Selection of Vaccine Candidates

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Selection of Vaccine Candidates

• Is this disease amenable to prevention by a
  vaccine
• Does natural infection confer immunity?
• Have protective vaccines been developed
  before?
• Do immune responses correlate with protection?

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Selection of Vaccine Candidates

• Does the disease burden warrant investment
  
• of resources to develop a vaccine?
• Can the vaccine attract financial
• resources needed for development to
• licensure and use as a public health tool?

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Selection of Vaccine Candidates

• Was vaccine construction scientifically sound?
• Do pre-clinical data show immunogenicity and
  efficacy
• Is the formulation practical and amenable to
  public health use in the target population?

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Iterative Steps to a Vaccine
Vaccine
Manufacture
Pivotal-Phase 3 trail
Phase 1, 2 trails
Pilot Lots
Preclinical
Process development
Pathogenesis
Basic Research
Epidemiology
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Stages of a Clinical Development Program for a
Vaccine
Phase I
Phase II
Phase III
Phase IV
Safety Immunogenicity Proof of Principle N ? 50
Safety Immunogenicity Dose ranging Schedule N100
s
Pivotal Licensure Studies Safety Immunogenicity Ef
ficacy Endpoint Specific Sample Size?
Postmarketing Studies Safety Surveillance 2
endpoints Effectiveness N gt 10,000s
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Phases of Clinical Trials

• Phase 1 Safety and Immunogenicity

• Outcome measures
• Common short-term side effects
• Immunogenicity
• Dose-response, usually stepwise evaluation
• Live vaccines excretion, transmission to
• contacts

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Elements of a Phase 1 Clinical Trail

• Facilities
• Investigators
• Vaccine
• Clinical protocol
• Consent forms
• Recruitment materials
• IND
• Good clinical
  laboratory practice

• IRB review
• Clinical lab activities
• Documentation
• Quality assurance
• Routine SAE reports
• Monitoring
• Statistical analysis
• Publication

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What is Phase II?

• A program of clinical trial activities
• Lays the foundation for Phase III studies
• Establishes an adequate safety database
• Develops data supporting optimal
• formulation
• route
• dose and schedule
• Introduction of vaccine into target population
• Allows refinement of clinical endpoints

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The Phase II Program

• Forms the core of the clinical development plan
• Answers critical questions needed to proceed to
  pivotal efficacy trial
• Includes concurrent or sequential trials, each
  designed to answer a limited set of questions
• NOT A SINGLE TRIAL

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Why is Phase II so Important?

• Impact on the design and validity of Phase III
  trials
• Establishes the dose and schedule for pivotal
  trial
• Safety database helps guide optimal data
  collection
• during pivotal trial
• Selecting the right study population
• Estimating the limits of the sample size
• Identifying immune correlates of protection

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What About Efficacy in Phase II?

• Even if can estimate VE due to high incidence,
  avoid making efficacy a primary endpoint, rather
  study incidence of disease during study
• For high incidence disease, Phase II studies
  provide
• Insight into complex efficacy endpoints
• Justification for large and expensive Phase II
• Phase II a challenge studies can predict efficacy
  from very small number of subjects (5!)
• e.g., shigella, malaria, influenza, cholera

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Evaluating Safety in Phase II

• Purpose is to confirm or exclude potential safety
• issues raised in preclinical and Phase I studies
• Estimations of adverse event rates is rarely the
• primary objective of clinical trials,
  particularly for rare
• adverse events
• Close monitoring should detect common events
• The power of recognizing uncommon events is low
• Some signals may only become obvious if subgroup
• analysis us carried out

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Evaluating Safety in Phase II

• Establish a consistent approach to safety
  evaluation
• Solicit expected adverse events for defined time
• All adverse events graded independently for
  severity and causality by study investigator
• Establish a clear process for adverse events (AE)
  reporting
• importance of good Case Report Forms
• AE reporting frequently linked to dosing
• Serious AE reporting to regulatory bodies in a
  timely fashion

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Phase II Summary

• A series of trials setting stage for Phase III
• Dose ranging studies, explore optimal schedules
• Data on biological activity of elicited responses
• Rigorous safety assessment, over longer period
• of time, using standardized methods
• Comparisons with other vaccines or placebos
• Conducted in individuals who more
• closely resemble the ultimate target population

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New Vaccines Licensed1985-2000

• New Vaccines
• Hepatitis A
• Varicella
• Japanese
• Encephalitis
• Hib conjugates
• Lyme vaccine
• Rotavirus
• Pneumo conj

• Improved Vaccines
• Typhoid vaccines
• DTP for infants
• Hib-HBV
• Hepatitis B
• U.S. Priority
• Global

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Model of Net Cash Flow Over Product Lifetime
Phase IV

Preclinical
Clinical
-
Phase I
Phase II
Phase III
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Oversight and Safety Data Monitoring During
Clinical Development
Phase I
Phase II
Phase III
Phase IV
IRB OPRR IND FDA Safety Reports
IRB OPRR IND FDA Safety Reports
Postmarketing Studies VAERS Govt. Studies Company
studies Case reports IOM Reviews Press Interest
groups Parents/Vaccine FDA/CDC/NIH Physician Compa
ny NVICP
IRB OPRR IND FDA AE profile SAEs
Investigators Nurse Clinical Monitor Company
Statistician Medical Monitor Independent
Monitor QA/OC Peer review
Safety Monitoring Committee Or Data
Safety Monitoring Board
DSMB
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Detection of Rare Events
1000 100 10 1 0.1 0.01 0.001
Risk per thousands
1 10 100 1000
10, 000 100,000 1,00,000
Number of subjects
Sample size needed to reduce the maximum true
proportion to a certain level when no adverse
event is observed (p0.05) Gedde-Dahl TW, NIPH
Annals, 14.92-93,1991