1. INADs and Beginning the Review Process Larisa Rudenko, PhD, DABT

2. GE Animal: Investigational Use Outlines obligations and responsibilities Opens path for confidential communications 21 CFR § 511.1b INAD = file; not authorization Allows for certain activities during development Animal (drug) shipments/labeling Record keeping Disposition No investigational animals/products in food/feed supply without prior authorization First look at environmental considerations for animal/product Qualified investigators/collaborators

3. The NADA/INAD Review Process aka “Ziggy” Hierarchical, weight-of-evidence, risk-based Satisfies statutory requirements for safety, effectiveness Follows NADA regulations, with adaptations for technology/expertise y x

5. Early Interactions w Sponsor Usually occurs right after opening INAD to ensure confidentiality Sponsor provides some information prior to meeting Generally starts with open seminar, then closed session with review team Discusses nature of submissions; data/information to prepare Follow up includes MOC ? ? ?

6. In House Review of Submissions Group composition determined by subject area issues, availability Convene Review Group Group Discussion of issues  Suitability, Completeness Assignment of reviews to subject area experts Prepare preliminary review by in-depth reviewers Peer review by group Issue response to Sponsor y x

7. Our First Approval: GTC’s ATryn ® Producing GE Goats

8. ATryn Goat Approval (2/6/09) 2 Separate Legal Actions CVM NADA approval rDNA construct in GE goat to produce rh antithrombin in milk CBER BLA approval for ATryn Anticlotting agent for individuals with hereditary clotting disorders in high risk situations

9. Approval Path

10. Describes the animal, construct, and proposed claim Product Definition

11. Broad statement identifying the GE animal, its proposed product or traits (Animal/rDNA construct + claim) Suggested format: An [x-ploid][n-zygous] [animal common name/breed, line] [genus, species] containing [copy number] copy/ies of the [construct name] construct at [genomic location] in the [animal breed/line] that [claim].

12. GTC 155-92 Product Definition A specific hemizygous diploid line of domestic goats (Capra aegagrus hircus) containing 5 copies of the Bc6 transgene located at the GTC 155-92 site directing the expression of the human gene for antithrombin (which is intended for the treatment of humans) in the mammary gland of goats derived from Founder 155-92.