genome-edited experimental research animals CANNOT enter the U.S. food supply, regardless of the changes they carry, unless the researcher who produced that animal has submitted a new drug experimental animal (INAD) from the FDA and has additionally obtained a food use authorization that requires a ton of paperwork and also data collection. PERIOD.
So when I read the title, “Genetically Modified Beef Cattle Receive Regulatory Approval in the United States», I felt the need to write this blog.
If it is true that the FDA decided to exercise its enforcement discretion for two [a cattle breed] founding animals produced by a company, Recombinetics, this “discretion“The option is only available to developers. And this decision was not a “regulatory approval”, but rather a determination by the FDA that this product was low enough risk that it was not a priority In other words, we will turn a blind eye to the sale of this “unapproved animal drug” because it is deemed low risk.
And that would be entirely appropriate given the low risk of this product, but what isn’t obvious from the media coverage is
- This decision is made on an individual animal basis (i.e. data from EACH animal whose genome has been edited must be submitted to the FDA) and this particular decision involved two animals, and
- its path is only available to commercial developers bringing a product to market, not academic or university researchers studying genome editing.
If, as a university researcher, I were to perform the exact same modification and create a genome-edited cow, the only way for me to get that animal into commerce and the food supply would be to open an INAD and then ask for food use permission. And I know exactly how much work it takes to do that, because I’ve spent pretty much the entire pandemic trying to get food use clearance for some genome-edited knockout (gene deletion) sheep and cattle. that we produced at UC Davis.
Spoiler alert – I did not obtain food use clearance. However, I was eventually allowed to return them, which means their carcasses could enter the animal feed (i.e. dog food) chain.
To apply for an INAD, the sponsor (meaning me in the case of a university professor), must provide the FDA with information including an outline of the project’s objectives, a description of the constructions or alterations in animals, a description of the method(s) or technologies used to produce and deliver/introduce the genomic alteration, and a description of any studies completed, including any relevant information from other animals in which the same genes were knocked out (e.g., references to published articles describing knocked out mice).
In addition, a request for “categorical exclusion from the requirements for the preparation of an environmental assessment” must be submitted to accompany the INAD file. When the FDA reviews and approves new drugs for animals, it must comply with the requirements of the National Environmental Policy Act, which includes a review of environmental risks, if any, where applicable. Requesting this exclusion involved certifying that there were no extraordinary circumstances in which genetically modified cattle could significantly affect the quality of the human environment.
This required documenting the location of facilities where animals were housed, containment measures, management practices and conditions of all facilities, animal waste and animal disposal, and a description of operational procedures. standard, and to submit this information to enable a decision to be made. .
When obtaining an INAD, an Experimental Food Use Authorization (FUA) must be applied for to introduce knockout sheep and cattle into the food supply at the end of the experiment, rather than incinerate them . For this, the information in Table 1 was requested.
The in silico “Predicted Off-targets” analysis included 10 sequences with three mismatches with the guide sequence in the reference bovine genome. There were no sequences with less than three mismatches other than our target, according to our guide design criteria. Given the expense of performing this off-target sequence verification for 10 loci for each animal, and the fact that these analyzes were unrelated to our scientific interest in these animals (meaning we would be doing these analyzes only for the FUA), the FUA was abandoned in favor of a request for authorization to use rendering.
This meant the animals would be allowed to enter the animal food chain, rather than the human food chain at the end of the experiment. Obtaining a rendering license required a separate application to the Food Division of the FDA. Information similar to that described in Table 1 for FUA was requested, but this request did not require off-target sequence verification.
These regulatory exchanges involved a substantial investment of time, both for regulators and investigators. Such regulatory interactions are not routine in basic university research in animal breeding and animal genetics. Nor the disposal of all animals by incineration, burial or composting at the end of a research project. This is particularly costly when working with large species of livestock and is a one-time expense associated with the use of gene editing in food animals that is not incurred when researching conventional farming methods.
Additionally, such regulatory data is usually requested before the conclusion of experimental work, rather than at the end of the research when manuscripts describing and detailing the methods and results are usually compiled and written. As such, preparing these documents required me to devote a significant amount of time solely to regulatory compliance, and pursuing an FUA would have required additional experimental work. This experience definitely dampened my enthusiasm to continue my research on genome-edited cattle in the United States.
I should mention that there are also fees associated with all of this. As an academic institution, UC Davis is eligible for a fee waiver, but the Product and Sponsor Fees for Users of Animal Drugs (ADUFA) are substantial. And while that fee may be quite reasonable for an actual evaluation of a new animal chemical drug, it becomes difficult to figure out half a million dollars to get a single nucleotide polymorphism approved, when the nature has literally manufactured millions of unregulated SNPs in livestock. genomes. Somewhat amusingly, UC Davis recently received an ADUFA bill for over $140,000 because FDA fee waiver requests were apparently misplaced, and this definitely caught the University’s attention!
Ultimately, most academic researchers did not sign up to become regulatory scientists. And while I appreciate the need for these scientists to provide data to gain approval for commercial products, it’s not something I’m interested in academically. I have little inclination to undertake research to show that there are no substantial differences in nutritional content or edible tissue composition between edited and unedited animals, unless that is the purpose edition (my next article on the composition of the meat and milk of the descendants of a genome-modified polled bull does not resist!
Alison Van Eenennaam is Extension Specialist in Animal Biotechnology and Genomics, Department of Animal Science, University of California, Davis. Follow her on Twitter @biobeef