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

Todays 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/d
efault.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, 347355 (2014)

A Name Is Not a Regulatory Trigger

GMO.genetically engineeredtransgenic
gene/genome edited/ingtechniques 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 animals DNA by altering
the DNA sequence encoded in the animals genome. These
alterations affect the function of the animals 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.

CVMs INAD/NADA Review Process

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

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?

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

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?)

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?

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?

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

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

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?

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 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. 514.4(a).

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THANK YOU

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Dr. Larisa Rudenko

FDAs Risk Analysis Process for Biotechnology
Products
December 9th, 10:30 a.m. webinar on US
Regulations on Biotechnology
http://nas-sites.org/gene-drives/2015/11/14/webinar-usregulations/
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