Regulation gone wrong: A critique of the FDA’s nonsensical animal gene-editing rules

regulations
Credit: University of Pennsylvania
The “Guidance for Industry #187” entitled “Regulation of Intentionally Altered Genomic DNA in Animals” was published in the Federal Register in 2017, and a public comment period followed. The FDA took comments on this draft revised guidance during the 90-day public comment period which closed June 19, 2017. As I wrote in January 2019, and what remains true today, is that there has been ZERO formal response to the many comments by public sector scientists working in this field who submitted detailed comments, and who see that this regulatory approach will make food animal research using genome editing cost prohibitive, and effectively preclude the use of gene editing in food animal breeding programs.

To date, there have been two food use approvals for genetically engineered animals in the US, ever. One, the AquAdvantage salmon, the founder event of which occurred in 1989, and which has still yet to be sold in the US despite approval in 2015 as discussed here. AquaBounty estimated it has spent $8.8 million on regulatory activities to date including $6.0 million in regulatory approval costs through approval in 2015, $1.6 million (and counting) in legal fees in defense of the regulatory approval, $0.5 million in legal fees in defense of congressional actions, $0.7 million in regulatory compliance costs (~$200,000/year for ongoing monitoring and reporting, including the testing of every batch of eggs), not to mention the $20 million spent for maintaining the fish while the regulatory process was ongoing from 1995 through 2015.

On December 14, 2020 the FDA announced its second food animal approval for an Alpha-gal (galactose-α-1,3-galactose) knockout “GalSafe” pig. The press release announced the “First-of-its-Kind Intentional Genomic Alteration in Line of Domestic Pigs for Both Human Food, Potential Therapeutic Uses.” This wording, “intentional genomic alteration,” at first made me think this was approval for a genome-edited knockout. But then I read an article quoting a spokesperson for the developer saying they have been working on the GalSafe pigs since 2007. That is pre-genome editing in food animals. I searched PubMed and realized that this approval was for a traditional gene knockout approach to achieve a homozygous founder event that was followed by cloning, or old school genetic engineering, and that was first published in the peer-reviewed literature in 2003.

petition calling for a harmonization of the US regulatory approach to gene editing in food species so that both plant and animal breeders have access to gene editing innovations was launched at the Plant and Animal Genome Conference in 2018, signed by over 300 scientists, and shared with the federal regulatory agencies that June.

Comments from scientists included:

It is long-standing U.S. policy to regulate an item derived from biotechnology as a product, not by the process through which it was produced. We must base oversight on assessed risk, not on the basis of political considerations.

Regulatory uncertainty and inconsistency are barriers to innovation. Importantly, [they prevent] small to medium businesses from having a pathway to market for products that could be of immense benefit, including the welfare of animals. Draft Guidance for Industry #187 is out of step with crop plants and is not consistent with a science-based, risk-based regulatory framework. It is disappointing that this Draft undermines a regulatory system that has, until now, been regarded as robust and well respected. The Draft is not fit for purpose.

In the meantime, the USDA announced the SECURE (Sustainable, Ecological, Consistent, Uniform, Responsible, Efficient) revision of APHIS’ biotechnology regulations that was published in the Federal Register on May 18, 2020, following a detailed response to public comments. It includes up-front exemptions from the regulations for certain types of modifications, specifically a modification (1) resulting from natural cellular repair of a targeted DNA break without any introduced DNA to direct the repair;  (2) a targeted single base pair substitution; or (3) a modification that introduces a gene known to occur in the plant’s gene pool, or causes a change in a gene that corresponds to a version of that gene present in the organism’s gene pool.

Related article:  Talking Biotech: Should milk, meat and eggs from animals fed GMO crops be labeled?

These exemptions were primarily designed to exclude from oversight plants without intergeneric DNA combinations that could have been achieved using conventional breeding, albeit likely less efficiently. Food (e.g high oleic oil from the biotech company Calyx) from genome- edited plants has already entered the US market.

Credit: Pamela Smith/DTN

The FDA doubled down on their new animal drug regulatory approach in a 2020 Nature Biotechnology correspondence entitled “Genome editing in animals: why FDA regulations matters” There, FDA Center for Veterinary Medicine (CVM) Director Steven M. Solomon made the case for “why it is necessary for there to be regulatory oversight of intentional genomic alterations in animals, even when the intended modification seeks to replicate a naturally occurring mutation.” He then specifically distanced his argument from intentional genomic alterations performed in organisms from other kingdoms that we eat, i.e. plants and microbes, with the statement “Readers should note that our statement here relates to intentional genomic alterations in animals; we are not commenting on alterations in plants or other organisms.”

As I wrote earlier this year, Nature Biotechnology published its own editorial response to the FDA’s correspondence, countering that “the origin of a DNA arrangement (conventional breeding, recombinant DNA or gene editing) makes little difference to an animal. The genomes of domestic cattle contain millions of natural variants: the 1000 Bull Genomes Project found >86.5 million differences (insertions, deletions and single nucleotide variants) among cattle breeds. According to prominent researchers in the field, none of these variants has been shown to produce ill effects on consumers of milk or meat. Amidst this background of innocuous variation, how can the presence of one identifiable variant justify the costs and delays of mandatory FDA oversight?

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Nature Biotechnology ended its editorial with the following argument:

A cautious, process-based regulatory route keeps the FDA out of trouble and lowers litigation risks for CVM’s lawyers. But the agency could still alter course without reversing direction completely.

Mandatory oversight could be phased out to a system whereby the agency exercises discretion over which gene-edited animals are regulated according to the hazard represented by the introduced trait. This would be consistent with USDA policy and longstanding US regulatory policy. It would give the animal biotech sector a chance to bloom. And it would counter the narrative of fearmongers who would taint all gene-edited animals as hazardous to public health and injurious to animal welfare.”

And so we come to December 2020, and the UDSA advance notice of proposed rulemaking “Regulation of the Movement of Animals Modified or Developed by Genetic Engineering,” which was published in the Federal Register on December 28. What is the USDA proposing? And how does it differ from the FDA’s approach? Does the contemplated regulatory framework improve things? More on that in the next installment.

Alison Van Eenennaam is an extension specialist in animal biotechnology and genomics, Department of Animal Science, University of California, Davis.

A version of this article was originally posted at the BioBeef Blog and has been reposted here with permission. BioBeef can be found on Twitter @BioBeef

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