Regulatory Considerations for Genetically Engineered Animals

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1 Regulatory Considerations for Genetically Engineered Animals Malini Wileman, M.S., Ph.D. Animal Biotechnology Interdisciplinary Group Center for Veterinary Medicine Food and Drug Administration Gene Editing to Modify Animal Genomes for Research - Scientific and Ethical Considerations December 7-8, 2015

2 Today s Presentation Review Overall Regulatory Process Reprise Statutory Authorities Regulatory Triggers INAD/NADA Review Process at FDA-CVM Case Study Animal Models of Human Disease

3 Statutory Authority Federal Food, Drug, and Cosmetic Act (FD&C Act) Products are regulated; not processes National Environmental Policy Act (NEPA) Procedural; orders agencies to evaluate impacts of agency actions

4 FD&C Act (New Animal Drug Provisions) 21 CFR 511 and 21 CFR 514 Prohibits introduction of unapproved drug into commerce Drugs are defined as articles intended to Diagnose, cure, mitigate, treat, or prevent disease Affect the structure or any function of the body Exemption for research Investigation/Investigational Animal For approval, sponsor of application must demonstrate Safety to animal Food safety (for food animals) Effectiveness (does the article do what the sponsor claims?)

5 Statutory Authority Clarified in Guidance for Industry 187* Covers all types of GE animals Heritable and non-heritable rdna constructs Definition of article rdna construct intended to affect the structure or function of the animal 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 * efault.htm

6 Genome Editing Use of engineered nucleases to effect structure/function alterations Targeted insertions Small mutations Substitutions Deletions Large mutations Perception as non-ge Sander and Joung, Nature Biotechnology 32, (2014)

7 A Name Is Not a Regulatory Trigger GMO.genetically engineered transgenic gene/genome edited/ing techniques of modern biotechnology Are NOT regulatory triggers for the Federal Food, Drug and Cosmetic Act.

8 So what is the regulatory trigger The term drug means (A) articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C).

9 How Does This Translate for Genome Edited Animals? Genome editing technologies are intended to affect the information-transmitting quality of an animal s DNA by altering the DNA sequence encoded in the animal s genome. These alterations affect the function of the animal s cells (by changing the nature and level of proteins expressed by the cell) and ultimately affect the physical traits or health of the animal. For insertions of DNA by genome editing, GFI 187 as written now applies. For deletions and substitutions, the agency remains in a deliberative process. 9

10 CVM s INAD/NADA Review Process

11 Product Definition Describes the construct in the animal, and proposed claim as basis for hazard identification.

12 Molecular Characterization: Construct Are there sequences likely to contain potential hazards to the animal, humans or animals consuming food from that animal, or the environment? e.g., mobilizeable sequences from viruses endemic in that species?

13 Molecular Characterization: GE Animal Lineage Does the insertion of the rdna construct pose a hazard to the animal, humans or the environment?

14 Phenotypic Characterization Direct and indirect risks posed to the GE animal? (e.g., can surveying the health and other phenotypic characteristics of the animal inform us with respect to risk to the animal and potential human food safety concerns?)

15 Durability Assessment and Plan Are the genotype or phenotype of the animal changing over the lifespan in a way that would affect the risk(s) associated with the product? Is there a plan for monitoring stability to anticipate or identify those changes?

16 Food/Feed Safety IF INTENDED FOR FOOD/FEED Risk of direct or indirect adverse outcomes associated with the consumption of the GE animal as food or feed? IF NOT INTENDED FOR FOOD/FEED Evidence provided to demonstrate that investigational or postcommercialized GE animals will not enter the food supply?

17 Environmental Safety Direct or indirect effects from introduction of the GE animal into the environment? Basis for satisfying NEPA requirements.

18 Claim Validation Does the GE animal meet the claim established in the product definition?

19 Potential Risk-Based Questions for GE Animal Models of Human Disease What is the likelihood of Introduced or altered sequences recombining with endogenous sequences/endemic viruses to pose infectious risk to humans or animals Edible products from investigational animals entering food supply without authorization Record keeping Animal ID/tracking Containment Appropriate disposition Direct or indirect unintended effects on animal health Is the claim valid and durable?

20 Hypothetical Case Study: Pig Model of Human Cancer Model: Heritable site specific insertion of the human lmp GPCR gene affecting expression levels of a chemokine receptor. Useful for studies of small cell lung cancer, among other cancers. Short description of event (construct in the lineage) Site specific insertion via TALENs Site identified Flanking sequences (~ 1 kb at 3 and 5 ends) Number of copies Sequence (as compared to construct alone)

21 Hypothetical Case Study: Cattle Altered for Disease Resistance Model: Heritable site specific insertion into Bos taurus of a Buffalo buffalo gene for resistance to mastitis. Short description of event (construct in the lineage) Site specific insertion via a sequence-specific nuclease Site identified Flanking sequences (~ 1 kb at 3 and 5 ends) Number of copies Sequence in the animal (as compared to construct alone)

22 Continued Phenotypic characterization Animal safety Growth characteristics Reproductive capacity Abnormalities Blood chemistry Presence of altered protein in situ Animal health/husbandry Description of conditions, care Affirmative daily animal observation records Veterinary treatment reports Biosurveillance

23 .Continued Claim Validation (Effectiveness) Statutory requirement: Substantial evidence for the effect under the prescribed conditions of use 21 U.S.C 360b(d)(1), where Substantial evidence means evidence consisting of one or more adequate and wellcontrolled investigations In the target animal Laboratory animals, field, bioequivalence, or in vitro studies on the basis of which qualified experts could conclude that the regulated article will have the intended effect under the conditions of use in the labeling. 21 C.F.R (a). 23

24 THANK YOU 24

25 Dr. Larisa Rudenko FDA s Risk Analysis Process for Biotechnology Products December 9 th, 10:30 a.m. webinar on US Regulations on Biotechnology 25