Vaccines and Related Biological Products Advisory Committee VRBPAC May 21, 2002 Prevnar, Pneumococca

1
Vaccines and Related Biological Products Advisory
Committee (VRBPAC)May 21, 2002Prevnar,
Pneumococcal Conjugate Vaccine 7-valent, for the
Prevention of Acute Otitis Media 

• R. Douglas Pratt, M.D., M.P.H.

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Review Team

• Jingyee Kou, Ph.D.
• Marion Gruber, Ph.D.
• Carl Frasch, Ph.D.

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Proposed Indication

• For active immunization of infants and toddlers
  against invasive disease and otitis media caused
  by Streptococcus pneumoniae due to capsular
  serotypes included in the vaccine (4, 6B, 9V, 14,
  18C, 19F, 23F)

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Regulatory Background

• November 1999
• February 2000
• June 2000
• May 2001
• October 2001
• March 2002
• May 2002

• VRBPAC for invasive disease
• Prevnar licensed for prevention of invasive
  disease
  
• AOM license amendment submitted
• FDA Letter to sponsor
• Response to FDA letter received
• Second FDA letter to sponsor major amendment-
  Finnish follow-up data
  
• VRBPAC for otitis media

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Global Issues

• Efficacy estimates for AOM outcomes are
  comparatively low for preventive vaccines
  
• Possible increased risk of AOM (negative
  efficacy) for pneumococcal serotypes not included
  in Prevnar
  
• Potential for unrealistic public expectations
  regarding benefit in preventing AOM
  

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Comments from Medical CommunityCorrespondence
to New England Journal of Medicine

• Clinical significance of overall treatment effect
  questioned (Lavin A Damoiseaux R Cantekin E
  Sauder K)
  
• Concern that limited benefit may be misunderstood
  by the public (Sauder K)
  
• Concern that credibility of existing
  recommendations may be compromised (Sauder K)
  
• Misunderstanding of FDA action taken regarding
  AOM (Cantekin E)

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Clinical Studies Reviewed
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Outline of FDA Presentation

• Introduction
• Efficacy data from Finnish OM study
• Supplementary analyses
• Finnish follow-up study
• Efficacy data from the NCKP study
• Safety data from Finnish OM study
• Considerations
• Questions to the Committee

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Finnish OM StudyPrimary Objective

• Determine the protective efficacy of the
  pneumococcal conjugate vaccine against
  culture-confirmed pneumococcal acute otitis media
  (AOM) due to vaccine serotypes

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Finnish OM StudySecondary Objectives

• Determine
• Efficacy using different levels of etiologic
  diagnosis
  
• Efficacy in preventing nasopharyngeal carriage
• Antibody response
• Safety and tolerability

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Finnish OM Study Elements of the Study Design

• Randomized equally to one of 3 vaccines
• PncCRM (Wyeth-Lederle)
• PncOMP (Merck)
• HBV (Control)
• Only data relating to PncCRM were provided in the
  application
  
• Double-blind
• Healthy 2 month old infants enrolled

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Finnish OM Study Vaccine Schedule and
Concurrent Immunizations
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Finnish OM study

• Case surveillance and ascertainment
• Free access to study clinics 7 days/week
• Children brought to study clinics for respiratory
  infections or symptoms suggesting AOM
  
• Myringotomy with aspiration of middle ear fluid
  for culture, if AOM diagnosed at the visit
  
• If S. pneumoniae found, the serotype was
  determined
  
• Follow-up of each child until age 2 years

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Finnish OM StudyClinical Definition of Acute
Otitis Media

• Visually abnormal tympanic membrane (in regard to
  color, position, and/or mobility) suggesting
  effusion in the middle ear cavity
  
• And at least one of
• fever, ear pain, irritability, diarrhea,
  vomiting, acute otorrhea not caused by external
  otitis, or other symptoms of respiratory
  infection.

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Finnish OM Study AOM Efficacy Endpoints

• Primary AOM episodes due to vaccine serotypes
• Secondary
• First and Subsequent AOM episodes due to vaccine
  serotypes
  
• Other
• AOM due to vaccine serotypes by dose
• All pneumococcal AOM, regardless of serotype
  (culture and/or PCR)
  
• All AOM episodes with MEF, regardless of
  etiology
  
• All AOM episodes regardless of etiology
• Children with recurrent AOM

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Finnish OM Study- Definition of Primary Endpoint

• AOM episode due to vaccine serotypes
• At least 30 days since beginning of previous AOM
  due to the same serotype
  
• Or, any interval for different vaccine serotype
• Culture confirmed

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Finnish OM StudyPrimary Endpoint Definition
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Finnish OM Study-Analysis of Primary Endpoint

• Generalized Cox regression model with
  Anderson-Gill counting method
  
• Risk of AOM estimated piecewise, i.e., from
  event to event
  
• Assumes proportional hazards between groups over
  time
  
• Robust variance estimates used to compensate for
  interdependency of events within subjects
  
• Provides average vaccine effect on AOM episodes

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Finnish OM Study-Definitions of Follow-up Periods

• Per protocol (PP) follow-up
• Begins 2 weeks after the 3rd vaccine dose
• Intent-to-treat (ITT) follow-up
• Begins at time of 1st vaccine dose

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Finnish OM StudySelected Population
Characteristics
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Finnish OM Study-Primary Analysis, AOM due to
Vaccine Serotypes
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Finnish OM Study-AOM due to Individual Vaccine
Serotypes, (Intent-to-treat)
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Finnish OM Study-Secondary Analyses, First and
Subsequent AOM Episodes due to Vaccine Serotypes
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Finnish OM Study-Efficacy for All
Culture-Confirmed Pneumococci, Regardless of
Serotype
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Finnish OM Study-Efficacy for Vaccine-Related
Serotypes
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Finnish OM Study-AOM due to Individual
Vaccine-Related Serotypes, (Intent-to-treat)
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Finnish Otitis Media Study-Efficacy for
Vaccine-Unrelated Pneumococcal Serotypes
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Finnish Otitis Media Study-Efficacy for
Recurrent AOM
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Finnish Otitis Media Study-Efficacy for Other
Planned Analyses
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Finnish OM Study-Efficacy for Nasopharyngeal
Carriage of Vaccine Serotypes (per protocol)
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Finnish OM StudySerum Geometric Mean Antibody
Concentration (GMC) After 3rd and 4th Doses
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Finnish OM StudySerum Antibody Concentrations
(GMC) and Serotype-Specific Efficacy
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Finnish Otitis Media StudyInvasive Disease Due
to Pneumococcus
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Finnish Otitis Media Study Review Issues and
Supplementary Analyses
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Finnish OM Study Analysis of CovariatesEfficac
y Estimates Adjusted for Gender, AOM Prior to
Enrollment, Gestational Age, Birth Weight,
Daycare, Breast-feeding, and Household Smoking
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Finnish OM Study Example from the Data,
Multiple Episodes Due to Same Serotype
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Finnish OM Study Examples from the Data,
Multiple Episodes Due to Same Serotype
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Finnish OM StudySupplementary Analysis
Subsequent AOM Episodes due to Same Serotype
Excluded, Vaccine Serotypes (PP)
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Finnish OM StudySupplementary Analysis
Subsequent AOM Episodes due to Same Serotype
Excluded, All Pneumococcal Serotypes (Per
Protocol)
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Finnish OM StudySupplementary Analysis
Pneumococcal AOM by PCR/Culture
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Finnish OM StudySupplementary Analysis
Antibiotic Use
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Finnish OM Study-Supplementary Analysis First
Tympanostomy Tube Placement
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Finnish OM Follow-up StudyTympanostomy Tube
Placement

• To assess long-term effect of vaccine on
  procedures for ear tube placement
  
• Children evaluated at 4-5 years of age
• Unblinded
• Two populations evaluated
• Volunteers in follow-up study, N 756
• Original randomized population, N 1662

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Finnish OM Follow-up StudyPrimary Analysis,
Rate of Ear Tube Placement among Children
Enrolled in Follow-up Study
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Finnish OM Follow-up StudySecondary Analysis,
Rate of Ear Tube Placement among All Children
Followed to 4-5 years of Age
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Northern California Kaiser Permanente (NCKP)
Otitis Media Efficacy Results
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Northern California Kaiser Permanente (NCKP)
Study Elements of Study Design

• Randomized, double-blind
• Investigational meningococcal C conjugate vaccine
  control
  
• AOM a secondary endpoint
• No standardized AOM clinical case definition
• No tympanocentesis or routine culture of MEF
• Automated database searches to identify OM
  diagnoses
  

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NCKP Study Case Definitions

• AOM Diagnosis Based on clinical practice
• AOM Episode A clinic visit at which AOM was
  diagnosed, and at least 21 days had elapsed since
  any previous visit for AOM
  
• Frequent AOM 3 AOM episodes within 6 months,
  or 4 episodes within 12 months
  

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NCKP Study Prospectively Defined AOM Endpoints

• Primary All AOM episodes
• Secondary
• First AOM episode
• Frequent AOM
• First tympanostomy tube
• All OM clinic visits
• Ruptured ear drums

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NCKP Study Primary Analysis,Overall Reduction
in AOM Episodes
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NCKP Study Secondary Analysis,Reduction in
Risk of at Least 1 Episode
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NCKP Study Frequent Acute Otitis Media
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NCKP Study First Tympanostomy Tube Placement
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NCKP Study Ruptured Ear Drums with
Pneumococcus Isolated
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NCKP Study Serotype Distribution of Ruptured
Ear Drums with Pneumococcus Isolated (ITT)
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NCKP Study Efficacy Through Extended Follow-up
(ITT)
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Summary of Efficacy Estimates (ITT)
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Finnish Otitis Media Study Safety Analysis
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Finnish OM Study Safety Analysis

• Relevance of safety data to US population is
  limited
  
• Use of concurrent DTwP-Hib combination vaccines
  for first 3 doses, rather than DTaP, complicates
  assessments of systemic reactions
  
• Homogeneous study population
• Study not large enough to detect uncommon adverse
  events
  

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Finnish OM Study Safety Analysis, Local and
Systemic Reactions, First 3 Doses
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Finnish OM Study Safety Analysis, Local and
Systemic Reactions, 4th Dose
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Finnish OM Study Safety Analysis, Conclusions

• Safety data are consistent with earlier
  observations regarding the safety of Prevnar
  
• Increased rate of low-grade fever
• Complications of post-vaccination fever were
  uncommon
  
• No new safety concerns were identified

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Considerations
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Required Level of Efficacy

• The minimum level of efficacy required for
  licensure of a preventive vaccine is not
  specifically addressed by FDA regulations or
  published guidance.

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Considerations Licensure of Other Pneumococcal
Vaccines for Otitis Media

• AOM indication should stand on its own.
• License applications for new pneumococcal
  vaccines for prevention of AOM may not include
  evidence of efficacy for prevention of invasive
  disease.
• If approved, a level of efficacy, preferred
  endpoints, and type of data (number of trials)
  sufficient for approval for AOM would be
  established.
• Prevention of more AOM episodes with less
  vaccine- serotype-specific efficacy is a possible
  scenario.
  

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Considerations Description of the treatment
effect

• Primary outcomes in NCKP study and Finnish OM
  study differ
  
• Prevention of AOM due to vaccine serotypes does
  not capture
  
• Positive treatment effect on vaccine-related
  pneumococcal serotypes
  
• Negative efficacy for unrelated pneumococcal
  serotypes
  
• Efficacy estimates relatively low for some
  outcomes
  
• Confidence intervals wide for some outcomes

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Considerations Clinical benefit vs. economic
benefit

• Substantial evidence of clinical benefit must be
  provided from adequate and well-controlled
  studies.
  
• Economic benefit is not considered in the
  efficacy evaluation by FDA.

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Considerations Marketing Implications

• Promotional materials based on approved labeling
• Potential for unrealistic expectations
• FDA is empowered to restrict marketing claims
• Advertisements and promotional labeling are
  reviewed by CBER
  
• Advertisements that are misleading (defined in 21
  CFR 202.1) can result in a product being
  misbranded. If a company fails to correct such
  violations, CBER is empowered to take multiple
  corrective actions (21 CFR 601.5 and 601.6).

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Questions to the Committee

• Are the data adequate to support the efficacy of
  Prevnar in infants and toddlers for prevention of
  otitis media caused by Streptococcus pneumoniae
  due to capsular serotypes included in the vaccine
  (4, 6B, 9V, 14, 18C, 19F, 23F)?
• If not, would additional analyses from the
  Finnish otitis media study, the Northern
  California Kaiser Permanente efficacy study, or
  additional clinical trials be useful in
  establishing efficacy?

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Questions to the Committee (cont.)

• 2. Please discuss the strength of the data with
  respect to secondary otitis media outcomes
  
• Acute otitis media episodes caused by S.
  pneumoniae, regardless of serotype
  
• Overall reduction in acute otitis media episodes
• Frequent otitis media
• Tympanostomy tube placement