The oft-quoted quip “To a man with a hammer, everything looks like a nail” anticipated the practice of federal agencies expanding their mandate by shoehorning policy initiatives into regulatory regimes for which they were never intended. This practice seems to run contrary to Article I of the US Constitution, which vests all legislative power in the Congress, yet it can happen because Congress has delegated broad rule-making authority to executive branch agencies, which in turn interpret their rules to their own advantage.
Congress has established some controls over runaway agency rule-making, notably in the 1946 Administrative Procedure Act, which created a public notice-and-comment process for the orderly and public promulgation of regulations and provided for judicial review of regulations. Increasingly, however, agencies have ducked the formal requirements by issuing flexible, nonbinding “guidance documents” that interpret existing rules in a manner that can greatly distort or expand the scope of regulations to entirely new purposes. That’s how the Food and Drug Administration (FDA) has managed to craft inventive but feckless regulation of animals modified using molecular genetic engineering techniques.
Although a typical FDA guidance document asserts that it “does not create or confer any rights for or on any person and does not bind FDA or the public,” anyone ignoring its provisions would likely face an agency compliance action or be denied approval of a product or activity for which approval was being sought. Moreover, because the power of a gatekeeper agency such as the FDA—whose approval is required for a product to be marketed—is so great, manufacturers will not commonly challenge the FDA’s approach, requirements, or approval conditions because to do so could risk future delays, disapprovals, and difficulties with other products regulated by the agency. Thus, for practical purposes, guidance is equivalent to a rule—except that it’s not legally binding on regulators.
In an FDA guidance document titled “Regulation of Genetically Engineered Animals Containing Heritable rDNA Constructs,” issued in 2008, the agency announced that “recombinant DNA” when introduced into the DNA of an animal is a “new animal drug” and thereby requires the animal to be reviewed as a drug under the Federal Food, Drug, and Cosmetic (FD&C) Act. Accordingly, in order to be sold, the animal must undergo government review and approval, the same as a veterinary drug such as an antibiotic or pain reliever. The guidance focuses inappropriately on the use of a single precise breeding technique among the spectrum of techniques used by animal breeders, but without identifying a demonstrable, rather than speculative, risk as the basis for imposing the high evidential standard of drug “safety and effectiveness” required by the FDA’s new animal drug regulations.
There is no hint anywhere in the FD&C Act, the FDA’s primary enabling statute, that animals could be, in effect, regulated as a drug. Nor was such an interpretation necessary for the safe sale and consumption of genetically engineered animals. A more apposite model is the way that another FDA component, the Center for Food Safety and Nutrition, regulates other foods. The law places the burden of ensuring the safety of foods and food ingredients on those who produce them. It prohibits the adulteration (contamination) or misbranding (mislabeling) of food, but does not require the inspection or evaluation of all food before its sale in shops, supermarkets, or restaurants. Rather, the FDA’s oversight, encompassing all food except meat, poultry, and egg products, which are regulated by the US Department of Agriculture (USDA), relies on market surveillance or post-marketing regulation, and the FDA takes action only if there is an apparent problem.
The law does require a premarketing review for certain food-related products. These include most food additives—a class of ingredients that includes preservatives, emulsifiers, spices and sweeteners, and natural and synthetic flavors or colors, among others. In general, a food additive must be approved if it becomes a component of or otherwise affects the characteristics of a food and it is “not generally recognized as safe (GRAS) by qualified experts for its intended use.”
GRAS is an important concept, especially in the context of genetically engineered animals. Before a new food additive is marketed, it is the responsibility of the producer to determine whether or not the substance is GRAS. The agency routinely reviews food additive applications for safety only when the substance in question has been determined not to be GRAS by the producer. If the producer determines that a substance is GRAS, then the FDA requires only that it receive a notification, which is then subject to agency review.
Another important aspect of the GRAS concept is that multiple GRAS substances that have been combined are still considered GRAS. Similarly, because adding a GRAS gene to a GRAS organism is likely to yield a GRAS outcome, a lengthy FDA premarketing review should not be necessary for genetic constructions.
It should come as no surprise that the resulting practically unworkable FDA approach has been a disaster for research and development (R&D) advances in the entire, once-promising sector. Two examples will illustrate the FDA’s dysfunction, which is the reason there is meager R&D on genetically engineered animals in the United States.
The first is a genetically engineered Atlantic salmon that reaches maturity 40% faster than its unmodified cohorts. The genetic changes confer no detectable difference in the fish’s appearance, ultimate size, taste, or nutritional value; it just grows faster and consumes less food over its lifetime. Also, because the fish are all sterile females and farmed inland in closed systems, there is negligible possibility of any sort of genetic contamination of the wild fish gene pool or other environmental effects.
More than a decade before the FDA issued its guidance in 2008, its officials had told the developer to submit a marketing approval application to the agency, without identifying a clear regulatory rationale or pathway. The FDA held up the application for approval of the salmon for almost 13 years before even reaching a decision on how this fish should be reviewed. Review of the salmon as a “new animal drug” required several more years. At the end of a two-decades-long regulatory process, the FDA concluded what should have been obvious long before: that no health or environmental risks or food quality concerns existed. The salmon is not yet available in the United States because of congressional delays over labeling. However, in Canada, the faster-growing salmon was approved without difficulty, is available without special labeling in supermarkets, and is selling well.
A delay in the availability of cheaper salmon isn’t the end of the world, of course, but the FDA also unnecessarily and inexplicably delayed small-scale field trials of an innovative method to reduce the population of Aedes aegypti mosquitoes that transmit Zika virus, yellow fever, dengue fever, and chikungunya. The method uses a genetically engineered male mosquito constructed with a genetic defect that causes it to require a certain growth supplement for survival. When released in the absence of the supplement, the mosquitoes survive only long enough to mate with wild females and pass the lethal gene to their progeny, which soon die. Because male mosquitoes don’t bite, they present no health risk, and because the progeny die before they can reproduce, none should persist in the environment. This approach has been successfully tested in several countries.
The FDA took an unconscionable five years (2011-16) to approve a single small-scale field test of this mosquito, and that came only after mounting pressure from the growing Zika threat and the consequent need to control A. aegypti. In August 2016, the agency finally approved a field trial at one site in the Florida Keys, some 160 miles from the Zika outbreak in Miami, but that trial has yet to begin.
The use of the new animal drug regulatory pathway for the mosquito presented an insoluble legal conundrum for the FDA. In order to approve it for marketing as a drug, regulators would have to conclude that the genetic material that causes a male mosquito to self-destruct after producing defective, doomed offspring is safe and effective for the mosquito, the requirements for approval specified in the FD&C Act. The FDA would have found itself tied up in legal knots if its ultimate approval of the insect were challenged in court by environmentalists and anti-genetic-engineering activists, as would have been inevitable. After we first pointed out the “safe and effective” impossibility in the Wall Street Journal in 2016, the FDA in January 2017 ceded the regulation of mosquitoes to the Environmental Protection Agency (EPA), an agency that does have the statutory authority to regulate insecticides.
The FDA had previously confronted the question of how to regulate the new and increasing number of lines of genetically engineered laboratory animals created for medical research. The agency’s solution was simply to exempt them from the excruciating approval process by magisterially invoking “enforcement discretion,” meaning the agency would not enforce requirements under the FD&C Act. The FDA also invoked enforcement discretion to obviate the need for review and approval of GloFish, genetically engineered varieties of aquarium fish. Regulators’ rationale was that the fish posed no threat to the food supply, and that there was no evidence that it posed any more threat to the environment or to public health than their unmodified counterparts. Thus, as viewed through the FDA’s distorted lens, a small-scale field trial of a suicidal mosquito with only non-reproducing offspring that would reduce the mosquito population for a clear public health benefit poses a greater risk than the unregulated presence of unlimited numbers of reproducing aquarium fish and many lines of genetically engineered laboratory animals.
The illogic of the FDA’s use of the new animal drug regulatory pathway demonstrates how the agency’s contortions enabled it to arrogate regulatory jurisdiction over animals modified with recombinant DNA techniques. Far from having seen the error of its ways, in January 2017 the FDA doubled down and sought to further expand its regulatory turf. Anticipating that the incoming Trump administration would not agree with its intention to regulate all emerging animal breeding technology, in the last hours of the Obama administration the FDA rushed to publish proposed guidance that would encompass all molecular genetic modification techniques (including gene-editing techniques such as CRISPR-Cas9) that lay outside the definition in the 2008 guidance. Thereby, the FDA proposed to adopt a scientifically unwarranted precautionary policy that would require the agency to review and approve all new molecular animal breeding innovations. The FDA’s approach is flawed in several ways:
- Its rationale is not supported, and in fact is repudiated, by the history of innovative and safe animal breeding using various modern techniques to improve the characteristics of food animals, including by means of cloning and interspecies hybrids that are overseen by breeders, ranchers, farm organizations, states, and other federal agencies.
- It is inconsistent with the federal government’s overarching principle of biotechnology regulation, laid out in 1986 in the Coordinated Framework for the Regulation of Biotechnology. This principle holds that the regulation of recombinant DNA-modified organisms should be risk-based and avoid requiring process-based regulation and case-by-case review of all products, regardless of whether they are of high, moderate, low, or trivial risk.
- It is unnecessary, a solution in search of a problem. The FDA’s existing oversight of foods and food additives by its Center for Food Safety and Nutrition is sufficient to ensure the safe consumption of genetically improved animals. Other federal agencies already have jurisdiction over nonfood animals.
The FDA’s expanded proposed guidance has not gone unnoticed on Capitol Hill. On October 17, 2017, scores of members signed a letter to the secretary of agriculture, the FDA commissioner, and the EPA administrator raising serious concerns about the contradictions between the FDA’s approach and the USDA’s “thoughtful and science-based” regulatory approach, which did not expand its regulation to include all genetic modification techniques (as did the FDA), and complaining about the resulting negative impact of the inconsistencies domestically and internationally.
The letter affirms that once Congress has delegated authority to regulatory agencies, it is difficult for it to pull back the authority or even to oversee the myriad intricacies of daily regulatory activities. Although the passage of corrective legislation and the placing of limits on appropriated funds and personnel slots can address specific regulatory excesses, and the cumbersome and limited Congressional Review Act can provide ex post facto redress of executive branch actions, these processes are not easy to use. The current Congress is considering new proposals, such as the Regulations from the Executive in Need of Scrutiny (REINS) Act and the Regulatory Accountability Act, that call for greater congressional and Office of Management and Budget oversight.
Until Congress takes more control, it will fall to the White House to bring rationality to the oversight of biotechnology products. So far the Trump administration has not focused on biotechnology in its efforts to roll back and rationalize regulation. In the short term, the White House should direct the FDA to cease its efforts to regulate animals via the new animal drug framework and to clarify to what extent and how genetically engineered animals, whatever the techniques employed, will be overseen by the FDA’s Center for Food Safety and Nutrition, the USDA, and other federal and state agencies with oversight over animals.
Time is of the essence if the United States is to regain its competitive position in a field where other countries such as China are taking advantage of the void created by overbearing and dysfunctional US regulation.
John J. Cohrssen is an attorney who has served in senior staff positions in the White House and Congress. Henry I. Miller, a physician and molecular biologist, is the Robert Wesson Fellow in Scientific Philosophy and Public Policy at Stanford University’s Hoover Institution. He was the founding director of the Office of Biotechnology at the Food and Drug Administration. Follow him on Twitter: @henryimiller.