Vaccines from Bench to Clinic

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Vaccines from Bench to Clinic
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Behavioral Objectives

• List and describe the different stages of vaccine
  development needed for vaccine licensure and
  discuss their aims.
• Discuss 4 obstacles to the use of licensed
  vaccines or the development of new vaccines.
• Define FDA, CBER, IRB, IND and BLA and the
  function they have in vaccine development.
• Define informed consent.

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Vaccine Development

• Discovery
• Phase 1
• Phase 2
• Phase 3

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Discovery or Pre-Clinical Phase

• Usually the result of experimentation in
  academic, pure research or biotech labs
• Data provide Proof of Principal and suggest
  commercialization of idea
• Academic labs incapable of further product
  development
• Idea should be patented to protect intellectual
  property
• Patent can be licensed to drug companies for
  commercialization

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Clinical Development

• Costs 600 million-1 billion
• Takes 8-10 years
• Incentive-Profit
• Vaccines must be made employing good
  manufacturing practice (GMP)
• Cost and time needed to assure vaccine is safe
  and efficacious.
• Begins with submission of an Investigational New
  Drug (IND) application to the FDA

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• FDAs Center for Biologics Evaluation and
  Research (CBER) is responsible for regulating
  vaccines in USA
• Successful completion of all 3 phases of clinical
  development can be followed by submission of a
  Biologic License Application (BLA)
• Following review, the findings may be presented
  to FDAs Vaccines and Related Biological Products
  Advisory Committee for advice to the agency
  regarding the safety and efficacy of the vaccine
  for the proposed indication
• Vaccine approval also requires adequate labeling
• FDA continues to monitor product and
  manufacturing of vaccine to ensure continuing
  safety

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Phase 1

• Following submission of IND a candidate vaccine
  is tested in a small number (10-30) healthy human
  adult volunteers who are not at risk for the
  disease in question.
• Main goal is safety and to a lesser extent
  immunogenicity involving different doses and
  different immunization schedules.
• Phase 1 studies usually take 8-12 months and can
  be done in academic setting or biotech settings
  but need institutional
• Investigative Review Board (IRB) approval
  
• Including informed consent to protect
  volunteer rights
• GMP, GCP, GLP must be used throughout

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GLP

• Requires learning new ways of laboratory practice
  e.g. ELISA working toward a validated assay
• SOP standard operating procedure
• Follow written protocols with detailed record
  keeping
• Provide documentation of accuracy, sensitivity,
  specificity and reproducibility of methods

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Phase 2 Studies

• Involves a larger number of volunteers (50-500),
  usually a mixture of low-risk and higher risk
  individuals from the population where phase 3
  studies will be done. Informed consent must be
  obtained from all participants.
• Main goal is to generate safety data as well as
  information for refining dosage and immunization
  schedule, vaccine formulations and lot
  consistency
• May also provide preliminary data relative to
  efficacy
• If challenge studies are to be included, they
  must not include vulnerable populations
• Trials usually take 18-24 months because of
  screening and enrolling large numbers of
  participants

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• Phase 1 2 studies lay the foundation for
  proceeding to pivotal phase 3 trials.
• They provide for an understanding of safety and
  safety of new vaccines, allow for the refinement
  of immunologic assays and the identification of
  clinnical correlates of immunity
• They also provide proof of principal on a pilot
  basis

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Phase 3 Studies.

• The randomized, controlled clinical trial aimed
  at providing scientific evidence about the
  clinical performance of vaccines.
• Involves 1000s of participants from high risk
  populations where individuals, having given
  informed consent, are randomized into test and
  control groups to be given vaccine or placebo in
  a blinded study to avoid bias.
• The goal of phase 3 trials is to determine
  vaccine safety and efficacy in a large study
  population sample leading to licensure
  application

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• Surveillance is key to knowing what is going on,
  active or passive and when it should be
  terminated
• The application will require designs and
  procedures that conform to good clinical
  practice.
• Trial will usually require a minimum of 3 years

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Phase 4 Trials

• Phase 4 (phase IV)Phase 4 trials are done after a
  vaccine has been shown to work and has been
  granted a license. So they are looking at
  vaccines that are already available for doctors
  to prescribe, rather than new drugs that are
  still being developed.The main reasons
  pharmaceutical companies run phase 4 trials are
  to find out more about the side effects and
  safety of the vaccine, what the long term risks
  and benefits are, and how well the vaccine works
  when it is used more widely than in clinical
  trials

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Barriers to the Optimal Use of Licensed Vaccines

• Technical obstacles
• Economic obstacles
• Cultural obstacles
• Legal obstacles
• Pregnancy and the application of licensed
  vaccines
• Regulatory issues.

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Technical Barriers

• Manufacturing problems-too few manufacturers
• Vaccine incompatibility
• Need to replace banned materials
• Deployment of licensed vaccines in 3rd world

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Economic Barriers

• Pricing structure-manufacturers may not be fairly
  compensated .
• Need to use auto-disposable needles in developing
  world in order to improve safety
• Lack of access to vaccines in poor nations

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Cultural Barriers

• Refusal to accept vaccines on religious or
  ethical grounds
• Existence of different infant immunization
  schedules in different countries
• Consumer ignorance regarding benefits of
  immunization
• Belief that contracting disease is more
  beneficial
• Opposition to genetically modified organisms in
  vaccines
• Too many injections

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Legal Obstacles

• Litigation associated with vaccine side effects
  particularly in USA
• Intellectual property rights
• Licensure of combination vaccines difficult and
  expensive

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Pregnancy

• Vaccines rarely prescribed to pregnant women
  because of liability to physicians and
  manufacturers
• Reluctance to expose pregnant women and fetuses
  to risks associated with vaccination.

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Regulatory Issues

• Removal of vaccines from the marketplace
• Safety issues
• Obsolescence
• Disease eradicated
• Error in judging market size
• U.S. single largest market for vaccines When
  reimbursement is denied vaccine availability
  throughout world may suffer

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Need for New Vaccines

• Sexually transmitted vaccines
• Respiratory infections
• Enteric infections
• Vector borne diseases
• Nosocomial agents
• Other viruses,bacteria, and fungi

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Barriers to the development of new vaccines

• Legal
• Technical
• Economic
• Regulatory