1. Background, Introduction, Statutory Authority, Introduction to Risk-Based Approach Larisa Rudenko, PhD, DABT

2. 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

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

4. Animal Biotechnology (from the Regulator’s 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.

5. 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

6. 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

7. 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

8. 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

9. Review of Basic Concepts in Hazard…Risk…Safety

10. 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  f outcome (exposure, hazard), or “the likelihood of harm” Receptor ≡ individual or population experiencing risk Safety ….reasonable certainty of no harm (established standard)

11. 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

12. 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.

14. 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/DevelopmentApprovalProcess/GeneticEngineeri ng/GeneticallyEngineeredAnimals/default.htm

15. Goal/Structure of Draft Guidance Three parts Clarification of FDA’s 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

16. 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

17. Key Concepts -1 Statutory/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)

18. Key Concepts -2 Risk-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”)

19. 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