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October 01, 2021

Academic groups seek easier approval path for gene-edited food animals

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When geneticists modify a food-producing animal, the changes are typically regulated as drugs.

Two academic groups argue that the amount of regulatory oversight for genetic changes should be decided case by case—that the changes introduced through gene editing should be regulated differently if identical changes could have occurred through traditional selective breeding. If, for example, gene editing creates a hornless version of Holstein cattle, the developers could argue that the change merely hastened a process that otherwise would have required multiple generations of animals and risked selecting for other genetic changes along the way.

The groups, the American Association of Veterinary Medical Colleges and Association of Public and Land-grant Universities, also say the researchers developing genetic engineering applications see the federal regulatory processes for those modifications as ambiguous, slow, and cost prohibitive. This summer, the organizations published their Gene Editing in Agriculture Task Force Report, which argues for “a remodeling of the federal regulatory landscape” for gene editing.

They argue, in part, that researchers and agricultural companies should be able to meet less-extensive evidence collection requirements for introducing a single-nucleotide polymorphism, for example, than they would for creating a transgenic animal.

Officials with the Food and Drug Administration responded that they are willing to consider alterations as low risk and to be flexible in how those products would be regulated. That low-risk determination, though, requires conversations with agency officials about the project, the intended results, and how to show the results would be low risk.

Agency officials have already applied the low-risk determination to nonfood applications on a case-by-case basis, such as glowing fish sold in pet stores and mice genetically altered for use as research models for human medicine. Those modifications are allowed without drug approvals. FDA officials also note that there is a program in place to help guide academic researchers and startups through the regulatory process of creating biotechnology products.

Angus cattle
These Angus cattle are naturally hornless, a feature that could be reproduced in other cattle breeds through gene editing.

Scientists describe frustration

Dr. Andrew Maccabe, AAVMC CEO, said researchers within AAVMC and APLU member institutions had described challenges because any genetic alteration that affects the structure or function of an animal is regulated by the FDA as a drug. Gaining drug approval requires studies to demonstrate efficacy and safety, and researchers are having difficulty getting funding for studies into changes that are difficult to bring to a market because of the work needed to gain drug approval, he said.

“Once they know they’ve got a product, they know it still can’t be used,” Dr. Maccabe said. “So it stymies the whole process.”

Dr. Maccabe said researchers on the task force contend that some of the modifications they are studying are no different from changes that occur in nature. The beef, pork, and chicken eaten today come from animals genetically modified through selective breeding, yet those products are regulated as foods rather than drugs, he said.

The organizations plan to use the report in lobbying members of Congress and talking with federal regulators, Dr. Maccabe said. The task force members want a rational regulatory system that would allow research and opportunities to bring the products of that research to market or otherwise used to help produce animal-source foods.

Jon M. Oatley, PhD, is associate dean for research and a professor at the Washington State University College of Veterinary Medicine, director of the interinstitutional Center for Reproductive Biology, and director of the Functional Genomics Initiative. He has led development of a method that uses gene editing to produce male cattle, goats, and pigs that are born sterile but are able to become surrogate producers of sperm from animals with desirable genetic traits.

Although those surrogates are edited, their offspring are born with genetics of unedited animals. Dr. Oatley said some of those products have advanced toward becoming commercial products, but, despite talks with FDA officials, he still lacks clear understanding what data are needed to satisfy regulatory concerns.

“It’s not really clear what the road map is to get approval or to get considered for approval,” he said.

He also said the regulatory structure is built for drugs and transgenic alterations, not gene editing applications. Addressing concerns about the possibility of off-target editing, for example, is nearly impossible because of the genetic variation animal to animal in livestock species and the natural genetic recombination in every generation.

“I think there’s a disconnect, sometimes, between the federal regulatory bodies and what reality of science or biology actually is,” he said.

He said FDA officials have helped him understand the process. But many researchers developing applications that use genetic changes in food animals, especially those working in academic institutions, lack the time to navigate a federal regulatory approval process that he described as lengthy and burdensome.

FDA flexible, open to talks

FDA officials have previously indicated they would use enforcement discretion in evaluating the risks of modifications involving animal species that are not raised for food or are raised in contained and controlled laboratory conditions for use in research. Modifications in many laboratory rodents, for example, are considered low risk by the agency because of controls already in place, so many such alterations are allowed without going through the drug approval process.

Heather Lombardi, PhD, director of the FDA Center for Veterinary Medicine’s Division of Animal Bioengineering and Cellular Therapies, said the agency would consider a similar low-risk determination for certain food animals after reviewing the risk.

“We’ve had examples where the developer is making an argument that something could be low risk based on something that could be found in nature,” Dr. Lombardi said. “And so that’s the case where they can provide information to show a history of safety for that product.”

That information could include scientific articles that describe occurrence of the proposed alteration in nature without known safety issues or data collected by the developer that supports a low-risk determination.

Laura Epstein, senior policy adviser in the FDA Center for Veterinary Medicine, said the agency also would consider low-risk determinations for alterations to food animal species raised as research models for human diseases, and the agency is open to discussing other alterations that developers think are low risk.

“We do have a process in place where we encourage folks to come in if they believe there is that low risk, and we’re doing it on a case-by-case evaluation basis.”

Epstein said a relatively small number of developers have worked with the FDA to submit data and go through the regulatory process, so many more likely are unfamiliar with that process and the case-by-case, risk-based evaluations.

Dr. Lombardi said she spoke at an AAVMC and APLU meeting in September 2019 ahead of the formation of the task force, and she learned from meeting participants in academia and industry that much of the FDA’s regulatory process for genetic engineering in animals remains unfamiliar to developers.

“It really made us realize that we need to do a better job of communicating with our stakeholders and, especially, those in academia,” she said, including how developers of genetic alterations can start conversations with FDA officials even if they don’t have a product ready for commercial use.

Epstein noted that, in October 2018, the agency had created the Veterinary Innovation Program to help guide small developers, such as academic researchers and startups, through the regulatory process of creating biotechnology products. An agency announcement published at the time stated that the FDA intended to improve regulatory predictability and efficiency, improve agency responsiveness, and allow early and sustained interactions with innovators.

FDA officials also recently resumed an outreach campaign, delayed because of the COVID-19 pandemic, with plans for a series of meetings with stakeholders and the public to help educate people on the regulatory process and hear from those affected.

“We’re actively seeking feedback from our developers, and we’re trying to make improvements and to clarify confusion about our process,” Dr. Lombardi said.

Epstein said agency officials are committed to using a science- and risk-based process, and regulating genetic alterations reassures the public that products are safe to consume, safe for the animals, and effective. But agency officials don’t want a process that delays progress, and they have worked to make the process more accessible and less burdensome.

In their report, the AAVMC and APLU argue that the ability to modify food animals is necessary to improve efficiency to feed a growing global human population.

“The next frontier in devising strategies to effectively feed a growing global human population will be defined by genetic enhancement; gene editing technologies are a key component in this endeavor,” the report states.

United Nations officials estimated in 2019 that the global human population would grow to 9.7 billion in 2050 and 10.9 billion in 2100. A study published in July 2020 by The Lancet suggests the global human population would peak in 2064 at 9.7 billion and fall to 8.8 billion by 2100.

The Food and Agriculture Organization’s 2021 report on the state of food security and nutrition indicates conflict, climate variability and extremes, and economic downturns all are major drivers of global food insecurity. Hunger will not be eradicated by 2030, as hoped, without bold actions—especially access to address unequal access to food, the report states.