Regulation of Gene-Edited Products in Selected Countries

A. European Union

The European Food Safety Authority (EFSA) Panel on Genetically Modified Organisms (GMO Panel) delivered a scientific opinion related to risk assessment of plants developed using the SDN-3 technique, in which major considerations include: (1) the source of the inserted gene and the safety of the gene product.

Regulation of Gene-Edited Products 123 greatly reduced, and at the same time, the SDN-3 technique can optimize the genomic environment for gene expression and minimize hazards associated with the disruption of genes and/or regulatory elements in the recipient genome.

The use of the NHEJ repair mechanism may involve the risk of duplicated insertions, partial deletion or insertion, and reversion of the inserted DNA sequence. Site-directed nucleases may cut DNA at unintended locations, which are called “off-target effects”; therefore, the alternations to the host genome must be considered. While the EFSA panel on GMO believes that the off-target effects caused by using the SDN-3 technique are similar to those using traditional mutagenesis techniques, products using SDN-3 still require risk assessment since they are considered GMOs due to the same technique as that for GMOs being used to produce the products.

Advocate General Michal Bobek of the Court of Justice of the European Union delivered an opinion on January 18, 2018^[490] addressing an inquiry about whether products obtained by mutagenesis are regarded as GMOs, an issue that must be answered depending on whether they are covered under the scope of GMOs or whether the method of altering the gene is natural.

B. United States

From January 2017 to June 2017, the US Food and Drug Administration (FDA) publicly solicited public comments on the management methods of gene-edited plant-derived food or feed,^[492] with four points for soliciting comments on gene- edited plants, as follows. (1) In what ways are the food safety risks associated

with human and animal foods from genome-edited plants the same as or differ­ent from those associated with other plant development methods (e.g. hybridi­zation, chemical- or radiation-induced mutagenesis, and non-targeted genetic modifications using in vitro recombinant DNA technologies)? (2) Are there cat­egories of genome-edited plant varieties for which there are scientific bases to conclude that foods from such categories are unlikely to present food safety risks different from or greater than those for traditional plant breeding? Similarly, are there categories of genome-edited plant varieties for which the regulatory sta­tus of the food derived from such plant varieties can be said to be no different from that of traditionally bred plants so that there is no need to seek advice from the FDA before marketing? (3) Are there categories of genome-edited plant varieties for which there are scientific bases to conclude that foods from these categories are more likely than traditionally bred plants to present food safety risks? (4) What steps can we take to help small firms, including those who may be considering using genome editing to produce new plant varieties for use in human or animal food, to engage with FDA about any questions related to food safety or the regulatory status of foods from their new plant varieties?^[493]

As for genetically engineered crops, the United States Department of Agri- culture/Animal and Plant Health Inspection Service (USDA/APHIS) is the agency in charge of regulatory oversight over genetically modified or edited crops in reviewing potential risks of harmful plants in certain genetically engi­neered corps according to the Plant Protection Act (PPA).

The USDA has completed the hearing of a total of 24 applications for gene-editing technology (Table 8.2). The species developed include corn, soy­bean, rice, wheat, potatoes, mushrooms, tomatoes, Setaria viridis, flax mustard

Regulation of Gene-Edited Products 125 (camelina), alfalfa, tobacco, lettuce, pennycress, and others. According to the Plant Protection Act, developing crops using genetically engineered organ­isms as a donor or carrier won’t subject they to USDA regulation as long as the product itself is not a harmful or a weedy plant and the product does not contain exogenous genes, or the exogenous genes are removed after screening. Nonetheless, USDA’s reply letter to every confirmation request always empha­sizes that the products still need to be regulated by the FDA and the Environ­mental Protection Agency (EPA).

In 2018, the USDA announced a statement on plants derived from new plant breeding techniques (NPBTs), which also include gene-editing technologies.

US Secretary of Agriculture Sonny Perdue announced the SECURE rule (the Sustainable, Ecological, Consistent, Uniform, Responsible, Efficient rule) on May 14, 2020, which is based on the Plant Protection Act. The Plant Protection Act has aimed to update and modernize the USDA’s biotechnol­ogy regulations. The SECURE rules will eliminate repetitive and outdated processes, thereby bringing USDA’s plant biotechnology regulations into the twenty-first century, so as to promote the development and availability of these technologies through a transparent, consistent, scientific, and risk-proportional regulatory system. This new regulation will help American farmers obtain key tools to increase agricultural productivity and sustainability, increase the nutri­tional value and quality of crops, prevent pests and diseases, and enhance food safety. The SECURE rule regulates the import, interstate transfer, and envi­ronmental release of organisms developed using genetic engineering technol­ogy that may become harmful plants. According to the revised regulations, certain types of genetically engineered plants are not subject to regulations. On August 17, 2020, the exemption and confirmation process will replace the existing “Am I regulated (AIR)?” process. For specific requesters and specific plants, organisms that were previously confirmed as unregulated by AIR reply are still considered valid and exempt from the new regulations.^[495]

Developers can check the regulations to assess whether a plant belongs to one of the exempt categories.

Table 8.2 US Department of Agriculture’s inquiry list for gene-edited crops

Regulation of Gene-Edited Products 127 pool or a change in a targeted sequence to correspond to a known allele of such a gene or to a known structural variation present in the gene pool. In addi­tion to these categories, modified plants will not be subject to the regulations if they have plant-trait mechanism of action (MOA) combinations that are the same as those of modified plants for which USDA has conducted a regulatory status review and found not to be subject to regulation.

C. Canada

The Canadian Food Inspection Agency (CFIA) and the Ministry of Health (Health Canada, HC) are jointly responsible for the regulation of plants with novel traits in accordance with the Novel Food Regulation. The new traits may be produced by traditional breeding, mutation, or genetic engineering, and such plants will be reviewed on a case-by-case basis. Given that gene-edited products derived from CRISPR/CAS9 technology or products derived from other new technologies are novel products, that is, plants with new traits, it is not necessary to modify the regulations for reviewing products using these new technologies in Canada.

Health Canada conducts safety assessments on novel plant foods based on the principle of substantial equivalence with the aim to confirm that their composition and nutrition are equivalent to those of traditional foods and that novel foods do not contain toxins or cause allergic reactions. As for the review of environmental safety and animal feed, the Canada Food Inspection Agency conducts an assessment to confirm that the novel plant does not have the potential for weedization after hybridization with other plants, the possibil­ity of the novel plant affecting biodiversity, and the safety of the novel plant for animal feed and the equivalent value of nutrition to the traditional plant. Moreover, it assesses whether exposure to such novel plants will cause harm to human beings and animals.^[497] Currently, the only gene-edited crops approved in Canada are rapeseed developed by Cibus using oligonucleotide-directed mutagenesis technology, which was approved for marketing in 2013.

D. Argentina

Argentina is the first country in the world to promulgate regulations for emerg­ing plant breeding technologies. The National Advisory Commission on Agri­cultural Biotechnology (CONABIA) of the Directorate of Biotechnology and the Biosafety Commission jointly discussed zinc finger nuclease technology in 2014 and preliminarily concluded that SDN-1 products of zinc finger nuclease technology are not genetically modified organisms, since they cannot be dis­tinguished from the products of traditional mutation technology and have little probability of increasing the risks regarding food safety. As for SDN-2 products of zinc finger nuclease technology, whether they are products of GMOs needs to be determined on a case-by-case basis, whereas SDN-3 products of zinc finger nuclease technology are considered GMOs because transgenic gene(s) are inserted into the host genome. With respect to the products of oligonucleo- tide-directed mutagenesis technology, the Argentine regulatory authority does not consider them GMOs because such technology will not increase or create new risks, and it is difficult to distinguish such derived foods from those with traditional mutations or naturally occurring mutations.^[498]

In 2015, in accordance with Resolution No. 763/11^[499] of Genetically Modi­fied Organisms^[500] of the Ministry of Agriculture, Livestock and Fisheries (Minis­terio de Agricultura, Ganaderia y Pesca, MAGyP), Argentina issued Resolution No. 173/15 adopting product-based regulation of GMOs and establishing a set of consultation procedures for determining whether the products of emerging plant breeding technologies are GMOs in order to determine if such products will be subject to GMO regulation. The standard of the decision is mainly based on whether the product of emerging plant breeding technology possesses a novel combination of genetic material and whether the final product of the emerging plant breeding technology contains foreign transgenic genes or DNA sequences.^[501]

Developers of products of emerging plant breeding technologies must pro­vide background information about the process of breeding and screening crops, techniques and methods used for introducing new traits, evidence of the introduced genetic modification in the final product, and evidence of the possible transient use of transgenic gene(s) during the development process. Through the consultation process, after 60 days of review time, the applicant

Regulation of Gene-Edited Products 129

can receive a reply from the authorities on whether the products of emerging plant breeding technologies are subject to regulation. According to this pro­cess, the end products of specific DNA sequence changes in crops by applying the SDN-land SDN-2 and ODM technologies will not be subject to existing GMOs regulation as long as they do not contain foreign gene(s).^[502]

E. Japan

The Ministry of Agriculture, Forestry and Fisheries (MAFF) ofJapan convened experts and scholars to establish a research committee on emerging breeding technologies on October 4, 2013. Seven meetings had been held as ofJuly 22, 2015. The Committee discussed issues ranging from the definition and scope of emerging breeding technologies to the impact of research and development and practical applications of such technologies on biodiversity. Since GMOs in Japan are governed by the Cartagena Protocol on Biosafety, GMOs are defined as organisms that possess nucleic acids, or a replicated product thereof, obtained through the use of genetic engineering technology. The committee suggested that for emerging breeding crops, (1) it should be considered whether there are foreign gene(s) in plants, and (2) it should adopt the same regulatory principles as the current ones; that is, organisms obtained by self-cloning and natural occurrence are not subject to regulation.^[503]

The Ministry of the Environment (MOE) is the agency in charge of the assessment of the impact of GMOs on environmental risks. On May 28, 2018, the Natural Environment Subcommittee of the MOE established a research group on gene editing technology to discuss whether gene-edited crops are within the scope of GMOs under the Cartagena Protocol on Biosafety and, if not, whether gene-edited crops can be regarded as general crops and it can be ensured that they do not affect biodiversity. The Natural Environment Subcommittee concluded in March 2019 that gene-edited products are not considered GMOs under the Cartagena Biosafety Protocol as long as the pro­cess of development does not involve foreign nucleic acids, such as SDN-1 technology using protein or ribonucleoprotein (RNP), or transient expres­sion. If foreign DNA is used and inserted into the genome, such as those in SDN-2 and SDN-3 technologies, the products should be regarded as GMOs. However, SDN-2 and SDN-3 products obtained by self-cloning and natural occurrence are not regarded as GMOs according to the Cartagena Biosafety Protocol. Developers are encouraged to submit a report to the regulatory agency before marketing, explaining the process and method of gene editing.

If such products are determined to be products with no foreign nucleic acids or obtained by self-cloning and natural occurrence, they are not considered GMOs.^[504]

The Ministry of Health, Labour and Welfare (MHLW) also adopted regula­tory measures for gene-edited foods in March 2019, stating that gene-edited foods are different from genetically modified foods and do not involve the genes of other organisms in the process. Such products simply edit the gene of the species itself and cannot be distinguished from the products obtained by traditional breeding methods. Therefore, they cannot be regarded as GMOs, such as SDN-1 and SDN-2 products. So the focus should be on whether the final product has foreign DNA to determine if it is a GMO. According to this test, SDN-3 products are regarded as GMOs. Developers of gene-edited foods are also encouraged to provide five pieces of relevant information before marketing: (1) the name and end use of the food, (2) the method and pro­cess of the gene-editing technology used, (3) confirmation of DNA changes and off-target effects, (4) residual status of foreign gene(s), and (5) changes in metabolites or nutrients. The MHLW will also publish relevant information on its website.^[505]

F. Australia and New Zealand

The Ministry of Health and Ageing of Australia, in accordance with the Gene Technology Act of 2000 and the Gene Technology Regulations of 2001, is responsible for approving and regulating genetically modified crops and emerging crops in Australia. In 2014, Food Standards Australia New Zealand (FSANZ) issued relevant opinions on emerging breeding technologies based on the scientific advice of the expert working group. When new genes are introduced into crops, this type of technology is equivalent to genetic modi­fication, so the derived food should be regarded as genetically modified food. As for foods derived from SDN-1 and SDN-2 types of zinc finger nuclease technology and oligonucleotide site-directed mutagenesis technology, they should not be regarded as genetically modified foods since such technologies are similar to traditional mutations used in traditional plant breeding, and it is difficult to distinguish the products of ODM technology from those of tradi­tional mutations or naturally occurring mutations.^[506]

The Australian government launched the National Gene Technology Scheme (NGTS) in July 2017 and established a professional advisory group for gene technology review to collect opinions from multiple parties through a

Regulation of Gene-Edited Products 131 three-stage consultation process. The first stage was to collect written opinions, and the second stage was to discuss possible policy solutions. In the third stage, the investigation results were presented followed by conducting two webinars. The NGTS separately discussed different aspects of issues surrounding technol­ogy, regulations, government, and social ethics. The results were announced in October 2018. It is recommended that the definition of the Gene Technology Act enacted in 2000 should be revised up to date, and consideration must be given to whether current emerging technology products are included in the scope of regulation.^[507]

Food Standards Australia New Zealand established an expert advisory group for emerging breeding technologies in 2017 to discuss regulatory methods for emerging plant breeding technologies,^[508] including gene editing technologies that do not have foreign gene(s). The public opinion consultation was con­ducted from February to August 2018, and it is expected that the final results and the proposal to amend the current laws and regulations will be announced at the end of 2019.^[509]

The Office of the Gene Technology Regulator (OGTR) discussed the definition of genetic modification in the current Gene Technology Act in October 2016 and proposed three principles: (1) all new technologies must be regulated, so both zinc finger nuclease technology and oligonucleotide- directed mutagenesis technology-derived crops must be regulated. (2) On the “technology-based” regulation, products derived from the SDN-2 and SDN-3 types of zinc finger nuclease and ODM technologies are subject to regula­tion because they have nucleic acid templates inserted into the genomes of organisms, while SDN-1 products of zinc finger nuclease technology can be exempted from regulation. (3) On “product-based” regulation, crops derived from the SDN-1 and SDN-2 types of zinc finger nuclease technology and ODM technology can be excluded, whereas products of the SDN-3 type of zinc finger nuclease technology are regulated as GMOs and subject to public consultation procedure.^[510] In April 2019, the Australian government announced that as long as no new genetic material was introduced, the Australian Gene Technology Authority would not regulate the use of gene-editing technology in plant, animal, and human cells.^[511]

G. Taiwan

Gene editing technology has become a popular gene manipulation technique for the next generation, especially the booming system of CRISPR/Cas9. Manufacturers have begun to develop gene-edited foods and even have prod­ucts ready to go on the market, so how to regulate such products should be a top priority. When making the regulatory policy for gene-editing technology, the authority should refer to the international trends of gene-editing regulation and take into account the legislative definition of genetic modification tech­nology in order to adopt regulatory principles that can avoid creating barriers to international trade and support the development of domestic biotechnol­ogy industry while minimizing consumers’ health risks at the same time. In 2018, the Food and Drug Administration commissioned the Food Industry Research and Development Institute to develop various regulatory plans for policy making regarding foods derived from gene-editing technology. Based on the suggestion of consulting experts, the most supportive option, among vari­ous plans, is the early consultation system. Under the proposed early consulta­tion system, applicants must provide relevant information of the gene-edited foods, including the process of gene editing, molecular characteristics, test data on whether foreign DNA or RNA fragments are present in the derived food, and related data or analysis regarding off-target effects. The competent author­ity shall determine whether the food is a genetically modified food and its cor­responding regulatory approach.

II.