With Final Guidance, FDA Moves Forward on Regulation of Genetically Engineered Animals

By Riëtte van Laack & Ricardo Carvajal –

On January 15, the Center for Veterinary Medicine ("CVM") published its final guidance on “Regulation of Genetically Engineered Animals Containing Heritable Recombinant DNA Constructs.”  The final guidance describes CVM’s application of the FDC Act’s new animal drug provisions and FDA’s related regulations to genetically engineered animals and foods derived from those animals. 

Under the FDC Act, an rDNA construct in a genetically engineered animal that is intended to affect the structure or function of that animal is a drug.  Consequently, the new animal drug provisions apply to such rDNA constructs.  Each new animal drug approval ("NADA") covers all animals that contain the same rDNA construct, so long as those animals are derived from the same transformation event (a transformation event is the introduction of an rDNA construct into the germline of an animal)  However, different transformation events are subject to separate NADA’s because animals derived from different transformation events are likely to have the rDNA construct present at different sites in the genome, which can affect the expression of the construct and the animal’s health.  Although the rDNA construct is the regulated article, the guidance refers to regulation of the construct as “regulation of the GE animal.” 

CVM’s final guidance also clarifies that the U.S. approach is consistent with the recommendations of the Codex Alimentarius Commission ("CAC").  The CAC, created by the Food and Agriculture Organization of the United Nations ("FAO") and the World Health Organization ("WHO"), published its Guideline for the Conduct of Food Safety Assessment of Foods Derived from Recombinant DNA Animals in July 2008.   [www.codex.alimentarius.net/download/standard/11023/CXG-068e.pdf]

CVM’s final guidance is a revised version of the September 2008 draft guidance.  Over 28,000 comments were submitted to CVM in response to the 2008 draft guidance.  The Agency’s responses to these comments are available here.  Simultaneous with the issuance of the final guidance, CVM updated its “Fact Sheet on Genetically Engineered Animals” and “Genetic Engineering Technology General Q&A.”

GE animals are developed for a variety of purposes, including production of pharmaceuticals and organs for transplantation (biopharming), hypoallergenic pets, improved disease resistance, increased performance characteristics, and animal models for human disease.  According to the final guidance, all GE animals are subject to premarket approval, but CVM intends to exercise enforcement discretion based on risk.  For example, CVM may decide not require a NADA for aquarium fish genetically engineered to fluoresce in the dark, or for GE engineered laboratory animals.  Moreover, CVM does not intend to take enforcement against “GE animals of non-food-species that are regulated by other government agencies or entities, such as GE insects” regulated by USDA’s Animal and Plant Health Inspection Service. 

Although the final guidance discusses the investigational new animal drug requirements for GE animals (meaning the rDNA constructs in such animals), its primary focus is the NADA requirements for GE animals.  See 21 C.F.R. Parts 511 and 514.  With the exception of the veterinary food directive, all NADA requirements apply. 

As with any NADA for food producing animals, CVM will not approve the rDNA constructs in a GE animal unless it has determined that any food derived from the GE animal is safe.  CVM’s evaluation is consistent with the CAC Guideline and includes assessment of direct toxicity, including allergenicity, and “potential indirect toxicity with both the [rDNA construct] and its expressed product.”  Only if “food from a GE animal is [materially] different from that of its [non-GE] counterpart” must the food from a GE animal be labeled to indicate that it originates from a GE animal.

Just like sponsors of other NADAs, sponsors of a GE animal must comply with the statutory registration and drug listing requirements and the requirements for adverse event and periodic reporting. However, CVM has yet to develop guidance as to how GMP requirements for GE animals can be met. 

Thus far, CVM has not approved any NADAs for GE animals.  The guidance repeatedly encourages developers to consult with CVM early and often about many aspects of the preparation and submission of a NADA, including the preparation of an environmental assessment that addresses issues and impacts related to “the use and disposal of the GE animal and its final product” (in the absence of a categorical exclusion, preparation of an environmental assessment is required under FDA regulations implementing the National Environmental Policy Act).  In addition, CVM intends to provide transparency of the GE animal review process by holding public advisory committee meetings prior to approval.  As with other NADA approvals, CVM will publish a detailed summary of the basis for its approval of a GE animal.  Language in the guidance suggests that a number of details have yet to be worked out, particularly with respect to coordination with other federal agencies, and that additional guidance documents on specific issues may be forthcoming.