbreviated as MnCC;
    Hepatitis B vaccine is abbreviated HBV.