Background, Introduction, Statutory Authority, Introduction to Risk-Based Approach

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Background, Introduction, Statutory Authority,
Introduction to Risk-Based Approach

• Larisa Rudenko, PhD, DABT

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What is Animal Biotechnology?

• Assisted Reproductive Technologies
• Help distribute genetics beyond natural matings
• AI, semen sexing, in vitro fertilization,
  embryo
  transfer, embryo splitting
• 1300s-present
• Cloning
• More rapid distribution of naturally occurring
  desirable traits in breeding stock
• 1990s-present in livestock
• Genetic Engineering
• Introduces/modifies genes not naturally occurring
  to introduce new traits
• 1980s-present in livestock

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Animal Biotechnology (from the Regulators
Perspective)
Natural Breeding
AI Frozen Semen
Cloning
Embryo Split
Selective Breeding
in vitro Fertilization
Animal cloning is on a continuum with other
ARTS...
Genetic Engineering
Genetic engineering is a distinctly different
technology
GE Animals with Heritable Constructs
Animals with Non-Heritable Constructs
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Animal Biotechnology (from the Regulators
Perspective)

• The previous slide presents a series of boxes on
  a horizontal axis that indicate a continuum of
  assisted reproductive technologies currently in
  use in US commercial agriculture ranging from
  natural breeding, selective breeding, artificial
  insemination/frozen semen, in vitro
  fertilization, embryo splitting, and ending up
  with cloning. It is intended to show that cloning
  falls on that continuum. On the horizontal below
  is a dotted line and a box saying "genetic
  engineering, which indicates that genetic
  engineering does not fall on that same continuum.
  Finally, the slide indicates a bifurcation of the
  term "genetic engineering" to indicate that GE
  animals can contain both heritable and
  non-heritable constructs.

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Challenges for the Technology

• Funding (basic research and commercialization)
• Effective communications
• Unbiased, credible sources of information
• Not overpromising the technology
• A tool in the toolbox
• No panaceas
• Faith in the regulatory system
• Public acceptance

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Challenges for the Agency

• Getting the word out
• Educating investigators
• Staying in touch with stakeholders
• Follow-on guidances
• Coordination across USG
• Continuing international outreach
• Continuing to have faith
  in
  the regulatory system maintained

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Possible Solutions

• Do the work
• Work harder at constructive engagements
• Abandon stale arguments
• Hazards vs risks
• Scientists vs the public
• Consider new approaches to sustainability
• Avoid reductionist approaches

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Transparency

• Agency interested in increasing transparency
  (Guidance 187)
• What does that mean?
• Transparency of processes
• Data acquisition?
• Interpretation?
• Transparency of deliberations
• Conclusions?
• What do they mean?
• Public VMAC meeting prior to approvals

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Review of Basic Concepts in HazardRiskSafety
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Definitions, Relationships, Standards

• Harm an adverse outcome
• Hazard substance or activity that has the
  potential to cause a harm
• Risk conditional probability of an adverse
  outcome provided that exposure to a receptor has
  occurred
• or
• Risk ? foutcome (exposure, hazard),
• or
• the likelihood of harm
• Receptor individual or population experiencing
  risk
• Safety .reasonable certainty of no harm
  (established standard)

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Intended, Unintended, Direct, Indirect
Effects/Risks

• Terms used to sort outcomes
• Direct/Indirect categorize based on mechanism of
  action
• Intended/Unintended categorize based on objective
  of modification

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Hazard to What, Risk to Whom?

• rDNA construct produces potential hazard(s) in
  rDNA animals. These may pose health risks to the
  animals.

• Humans/animals consuming edible products from GE
  animals may/may not experience food consumption
  risks.

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GE Animal
Guidance

• Final 1/15/2009
• Guidance for Industry 187 - Regulation of
  Genetically Engineered Animals Containing
  Heritable Recombinant DNA Constructs
• http//www.fda.gov/AnimalVeterinary/DevelopmentApp
  rovalProcess/GeneticEngineering/GeneticallyEnginee
  redAnimals/default.htm

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Goal/Structure of Draft Guidance

• Three parts
• Clarification of FDAs continued regulation of GE
  animals under NADA provisions of FFDCA
• Congruence with existing regulations (21 CFR 511
  (INAD) and 21 CFR 514 (NADA)
• Recommendations on how sponsors can prepare data
  and information for FDA to review

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Scope

• All GE animals covered specific recommendations
  for those with heritable rDNA constructs
• Explicitly includes biopharm animals
• Enforcement discretion possible for low risk
  applications
• INAD/NADA processes
• Post-approval responsibilities

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Key Concepts -1Statutory/Scope

• Definition of article
• rDNA construct intended to affect the structure
  or function of the animal
• All GE animals derived from the same tx event
  contain the same article, and subject to
  evaluation under a single new animal drug
  application. (Guidance 187 p 6)
• No products in commerce without FDA approval
  (minor exceptions ? enforcement discretion)

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Key Concepts -2Risk-Based Approach

• Each GE Animal/rDNA construct event poses unique
  risk(s)
• Specific set of risk questions
• Specific set of data/information driven responses
• Case-by-case evaluation for each transformation
  event (i.e., each article)

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Two Paths

• Default assumption INAD/NADA approach
• All species traditionally consumed as food
• All scenarios not considered low risk
• Certain low risk scenarios may be eligible for
  enforcement discretion