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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CVM’s INAD/NADA Review Process

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.

Claim Validation

Does the GE animal meet the claim

established in the product definition?

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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THANK YOU

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Dr. Larisa Rudenko

FDA’s 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-us-regulations/

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