Background, Introduction, Statutory Authority, Introduction to Risk-Based Approach

Larisa Rudenko, PhD, DABT

What is Animal Biotechnology?

Assisted Reproductive Technologies Help distribute genetics beyond natural matings AI, semen sexing, in vitro fertilization,

embryo transfer, embryo splitting 1300s-present

Cloning More rapid distribution of naturally occurring desirable traits in

breeding stock 1990s-present in livestock

Genetic Engineering Introduces/modifies genes not naturally occurring to introduce

new traits 1980s-present in livestock

Animal Biotechnology (from the Regulator’s Perspective)

Genetic Engineering

GE Animals withHeritable Constructs

Animals with Non-Heritable

Constructs

Natural Breeding

AI ± FrozenSemen Cloning

EmbryoSplit

in vitroFertilization

Selective Breeding

Animal cloning is on a continuum with other ARTS……...

Genetic engineering is a distinctly different technology

Animal Biotechnology (from the Regulator’s Perspective)

The previous slide presents a series of boxes on a horizontal axis that indicate a continuum of assisted reproductive technologies currently in use in US commercial agriculture ranging from natural breeding, selective breeding, artificial insemination/frozen semen, in vitro fertilization, embryo splitting, and ending up with cloning. It is intended to show that cloning falls on that continuum. On the horizontal below is a dotted line and a box saying "genetic engineering,” which indicates that genetic engineering does not fall on that same continuum. Finally, the slide indicates a bifurcation of the term "genetic engineering" to indicate that GE animals can contain both heritable and non-heritable constructs.

Challenges for the Technology

Funding (basic research and commercialization) Effective communications

Unbiased, credible sources of information Not overpromising the technology

A tool in the toolbox No panaceas

Faith in the regulatory system Public acceptance

Challenges for the Agency

Getting the word out Educating investigators Staying in touch with stakeholders

Follow-on guidances Coordination across USG Continuing international outreach Continuing to have faith

in the regulatory system maintained

Possible Solutions

Do the work Work harder at constructive engagements Abandon stale arguments

Hazards vs risks“Scientists” vs “the public”

Consider new approaches to sustainability Avoid reductionist approaches

Transparency

“Agency interested in increasing transparency” (Guidance 187)

What does that mean? Transparency of processes

Data acquisition? Interpretation?

Transparency of deliberations Conclusions? What do they mean?

Public VMAC meeting prior to approvals

Review of Basic Concepts in Hazard…Risk…Safety

Definitions, Relationships, Standards

Harm ≡ an adverse outcomeHazard ≡ substance or activity that has the potential to cause a harmRisk ≡ conditional probability of an adverse outcome provided that

exposure to a receptor has occurred…or

Risk foutcome (exposure, hazard), or

“the likelihood of harm”

Receptor ≡ individual or population experiencing risk

Safety ….reasonable certainty of no harm (established standard)

Intended, Unintended, Direct, Indirect Effects/Risks

Terms used to sort outcomesDirect/Indirect categorize based on

mechanism of actionIntended/Unintended categorize based on

objective of modification

Hazard to What, Risk to Whom?

rDNA construct produces potential hazard(s) in rDNA animals. These may pose health risks to the animals.

Humans/animals consuming edible products from GE animals may/may not experience food consumption risks.

GE Animal Guidance

Final 1/15/2009

Guidance for Industry #187 - Regulation of Genetically Engineered Animals Containing Heritable Recombinant DNA Constructs

http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/GeneticEngineering/GeneticallyEngineeredAnimals/default.htm

Goal/Structure of Draft Guidance

Three parts

Clarification of FDA’s continued regulation of GE animals under NADA provisions of FFDCA

Congruence with existing regulations (21 CFR 511 (INAD) and 21 CFR 514 (NADA)

Recommendations on how sponsors can prepare data and information for FDA to review

Scope

All GE animals covered; specific recommendations for those with heritable rDNA constructs

Explicitly includes biopharm animals Enforcement discretion possible for low risk

applications INAD/NADA processes Post-approval responsibilities

Key Concepts -1Statutory/Scope

Definition of “article” rDNA construct intended to affect the structure or

function of the animal

“All GE animals derived from the same tx event contain the same article, and subject to evaluation under a single new animal drug application.” (Guidance 187 p 6)

No products in commerce without FDA approval (minor exceptions enforcement discretion)

Key Concepts -2Risk-Based Approach

Each GE Animal/rDNA construct event poses unique risk(s)Specific set of risk questionsSpecific set of data/information driven responses

Case-by-case evaluation for each transformation event (i.e., each “article”)

Two Paths

Default assumption: INAD/NADA approachAll species traditionally consumed as foodAll scenarios not considered “low risk”

Certain low risk scenarios may be eligible for enforcement discretion