February 27, 2017

FDA proposes to regulate all animals with “intentionally altered” DNA as drugs


By Dr. Alison Van Eenennaam

You have the opportunity to comment on the FDA’s draft guidance on the “Regulation of Intentionally Altered Genomic DNA in Animals.” Please take the time to comment. Comments will be accepted through April 19, 2017 at the following link: https://www.regulations.gov/document?D=FDA-2008-D-0394-0279

Recently, at the American Association for the Advancement of Science (AAAS) Annual Meeting in Boston, the Agricultural, Food and Renewable Resources section hosted a seminar on “The Potential of Gene Editing to Revolutionize Agriculture.” During the session speakers from both academia and industry discussed how this breeding method could be used to introduce useful genetic variants into plant and animal breeding programs.

On the animal side, Dr. Alison Van Eenennaam from UC Davis discussed how several groups have used this technique to produce edited livestock, such as the porcine reproductive and respiratory syndrome virus (PRRSV)-resistant pigs at the University of Missouri, and recently cows that are less susceptible to bovine tuberculosis by a group in China. She also discussed animal welfare traits such as the polled Holstein bulls, where the Celtic polled allele from beef breeds was substituted for the horned allele at the POLLED locus by the Minnesota-based company, Recombinetics.

The overarching take home message from the AAAS conference, aptly themed “Serving society through science policy,” was the need for scientists to speak up and communicate both their work, and inform policy with evidence and facts. And in this regard there is an opportunity for animal scientists to do just that as it relates to the regulation of gene editing.

On January 18, 2017 the FDA produced a draft guidance entitled, “Regulation of Intentionally Altered Genomic DNA in Animals.” This latest FDA “Guidance for Industry #187” supercedes the never finalized 2009 document, “Regulation of Genetically Engineered Animals Containing Heritable rDNA Constructs.”

This new 2017 guidance for producers and developers of genetically improved animals and their products defines all intentional DNA alterations in animals as “drugs.” No longer is it the presence of a recombinant DNA (rDNA) construct that is considered to be a drug, as was the case when the guidance was written for genetically engineered animals in 2009, but rather it is proposed that the presence of ANY “intentionally altered genomic DNA” in the animal should trigger new animal drug application. Intention does not equate to risk.

The guidance states that “intentionally altered genomic DNA may result from random or targeted DNA sequence changes including nucleotide insertions, substitutions, or deletions,” however it clarifies selective breeding or other assisted reproductive technologies, including random mutagenesis followed by phenotypic selection are not included as triggers. This suggests that if a breeder meant for a change to happen such as the myostatin knockout Nellore produced at Texas A&M using gene editing, then the alteration would be regulated. However, if random mutations happened in nature or due to uncontrolled mutagenesis – such as all of the other myostatin mutations present in cattle breeds like the double-muscled Belgium Blue, then these alterations would not trigger new animal drug regulatory oversight.

The new draft Guidance then goes on to state “a specific DNA alteration is an article that meets the definition of a new animal drug at each site in the genome where the alteration (insertion, substitution or deletion) occurs. The specific alteration sequence and the site at which the alteration is located can affect both the health of the animals in the lineage and the level and control of expression of the altered sequence, which influences its effectiveness in that lineage. Therefore, in general, each specific genomic alteration is considered to be a separate new animal drug subject to new animal drug approval requirements.” So each intentionally-induced SNP or alteration is a separate new animal drug, but exactly the same SNP(s) and alterations resulting from de novo mutations are not.

There is currently a public comment period open for this draft guidance. If you consider that regulating intentional DNA alterations as drugs is not consistent with science-based regulation based on the unique risks associated with the product being regulated, then PLEASE comment before April 19th, 2017. The link to comment is https://www.regulations.gov/document?D=FDA-2008-D-0394-0279.

Be prepared to address the following questions:

  1. In the first, we seek the public’s input on how to refer to these animals. In the past, FDA has used the term “genetically engineered” to refer to animals containing recombinant DNA constructs intended to alter the structure or function of the body of the animal. For this draft revised guidance, we have used the phrase “animals whose genomes have been altered intentionally.” Other terms that could be used include “genome edited animals,” “intentionally altered animals,” or expanding the term “genetically engineered” to include the deliberate modification of the characteristics of an organism by manipulating its genetic material. The public is encouraged to suggest other phrases that are accurate and inclusive.
  2. The second set of questions for which we seek public input is on whether there is any existing empirical evidence demonstrating that certain types of genome editing may pose minimal risk, with particular emphasis on the following:
  • Are there categories of animals whose genomes have been intentionally altered for which specific empirical evidence indicates that there are no significant target animal, user safety, food safety, or environmental risks? If so, what is that evidence?
  • Are there categories of animals whose genomes have been intentionally altered for which empirical evidence exists to demonstrate that genome editing is durable on a genotypic and phenotypic level and would continue to be durable over the lifetime of a particular product? If so, what is that evidence?
  • Is there empirical evidence to demonstrate that there are degrees of introduced changes (e.g., insertions or deletions of any size or single nucleotide substitutions) that are likely to pose less risk than other changes? If so, what is that evidence?
  • Is there empirical evidence that indicates that the degree of taxonomic relationship between the introduced gene and the recipient animal influences the health of that recipient animal or the extent to which the trait is expressed? If so, what is that evidence?


Hopefully all animal scientists will take the time to comment on FDA’s draft guidance. As the famous quote goes, “Life Happens to Those Who Show Up.” The approach outlined goes against the recommendations of the 2016 National Academies report. They recommended a tiered regulatory approach focused on intended and unintended novel characteristics of the end product resulting from the breeding methods that may present potential hazards, rather than focusing regulation on the process or breeding method by which that genetic change was achieved. Likewise human intent could be added to the list of things not directly correlated or even relevant to risks that might be associated with the end product. A strong scientific voice in support of science-based regulations based on risk is important. Perhaps another famous quote is appropriate to end this piece, “If you’re not at the table, you’re on the menu.”