On March 7, 2022, the Center for Veterinary Medicine (CVM), which is housed within the Food and Drug Administration (FDA), announced it will allow Recombinetics, Inc., a biotechnology company, to market its genome-edited beef cattle. Recombinetics’s intentional genomic alteration (IGA) of beef cattle results in slick-haired animals, known as PRLR-SLICK cattle. This blog post explains how IGAs are regulated and discusses the “low-risk” determination that CVM made regarding PRLR-SLICK cattle.

PRLR-SLICK Cattle

Recombinetics’ subsidiary, Acceligen, Inc., created the IGA that was inserted into cattle embryos and led to two PRLR-SLICK animals. Acceligen created the IGA through a process known as “clustered regularly interspaced short palindromic repeats” or CRISPR. The PRLR-SLICK gene is inheritable, meaning that the two animals who currently carry the PRLR-SLICK gene can pass it down to their offspring.

The animals with the PRLR-SLICK gene have slick coats. The FDA cites scientific reports that “indicate that cattle with this extremely short, slick-hair coat are potentially able to better withstand hot weather.” Although the two animals with the PRLR-SLICK gene obtained the gene through genetic modification, other researchers and ranchers have obtained cattle with the same slick coat through conventional breeding.

The PRLR-SLICK gene is an IGA, which are considered animal drugs as defined by the Federal Food, Drug, and Cosmetic Act (FFDCA). The FFDCA defines “drugs” as “articles (other than food) intended to affect the structure or any function of the body of man or other animals”. 21 U.S.C. § 321(g)(1)(C). Therefore, the animal itself is not a drug, but the IGA the animal receives is a drug intended to affect the structure or function of the animal’s body.

NADA Determination v. Low-Risk Determination

FDA’s Guidance for Industry #187, entitled “Regulation of Genetically Engineered Animals Containing Heritable Recombinant DNA Constructs”, explains that “a new animal drug is ‘deemed unsafe’ unless FDA has approved a new animal drug application (NADA) for that particular use”. However, the Guidance also explains that CVM will exercise “enforcement discretion” regarding the NADA requirements for certain genetically modified animals. To further explain this point, CVM has said that it “may exercise enforcement discretion on a case-by-case basis if, after a risk-based review, it determines that the product or category of products is low risk to humans, animals and the environment.” Therefore, CVM has the option to approve IGAs either through a full NADA determination process, or through a less strenuous low-risk determination.

There are many differences between a full NADA determination and a low-risk determination. However, one main difference is the requirement to conduct a National Environmental Policy Act (NEPA) review. When CVM conducts a NADA determination, it must also complete a NEPA review. NEPA requires federal agencies to consider the environmental impacts of any major federal action they take. On the other hand, when CVM exercises its enforcement discretion and conducts a low-risk determination it does not have to conduct a NEPA review. However, in a low-risk determination, CVM considers certain environmental risks. Guidance #187 lists the following environmental factors CVM considers when determining whether to exercise enforcement discretion:

• Whether there is anything about the IGA that poses a human, animal, or environmental risk. For example, does the IGA contain gene sequences that can cause human or animal disease?
• Whether, in the event of an environmental release, the genetically engineered animal poses any more of an environmental risk than its non-genetically engineered counterpart.
• Whether there are concerns over the disposition of genetically engineered animals that could pose human, animal, or environmental risks.
• Whether there are any other safety questions that have not been adequately addressed by the sponsor or creator of the IGA.

When making a low-risk determination, CVM will also look at the risks associated with the molecular structure of the IGA, any risks associated with the resulting gene-expression, and the human food safety risk.

PRLR-SLICK Low-Risk Determination

Instead of conducting a NADA determination for PRLR-SLICK cattle, CVM exercised its enforcement discretion and conducted a low-risk determination. CVM felt it was appropriate to conduct a low-risk determination because conventional breeding has already achieved slick-coated cattle. In its low-risk determination, CVM reviewed the data submitted by Recombinetics.

In evaluating environmental risks, CVM determined the PRLR-SLICK cattle do not pose a significant environmental risk. CVM reasoned that if a PRLR-SLICK animal gets separated from a herd and is not found, the animal will likely not breed with other cattle because U.S. does not have a large population of feral cattle. CVM further reasoned that even if a PRLR-SLICK animal breeds with feral or other cattle, there will not be a significant environmental risk because non-bioengineered slick coated cattle already exist.

As for the other risks CVM evaluated, it concluded that the molecular structure of the IGA and the resulting gene expression do not pose any significant risks. This is primarily because the conventionally bred animals with similar genes causing short-hair have not experienced any significant harm. As for the human food risk, CVM concluded that the any beef produced from PRLR-SLICK animals will not be significantly different than beef produced from conventionally bred cattle.

Other CVM Approved IGAs for Human Food Consumption

CVM has previously approved two IGAs in animals intended for human food consumption. For both of these IGAs, CVM conducted full NADA determinations. These previously approved IGAs differ from the PRLR-SLICK IGA because these IGAs result in gene-expressions that are not present in conventionally bred animals. Therefore, there is a higher environmental risk if these IGAs are introduced into the general animal population as compared to the risks associated with the PRLR-SLICK IGA.

First, CVM approved AquaBounty’s AquAdvantage salmon in 2017. AquAdvantage salmons carry an IGA that, according to the FDA, allows the salmon “to reach a growth marker important to the aquaculture industry more rapidly than its non-[bioengineered] farm-raised Atlantic salmon counterpart.” According to AquaBounty, it started marketing and selling AquAdvantage salmon in June of 2021.

Then in 2020, CVM conducted a NADA determination and approved Revivcor, Inc., a subsidiary of United Therapeutics Corporation, to market meat products derived from their GalSafe pigs. GalSafe pigs are bioengineered so they do not produce alpha-gal sugars. Because the pigs do not produce these sugars, products derived from them can be consumed by people with Alpha-gal syndrome. People with Alpha-gal syndrome can have mild to severe allergic reactions when they consume alpha-gal sugar. According to the FDA, Revivcor intends to first sell GalSafe meat by mail order instead of in supermarkets, however GalSafe meat is not yet available.

Moving Forward

When meat derived from PRLR-SLICK animals hit the market, the Bioengineered Food Disclosure Standard (Standard) might apply. Under the Standard, an entity putting a label on a food product must disclose that the product is bioengineered if the entity has actual knowledge that the food is bioengineered. Although the Standard explicitly requires AquaAdvantage salmon to carry a bioengineered food disclosure, the Standard currently does not require products that are primarily meat, poultry, or egg to carry a disclosure. The Agricultural Marketing Service, the agency that administers the Standard, has not addressed how the Standard applies to bioengineered meat, poultry, and egg products. It is important to note that the Standard does not apply to restaurants or other retail food establishments.

In the FDA news release announcing the low-risk determination and approval of PRLR-SLICK cattle, Steven M. Solomon, director of CVM, states that CVM expects that its decision “will encourage other developers to bring animal biotechnology products forward for the FDA’s risk determination in this rapidly developing field” and that CVM’s decision “pav[es] the way for animals containing low-risk IGAs to more efficiently reach the marketplace.”

According to the FDA, Recombinetics anticipates that meat from PRLR-SLICK cattle will be on the market in about two years. However, according to Guidance #187, if CVM or the FDA learn of any safety concerns associated with the IGA, it “retains the discretion to take enforcement action”.

To read the summary of CVM’s risk assessment, click here.

To read FDA’s news release announcing the low-risk determination, click here.

To learn more about FDA’s enforcement discretion for IGAs, click here.

To learn more about AquAdvantage salmon, click here.

To learn more about GalSafe pigs, click here.

For more National Agricultural Law Center resources on biotechnology, click here.

**This article was written by former NALC Staff Attorney Jana Caracciolo.