1. Environmental Assessment of Genetically Engineered Animals at CVM (FDA) Animal Biotechnology Interdisciplinary Group Center for Veterinary Medicine U.S. Food and Drug Administration Evgenij A. Evdokimov, MS, PhD June 4, 2015

2. Major Statutes Governing Regulation of GE Animals Federal Food, Drug, and Cosmetic Act (FD&C Act) Products are regulated; not processes * GE animals are regulated under New Animal Drug Provisions of the Act * National Environmental Policy Act (NEPA) Procedural; major agency’s actions trigger NEPA assessment * Regulated article - article intended to affect the structure or function of the animal (e.g., rDNA construct)

3. Guidance for Industry 187* Regulated article = article intended to affect the structure or function of the animal (e.g., rDNA construct) Covers all types of GE animals All GE animals in a lineage are covered Event-based, case-by-case evaluation Enforcement discretion and approval paths New Animal Drug Application (NADA) means mandatory approval prior to marketing Post-market surveillance *http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/GeneticEngineering/GeneticallyEngine eredAnimals/default.htm

4. Are there significant direct or indirect effects from introduction of the GE animal into the environment? Basis for satisfying NEPA requirements. Hierarchical Risk-Based Evaluation

5. Finding of No Significant Impact (FONSI) NEPA Process Overview Regulated Article May Significantly Affect Environmental Impact Statement (EIS) No Significant Effects Record of Decision (ROD) Environmental Assessment (EA)

6. Biological Containment Physical Containment Source(s) Escape or Introduction Able to Survive Impact on Target Resources in the Environment (habitats, wildlife) Dispersion Direct and Indirect Effects Accessible Environments Able to Reproduce Establishment Spread of Transgene(s) Wild Conspecifics Feral Relatives Net Fitness Geographical/ Geophysical Containment Conceptual Framework for Environmental Assessment ? ? ?

7. Environmental Assessment: General Risk Questions For a specific GE animal (population) containing a specific regulated article…. –What is the intent (free release or contained use)? If contained use - what is the likelihood of escape? –What is the likelihood of survival in the receiving environment? –What is the likelihood of establishment and reproduction? –What are potential consequences/effects to the environment associated with introduction/inadvertent release? Considered in context of an appropriate comparator on a case-by-case basis

8. Potential Environmental Hazards and Harms HazardHarm Does the rDNA construct introduce any hazardous elements into the animal (e.g., viral or mobilizable sequences, sequencing encoding pathogens or toxins, vectors) (Characterized in Molecular Characterization steps) Increased probability of new pathogenic recombinants Do introduced traits affect species fitness or adaptation (Characterized in Phenotypic Characterization) Increased probability of disruption of existing ecosystems due to establishment of a GE animal in the environment

9. Fitness Fitness affects survival and reproduction Net fitness components include –Juvenile and adult viability –Age at sexual maturity –Female fecundity/male fertility/mating success

10. Impacts Pathogen / disease transfer Genetic disturbance Resource competition Displacement Habitat destruction Predation Population changes Community/Ecosystem disruptions

11. Consequences of Introduction, Escape, and Dispersion Will depend largely on: Specific physical locations of production or release; Extent of containment (if applicable); –Physical/mechanical –Biological (e.g., sterility, monosex) –Geographical/geophysical (environmental conditions) –Domestication of species (ability to become feral) Mobility of species

12. Areas of interest Potential risks associated with introduction of GE animals into the environment that are function of the introduced trait –Longevity; –Mating behavior; –Stability of genotype and phenotype over time;

13. Areas of interest Do we always need containment for GE animals?Do we always need containment for GE animals? –GE terrestrial livestock intended for food use? –GE animals for population control? –GE animals receiving gene therapy treatment? What risks do we guard against?What risks do we guard against? Is gene flow a risk per se?Is gene flow a risk per se?

14. Questions? Contacts at CVM: Dr. Evgenij Evdokimov evgenij.evdokimov@fda.hhs.govevgenij.evdokimov@fda.hhs.gov