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U.S. Department of Health and Human Services

Animal & Veterinary

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CVM Uses Seven-Step Process to Evaluate Safety, Effectiveness of GE Animals

by Melanie McLean, D.V.M., Communications Staff
FDA Veterinarian Newsletter 2008 Volume XXIII, No VI

The Food and Drug Administration’s Center for Veterinary Medicine evaluates genetically engineered (GE) animals through a rigorous, seven-step review process that looks at the safety of the introduced trait to the animals themselves, to any food derived from the animals, and to the environment. The process uses the same tough requirements for safety and effectiveness that are used for the review of any new animal drug.

A GE animal is an animal that contains altered or additional genetic material (DNA). This altered or additional piece of DNA, called recombinant DNA (rDNA or the rDNA construct), is introduced into the animal to produce a desirable trait, such as the ability to resist disease, produce a pharmaceutical for human use, or grow faster.

In the Federal Food, Drug, and Cosmetic Act (FFDCA), the term “drug” includes “articles (other than food) intended to affect the structure or any function of the body of man or other animals.” The rDNA construct (also called “the article”) that is introduced into the animal meets this legal definition of a drug because it is intended to affect the structure or function of the GE animal. So the GE animal itself is not a drug, but CVM has the authority to regulate GE animals carrying the rDNA construct under the new animal drug provisions of the FFDCA.

Products derived from GE animals are regulated by the appropriate FDA center. For example, human pharmaceuticals produced by GE animals are regulated by the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research, depending on whether the pharmaceutical is a drug or a biologic.

Conventional laws apply

CVM developed its approach for regulating GE animals using the existing laws.  For example, the FFDCA requires that all new animal drugs be the subject of a New Animal Drug Application (NADA). To be approved, the NADA must demonstrate the safety and effectiveness of the drug for its intended use, so any approval for an rDNA construct in a GE animal must be shown to be safe and effective. 

On January 15, 2009, CVM issued the final Guidance for Industry (GFI) #187: “Regulation of Genetically Engineered Animals Containing Heritable Recombinant DNA Constructs” (this guidance can be found at http://www.fda.gov/downloads/AnimalVeterinary/GuidanceCompliance
). GFI #187 provides specific recommendations to help developers of GE animals meet the statutory and regulatory requirements of the NADA process. GFI #187 states that although the FDA intends to regulate non-heritable rDNA constructs (which are not passed on to offspring) in much the same way as heritable rDNA constructs, its primary focus is on heritable rDNA constructs that are passed from generation to generation.

CVM developed a cumulative, weight-of-evidence, risk-based approach for reviewing data in support of an application for approval of an rDNA construct in a GE animal containing an rDNA construct. The approach is cumulative because as each step in the review process is completed, the knowledge gained “forms the basis and context for the evaluation of subsequent steps,” explained Dr. Jeff Jones, a Veterinary Medical Officer in the Animal Biotechnology Group at CVM. He described the weight-of-evidence component as “looking at all the information as a whole to make our decision,” and said that the risk-based component “focuses on where potential harm may arise from the use of this [GE] technology.”

The review process for a GE animal carrying an rDNA construct is “a big picture approach,” explained Dr. Barry Hooberman, a Regulatory Policy Analyst in CVM’s Office of Surveillance and Compliance. “We want to make sure that the questions we ask are appropriate for the product under review; in other words, scaling the risk questions to the product at hand.”

Seven-step review

The first three steps of the seven-step review process concentrate on defining and characterizing the rDNA construct and its integration into the resulting GE animal. The next three steps focus more on whether the GE animal poses any risks to humans, to its own health, or to the environment. The last step of the process addresses effectiveness and validates the claim proposed in the first step.

Step 1: Product identification/definition: The first step asks the question, “What is it, and what is its intended use?” The product identification is a broad statement that describes the rDNA construct and the GE animal containing it and also defines the proposed claim for or intended use of the rDNA construct.

Step 2: Molecular characterization of the construct: This step asks the question, “Will the rDNA construct itself or the way it is assembled pose any risks?” To determine if any risks exist, CVM evaluates whether the rDNA construct contains any DNA sequences that may be potential hazards to the GE animal itself, to humans or other animals consuming food from that animal, or to the environment.

Step 3: Molecular characterization of the GE animal lineage: This step asks the questions, “Does the introduction of the rDNA construct into the animal pose any risks?” and, “Is the rDNA construct stable over several generations of GE animals?” To answer the first question, CVM makes sure that the DNA sequences in the rDNA construct have not rearranged during the introduction process and that the insertion sites are identified. To determine the stability of the rDNA construct, CVM evaluates whether it is maintained in the animal in the same place, with the same number of copies, and with the same general structure over the life of the animal and over several generations of the animal’s offspring.

Step 4: Phenotypic characterization of the GE animal: The phenotype of an animal is its outward appearance and is determined by the interplay of the animal’s genes and environmental influences. Step 4 evaluates the safety of the rDNA construct on the phenotype of the GE animal. It asks the questions, “How does the animal look and act?” and, “Is the animal healthy?” CVM evaluates whether the rDNA construct poses any direct or indirect risks to the GE animal by reviewing comprehensive data on its health, including veterinary and treatment records, growth rates, reproductive function, and behavior. Data on the physiological status of the GE animal, including clinical chemistry, hematology, histopathology, and post-mortem results, are also reviewed.

Step 5: Genotypic and phenotypic durability assessment: This step describes a plan to ensure that the introduced trait will remain the same over time and continue to have the same effect. It asks the question, “Are the genotype and phenotype changing over time?” To demonstrate genotypic durability, data are evaluated to show that the rDNA construct is stably inherited and there is a reasonable expectation that it will continue to be stably inherited. To demonstrate phenotypic durability, the intended trait should be consistently and predictably expressed over multiple generations. CVM recommends that data on inheritance be collected from at least two non-contiguous generations (e.g., second and fourth generations). The durability plan also describes a detection method for determining if a given animal continues to contain the rDNA construct and if its expression has significantly changed over time. In addition, the durability plan describes what actions will be taken if any detected changes are anticipated to affect the safety and effectiveness of the rDNA construct in the GE animal.

Step 6: The food/feed safety and environmental safety assessments: This step includes two safety assessments. The first focuses on the safety of food or feed derived from a GE animal for consumption by humans or other animals. The second addresses the environmental component of the NADA.

The food/feed safety assessment asks the question, “What is the risk of direct or indirect toxicity associated with humans or other animals consuming edible products derived from the GE animal?” An example of a direct toxicity is allergenicity, or, simply put, if the edible product is a known food allergen in humans. Indirect toxicity may occur if the consumption of the edible product creates an unintended risk to the human or animal consuming it. If a GE animal is not intended to produce an edible product, there should be evidence to demonstrate that neither the animal nor any products derived from it will enter the food supply. In all cases, the food/feed safety assessment process includes developing and validating the method used to detect the rDNA construct in food and feed materials derived from GE animals.

The environmental safety assessment asks the question, “What are the direct or indirect effects from the introduction of the GE animal into the environment?” In compliance with the requirements of the National Environmental Policy Act, CVM assesses the potential environmental impact related to the use and disposal of the GE animal and its final product.

Step 7: Effectiveness/claim validation: This step demonstrates that the GE animal fulfilled the product definition stated in the beginning of the NADA review process. It asks the question, “Does the GE animal meet the product definition in Step 1?” For example, for a disease resistance claim, the GE animal should indeed be resistant to that disease. For a non-food product claim, such as a pharmaceutical for human use, the GE animal should indeed produce that product. In addition, this step evaluates the impact on public health if the GE animal does not meet the proposed claim.

Uses for GE animals

CVM applied this cumulative, weight-of-evidence, risk-based approach to the review of GE goats carrying an rDNA construct that gives the goats the ability to produce human antithrombin (AT) in their milk. After the human AT is purified from the goats’ milk, the biological product, called ATryn, is used as an anticoagulant to prevent blood clots in patients with a rare clotting disorder called hereditary AT deficiency. CVM reviewed and approved the rDNA construct in the GE goats, and the FDA’s Center for Biologics Evaluation and Research reviewed and approved the human anticoagulant produced by the goats. It is FDA’s first approval of a human biological product made by GE animals.

Goats producing human AT in their milk are an example of the use of GE animals for biopharm purposes. Biopharm means using GE animals to produce substances (e.g., in their milk or blood) for use as pharmaceuticals in human or veterinary medicine. Currently, most GE animals are being developed for these purposes. Another group of GE animals under development are to be used as sources of scarce cells, tissues, and organs for transplantation into humans (xenotransplantation). Other GE animals are intended for food and may be disease resistant, have improved nutritional or growth characteristics, or have less of an environmental impact during rearing. For those allergic cat lovers, genetic engineering may also find a way to develop a hypoallergenic feline.


The review of an rDNA construct in a GE animal is “a rigorous science- and risk-based process that asks questions that are appropriate for this technology,” said Dr. Jones.

Dr. Hooberman added, “We try to be sure that we’re asking and answering the right questions.”

As more GE animals are being developed, CVM expects more NADAs for GE animals carrying rDNA constructs to be submitted. CVM encourages developers of GE animals to discuss the NADA requirements with CVM early in the development process.