Advances in biotechnology have opened the doors to a variety of new agricultural products with novel mechanisms of action. This can pose a regulatory challenge, since developers have no precedents to reference. The Environmental Protection Agency (EPA) regulates pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), The definition of what is considered a pesticide is nebulous, wide-ranging, and can be unintuitive, thus the appropriate regulatory classification of a new-to-market product is often not obvious. Here, we present a regulatory case study of a hypothetical product.
Suppose a developer’s product is a crop engineered to contain a transgene (a gene not known to exist naturally in the plant’s genetic pool) for a protein that prevents it from being infected by a pest. The protein is not itself toxic to the target pest; rather, it neutralizes the pest’s ability to harm the plant.
EPA’s FIFRA Regulations
All products used as pesticides are subject to regulation under EPA’s FIFRA and must be registered, with a few exceptions. The EPA’s definition of “pesticide” is very broad: it includes not only products intended to “prevent, destroy, repel, or mitigate” pests, but also many other substances such as defoliants, nitrogen stabilizers, and plant growth regulators (PGRs) (FIFRA sec. 2(u)). PGR’s are defined as “any substance or mixture of substances intended, through physiological action, for accelerating or retarding the rate of growth or rate of maturation, or for otherwise altering the behavior of plants.” This excludes plant nutrients, trace elements, nutritional chemicals, plant inoculants, and soil amendments, or fertilizers (FIFRA sec. 2(v); 40 C.F.R. 152.6).
For the hypothetical product in this case study, both the protein and its genetic material would be subject to regulation by the EPA as a biopesticide, specifically a plant-incorporated protectant (PIP). Even though the protein does not directly affect the pest, it nevertheless is intended to mitigate the effects of the pest, which meets FIFRA’s definition of a pesticide. There are certain scenarios where PIPs can be exempted from FIFRA regulation. The plant itself is not regulated by the EPA
Pesticide registration is implemented under the Pesticide Registration Improvement Act (PRIA), last updated in 2022. For a PIP that involves a new (previously unregistered) active ingredient and which is intended for food crop use, the required registration (category B820) would cost $292,682 with an estimated decision time of 15 months (assuming EPA reviewers do not request additional studies). If reviewers determine that further review by the FIFRA Scientific Advisory Panel (SAP) is needed, the total cost and time will increase by $91,465 and 6 months respectively (category B905). Fee waivers up to 75% are available for small businesses.
If, instead of engineering a plant to produce this hypothetical pest-deterrence protein, the protein was administered directly to the soil, then it would likely be regulated as a biochemical biopesticide. This classification, unlike conventional pesticides, requires that the protein meet three criteria, in order of most to least stringent: 1) has a non-toxic mechanism of action, 2) is structurally similar to naturally-occurring molecules, and 3) has a history of safe exposure, which can be demonstrated via deduction from existing literature and/or data. The registration fee for establishing the maximum tolerance level of a new biochemical (category B580) is $73,173 with a decision time of 22 months. If the biochemical pesticide is safe enough to not require a maximum tolerance level, a tolerance exemption can be petitioned for (category B590).
The developer could attempt to make an argument, if applicable, that the protein has significant non-pesticidal applications, and thus have the product be exempt from registration. In this case, however, product would not be able to be marketed as having any pest-deterrent functionalities. This M009 application for exemption requires efficacy data as well as a fee of $3,389, with decision timeframe of 6 months.
USDA-APHIS and FDA Regulations
Crops modified to contain PIPs may be subject to further regulation by USDA-APHIS. The Biotechnology Regulatory Services (BRS) of USDA-APHIS evaluates genetically engineered plants for potential risk to plant health (e.g. weediness), and issues permits for their environmental release. While APHIS’s SECURE rule was recently amended to exempt from permitting “any GE plant modified solely to contain a PIP that is currently registered with EPA” (7 CFR part 340.5(g)), this does not apply to the hypothetical plant in this case study because this PIP involves a novel mechanism of action (MOA). Confirmation of regulatory exemption can be requested for qualifying modified plants. Even if a modified plant does not qualify for exemption, deregulation of the plant’s release can be requested via the Regulatory Status Review (RSR) process.
If the modified crop is intended for human or animal consumption, it will fall under the oversight of the FDA. In this case, developers should undergo the FDA’s voluntary plant biotechnology consultation program to ensure compliance with standards such as non-allergenicity and nutritional equivalence. Some proteins expressed by commonly used transgenes, such as nptII for conferring kanamycin resistance, have been granted GRAS (Generally Recognized As Safe) status when present in certain plants; such substances would not require FDA review.
Conclusion
Many emerging agricultural products involve novel MOAs for which the regulatory pathway to commercialization may not be obvious, and may hinge upon nuances in regulatory definitions and product properties. At the same time, there are three different regulatory agencies responsible for evaluating different aspects of new products, and a number of regulations are in the process of being revised. Given the complexity of the regulatory landscape, developers are advised to reach out to representatives of the agencies early and often in the R&D process, long before they attempt to apply for permits. Pre-application consultation meetings can be conducted jointly with all three agencies, and agency representatives can provide guidance on what data would be helpful for facilitating the evaluation process — potentially saving developers significant time and money.
– Vivian Zhong
