Regulatory Considerations for Genetically Engineered Animals
Malini Wileman, M.S., Ph.D.Animal Biotechnology Interdisciplinary Group
Center for Veterinary MedicineFood and Drug Administration
Gene Editing to Modify Animal Genomes for Research - Scientific and Ethical
Considerations December 7-8, 2015
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
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”
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?)
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*http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/GeneticEngineering/GeneticallyEngineeredAnimals/default.htm
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, 347–355 (2014)
A Name Is Not a Regulatory TriggerGMO….genetically engineered……transgenic……gene/genome edited/ing……techniques of modern biotechnology
Are NOT regulatory triggers for the Federal Food, Drug and Cosmetic Act.
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).
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.
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Product Definition
Describes the construct in the animal, and proposed claim as basis for hazard
identification.
Molecular Characterization: ConstructAre 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?
Molecular Characterization: GE Animal Lineage
Does the insertion of the rDNA construct pose a hazard to the
animal, humans or the environment?
Phenotypic CharacterizationDirect 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?)
Durability Assessment and PlanAre 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?
Food/Feed SafetyIF INTENDED
FOR FOOD/FEED
Risk of direct or indirect adverse
outcomes associated with
the consumption of the GE animal as food or feed?
IF NOTINTENDED FOR
FOOD/FEEDEvidence provided
to demonstrate that investigational
or post-commercialized
GE animals will not enter the food
supply?
Environmental Safety
Direct or indirect effects from introduction of the GE
animal into the environment?
Basis for satisfying NEPA requirements.
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?
Potential Risk-Based Questions for GE Animal Models of Human Disease
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)
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)
…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
….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 well-
controlled 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. 514.4(a).
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