Statistical issues with Flu vaccine development

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Statistical issues with Flu vaccine development

• Marc Fourneau for ISCB28,
• 30th of July 2007, Alexandroupolis

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Agenda
1. Introduction epidemiology-virus-vaccines
andnatural history of the virus
2. Immunogenicity and efficacy trials
Immunogenicity
Efficacy
Trials 2.1. Objectives 2.2.Regulatory
context 2.3.Experimental design
3. Issues/challenges (3.1. Immunogenicity 3.2
Efficacy)
4. Conclusions
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1.1. Influenza epidemiology
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1.2. Influenza virus and vaccines
Flu virus
Structure of hemagglutinin (H) and neuramidase
(N) periodically change -Minor change
epidemics -Major change pandemics
Vaccine composition change
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1.3. Natural history of influenza viruses
H5N1 ? H7N2 ?
Hong-Kong Flu
Asian Flu
?
Spanich Flu (20 106 deaths)
Annual vaccine (epidemy) 3 circulating strains
H1N1, H3N2, B
New strain (pandemy) 1 non-circulating strain
e.g. H5N1, H7N2 or ?
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2.1. Objectives in trials
Immunogenicity (antibodies)
Efficacy (disease)
Clinical Signs and Biological sample to
identify pathogen (culture/PCR)
SPR proportion of subjects with HI titre 40
SCR proportion of subjects with - HI titrePre
lt10 and HI titrePost 40 - HI titrePre 10 and
fold increase 4
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2.2. Regulatory context
1. Immunogenicity trials
Seasonal vaccines EMEA (1) for at least one
of the three parameters above point estimate FDA
(2) GMT and seroconversion l.l. of 95 CI of
estimate gt criterion
Pandemic vaccines EMEA (3) all three
parameters above point estimate FDA (4) for the
three parameters l.l. of 95 CI of estimate gt
criterion
2. Efficacy trials

• EMEA case by case discussion
• FDA guidance regarding efficacy trial
• Adequate and well-controlled
• Clinical endpoint with virus culture confirmation
• It is recommended that elderly be vaccinated

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2.3 Experimental design
1. Immunogenicity trials
-seasonal trial open, 1 group, 2 age
categories -comparative trials superiority
trials new generation or competitors, dose
of antigen/adjuvant non-inferiority new
formulation (IN, ID,) bio-equivalence
lot-to-lot consistency
2. Efficacy trials
-double-blind, two groups (placebo or active
control)
In children ??? (assesment in immuno) In non at
risk adults superiority against a placebo In
elderly -superiority against an active
control -non-inferiority if other improvement
targeted
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3.1. Challenges in immunogenicity trials
1. Multiplicity
and number of groups in the study design
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3.1. Challenges in immunogenicity trials
1. Multiplicity (cntd)
How to preserve type I or II errors in
hypothesis testing without Increasing in a
drastic manner the sample sizes ?
Proposals use - different critical value
in the test Nauta, 2006(5) - correlation
structure of endpoints Kong et al,
2006(6) New methods ?
2. Control group
How to decrease the size of control groups ?
New methods ? (Baysian tests, Mixed
Bayesian/Frequentist tests or ?)
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3.2. Challenges in efficacy trials
1. Objective health perspective
How to select one influenza case definition
(sensitivity, specificity and predicitive
values) ?
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3.2. Challenges in efficacy trials
2. Population How can we bridge the vaccine
efficacy from one age level to the other
? Set up trials to better define
symptomatology in each age category ?
3. Attack Rate
- Unpredictable - Circulation of variants
Attack rate 1 10 Virus circulating Matching
vaccine Y Y Strains (Y/N) Efficacy with
Marketed vaccine 60 60 New improved
vaccine 70 70
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3.2. Challenges in efficacy trials
4. Correlate
Proposals
4.1. Importance of level of HI titre before
exposure observation Hobson et al, 1973 (8)
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3.2. Challenges in efficacy trials
4.2. Understand vaccine efficacy results fit
mathematical model
level of HI titre
Link level of HI titre before exposure and
protection against influenza Dunning A., 2005
(9) Coudeville et al, 2007 (10)
vaccine antigen and circulating virus
Link antigenic distance between the vaccine and
the circulating virus Gupta et al, 2006 (11)
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3.2. Challenges in efficacy trials
4.3. Challenge Improved design and
methodologies for correlate
Multivariable correlate of protection (e.g.
anti-HI and anti-NI or ..)
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4. Conclusions
Immunogenicity SPR,SCR,CF EMEA, FDA Annual
and comparative
Efficacy Disease EMEA, FDA Field efficacy
Trials 2.1. Objectives 2.2.Regulatory
context 2.3.Experimental design
Progress have been made and we still need
improvement in -debate with authorities to
set-up clear guidances -correlate/surrogate
markers in clinical trials -epidemiological and
mathematical modelling of disease/pathogen -multip
licity -generate better data
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• References
• Note for guidance on harmonisation of
  requirements for influenza vaccines
  CPMP/BWP/214/96 12 March 2007
• Guidance for Industry Clinical data needed to
  support the licensure of seasonal inactivated
  Influenza vaccines
• http//www.fda.gov/cber/guidelines May 2007
• Guideline on dossier structure and content for
  pandemic for influenza vaccine marketing
  autorisation application
• CPMP/VEG/4717/03 5 April 2004
• 4. Guidance for Industry Clinical data needed
  to support the licensure of pandemic Influenza
  vaccines
• http//www.fda.gov/cber/guidelines May 2007
• 5. J. Nauta Statistical analysis of influenza
  vaccine lot consistency studies in Journal of
  Biopharmaceutical
• Statistics, 16 443-452, 2006
• 6. L. Kong, R. Kohberger and G. Koch Design of
  vaccine equivalence/non-inferiority trials with
  correlated multiple
• binomial endpoints in Journal of
  Biopharmaceutical Statistics,16 555-572, 2006
• 7. Nichol K. Heterogeneity of influenza case
  definitions and implications for interpreting and
  comparing study results
• Vaccine
• 8. Hobson D, Curry RL, Beare AS, Ward-Gardner A.
  The role of serum haemagglutination-inhibiting
  antibody in protection
• against challenge infection with influenza A2
  and B virus in Joural of Hyg. 70 767-777, 1972
• Dunning Aj. A model for immunological Correlates
  of protection. Stat Med 2006 May
  1525(9)1485-97)
• Coudeville L., Bailleux F., Megas F., Barret B.,
  André P. HI antibody response and clinical
  protection against

Contact Fourneau Marc marc.fourneau_at_gskbio.com