115TH CONGRESS SENATE REPORT
2nd Session 104-341
REGULATION OF INTENTIONALLY ALTERED GENOMIC DNA ANIMALS ___________________________________________________________________________
APRIL 4, 2018 – Ordered to be printed
[Insert full name], from the Senate Committee on [Insert Committee],
Submitted the following
REPORT ON COMMENTS
[To accompany, S. 1043]
The Senate Committee on FDA has looked at the guidelines by the FDA as well as the comments by various organizations and academia. The recommendation of the committee is that the regulation does not pass. This is because of evidence that questions its legality. Hence there is need for it to be reviewed.
Purpose of Proposed Rule
The Food and Drugs Administration (FDA) released the regulation on animals with intentionally altered genomic DNA on January 19, 2017. The draft was supposed to clarify their stand on the regulation of these animals and their products. The methods used to modify their genome include random or targeted Change in their DNA sequence through methods such as Insertions, substitutions, deletions and nucleotide insertions (FDA, 2017). The regulations apply to both the parent animal on which the alteration is initially done and the lineage of the offspring which contain the genomic alteration.
The regulations on genetically modified animals apply to domesticated pets and livestock that will be later be consumed or used in drug factories. The laws are not binding. However, the industry is expected to follow them closely in order to gain market approval. The laws encompass details that the FDA will be required to know about the identity of the animal, its characteristics, the biological process as well as their labelling (FDA, 2017). The agency would also wish to be informed about the safety and efficiency of use for the intended use of the animals. Consequently, the areas that will be studied include the environmental impacts that these animals will pose, the risks of these animals on health, as well as safety questions that the producers may not have adequately addressed.
The rules are based on the Food, Drug and Cosmetic Act that was established by the Federal government. The law states that the DNA that has been inserted on animals can be regulated as a new animal drug as documented in the 1938 law. Interpretation of this law envisions that when a single gene is inserted into two different animals that are of the same species, the result is the creation of two different forms of the same species. This is because DNA integrates itself randomly (FDA, 2017). The law is also of the case that the animal’s offspring need to be subjected to regulations because they bear a resemblance to their parents.
Establishing the Debate
The regulation of animals with intentionally altered genomic DNA is a topic that is of great interest to many Americans. Consequently, the issue has attracted a lot of comments from individuals in the academia and the industrial sector. This review aims at assessing the comments on the proposed regulations. Certain sections of the society are for the proposed regulation while others are against it. Califf and Nalubola in their article FDA’s Science-based Approach to Genome Edited Products support the government intervention. Their opinion is that such a bold move is a step in the right direction to alter the genome of animals, plants, and microorganisms in order to produce the desired characteristics. The Consumer Union (CU) also supports the regulations. They believe that genetically engineered animals need to undergo rigorous assessments while at the same time treating them as “New animal drugs.” Consequently, genetically modified animals should be treated just like any other animal whose genetic has been engineered. The third comment in support of intervention is one by Alison Van Eenennaam in his response ‘Will – And Should – Gene Edited Animals Be Regulated?’
There are other organizations that are more informed about the issue and they feel that it is not a step in the right direction. Those against intervention on these regulations include The Biotechnology Innovation Organization (BIO), the Information Technology and Innovation Foundation (ITIF), and the George Washington University (GWU). BIO is tasked with carrying out research and development in the field of agriculture, healthcare, environmental and industrial biotechnology products. The ITIF is of the opinion that the proposal is counterproductive and ill-considered because it doesn’t comply with principles enshrined in the U.S regulation for biotechnology products that was laid down back in 1986. The George Washington University (GWU) is of the opinion that the regulator’s approach that the FDA is trying to mimic is bound to fail.
Comments for Intervention
The Consumer Union agrees with the provisions of the FDA regulations. Their stand is that animals whose genomic DNA has been intentionally altered should be treated as a new drug (Hansen, 2017 p. 2). There are established laws that should be used to address this issue where the animals are treated just like genetically engineered animals. These animals pose as new “animal drugs” since safety assessment is necessary. Safety regulations are associated with new animal drugs.
One of the issues raised by the Consumer Union in their submission is the use of recombinant DNA constructs. It, therefore, implies that genetic materials are gotten from different sources using the most modern technologies such as genome editing. The method introduces inheritable changes in the animals (Hansen, 2017 p. 3). Changes in genetic materials are however not covered by GFI #187. In their submission, the Consumer Union states, ‘we urge FDA to define “altered genomic DNA” as the portion of the animal’s genome that has been intentionally or unintentionally altered and considered as a drug within the meaning of section 201(g) of the FD&C Act.’(Hansen, 2017 p. 3). According to them, the FDA regulations come out broadly on this issue where the proposed rules cover the already existing technology, emerging technology, as well as future inroads that may be made to alter the genome of animals.
The effects of gene editing techniques for example CRISPR-Cas9 remains unknown. In their submission, they state, ‘…the CRISPR-Cas9 system is not as accurate as many believe and may result in extensive off-target mutations that might not be detected through the use of simple in silico modeling that is widespread’ (Hansen, 2017 p. 5). Consequently, all gene-edited animals should be analyzed via whole genome sequencing as well as incorporating epigenetic profiling so that off-target effects are established. Thereafter, several tests should follow such as proteomics, metabolomics, and transcriptomics to determine the effects of modification of the animals. Furthermore, all genetically engineered animals need to be labelled. The strategy will ensure that there is transparency in addressing concerns raised by the consumers as well as establishing post-market health effects.
Califf and Nalubola are biotechnologists who have also weighed on the debate. Their take on the issue is that animals produced via genome editing is in line with the views of the FDA. In their submission, they state ‘With respect to foods derived from plants produced using genome editing, FDA has a longstanding program for foods derived from new plant varieties, including those developed by recombinant DNA (rDNA) techniques’ (Robert, Califf, & Ritu, 2017). The genome of animals that have been altered intentionally using modern genome editing techniques or via rDNA results in a drug. This is because the intention is to alter the function and structure of the animal. Hence there is need to regulate this move under the FDA regulations that have been proposed. Through industrial research, they have established that the industry is responsible for ensuring that products are safe and meet all requirements of law. The regulations by FDA are not countering existing law but rather, they are complementing them to ensure safe practices reign supreme.
The arguments by Alison Van Eenennaam are centered on his research on dairy cows. The breeds included 9n his research is mainly the Holstein which naturally grows horns. These animals are dehorned because they pose a threat to other cows and their caregivers. Consequently, he has conducted research in this field, and he has established that it is possible to produce cows that are genetically dehorned. By using horn free alleles from the Angus breed which is hornless (Eenennaam, 2018). The researcher’s take on the issue is that regulation on animals with intentionally altered genomic DNA will be a step in the right direction more so the regulations that FDA want to establish. In his submission, he indicates that ‘the best regulatory approach is one that allows new technologies to be used while preventing unacceptable risks to animal and humans’ (Eenennaam, 2018). It would be unhealthy and illegal to sell an animal which is classified as being unsafe. In a scenario where the genes of the breeding method remain unknown or are unclear, gene editing introduces different transgenic and foreign rDNA that cannot be distinguished from natural variations and alleles (Eenennaam, 2018). He states ‘It is possible that gene editing nucleases might introduce double stranded breaks at locations other than the target locus, and thereby induce alterations elsewhere in the genome’ (Eenennaam, 2018).If these changes remain unmonitored, the benefits that would have resulted from genetic engineering are likely not to be achieved.
Comments against Intervention
The Biotechnology Innovation Organization (BIO) is of the opinion that FDA did not adhere to principles set forth by the White House Office of Science and Technology Policy of 1986. The policy states that the risk of a product is based are the nature of the product rather than the process used to produce it (BIO, 2017 p. 4). Secondly, regulation should be commensurate to a degree of risk. Consequently, the findings of the coordinated framework of 1986 should be the only basis on which analysis is to be done (BIO, 2017 p. 5). Furthermore, it is on this basis that all future oversights of biology-based products should be done.
“Government intervention offers regulations based on certain fundamental principles. For instance, oversight should be done using a scope of discretion based on statutes and based on the evidence that risks presented is reasonable. Secondly, the characteristics of the organism should be used to determine whether the organism offers risks to the environment rather than relying on the technique used,” (BIO, 2017 p. 7). The comment by BIO shows that they are of the view that new technologies in molecular modification increase the probability of producing better breeds. This is because the method utilizes techniques that are more precise and efficient as compared to traditional crossbreeds (BIO, 2017 p. 7). “The new breeds introduced have new phenotypic traits that do not offer risks to the environment just like their parent species. Furthermore, if oversight were to be skewed on such technology it would lead to hindrance on the development of a technology that was promising,” (BIO, 2017 p. 8).
The organization is also against the intervention because the new rule violates the principles presented in the Organization of Economic Cooperation and Development (OECD) of 1995. The main principle of OECD is that government intervention should only be carried out when the issue is of a high magnitude. Such an issue can only be solved through government intervention (BIO, 2017, p. 15). In this case, the problem can be solved through an understanding between the academia and professionals in the field. Secondly, government intervention should only be carried out by first articulating the problem so that the problem is solved in a cost-effective manner without impeding innovation as the new regulation is doing (BIO, 2017 p. 9). The issue at hand would be impeding on the milestones that have been achieved in the area of genome editing.
The regulation is of the view that there is a taxonomic relationship between the recipient animal and the gene that is introduced into its DNA. However, according to the comment by BIO, this is far from the truth. There has never been any evidence to prove the allegation (BIO, 2017 p. 20). Scientists across the globe have strongly affirmed that risk relates to attributes of the product rather than the genetic modification.
The ITIF has also weighed in on the issue. Their take is that the regulations are ill-considered and are likely to be counterproductive. Furthermore, the organization feels that the regulations are non-compliant with the U.S regulation for biotechnology that was enacted in 1986 (ITIF, 2017 p. 2). “The FDA regulations exempt inconsumable animals and other animals based on the evaluation of their risk factors from regulation. Despite this, the FDA is establishing laws for the review and approval of animals whose genomes have been altered using new technologies. This is very important in advancing the frontiers of research,” (ITIF, 2017 p. 2). The new laws are therefore unreasonable and do not take these issues into consideration.
The FDA has also done very little to define the relationship between hazards and their relationship to the environment or human health. If the FDA was to exercise such authority over such a pertinent issue, the passing of the new regulations is a takeover from longstanding U.S policy where authorities are required to provide persuasive cases that clearly show the associated hazards that would result from failure to regulate (ITIF, 2017 p. 2). In the regulations, there is no evidence for such an effort. For example, the issue of gene-edited mosquitoes is a case where the hazards were clearly defined. The mosquito had been used to address diseases such as Dengue, Zika, and Chikungunya.
In addressing the issue at hand, the FDA has been reluctant in regulating it and has consistently deferred with the Environmental Protection Agency (EPA). The issue of species does not play any role in any ecosystem on earth. In so doing, they bypassed consultations that would have necessitated further regulatory action (ITIF, 2017 p. 3). Also the organization is of the opinion that consultations with the EPA would have been reasonable and consistent with existing practices especially in the field of molecular biology. Under rule no. 187 of its guidance document, the FDA has made it clear that the mosquitoes meet the definition of an “animal drug,” (ITIF, 2017 p. 2). Despite this fact, the FDA is defiant to regulate the gene edited variant used to suppress the transmission of human diseases. Consequently, credit for this should go to Congress.
The third organization that is against the intervention by government is the George Washington University (GWU). The argument that they rise is a departure from the coordinated framework for regulation of biotech of 1987 (GWU, 2017 p. 3). “The regulation aimed at controlling the product gotten from biotechnology based on the risks they pose rather than on how they are created. The regulation proposes that modern technologies that exclude mutagenesis and phenotypic selection should be used,” (GWU, 2017 p. 4). They are most likely to result in random genome alterations. Implementation of the new rules will be a takeover from modern technologies in which the guidance initially aimed at regulating.
The FDA’s approach is seen to be imposing strict regulations on emerging technologies which were seen to offer new frontiers in the field of research. It would have led to many genetic combinations and more phenotypic outcomes. This is then combined with the fact that the guidance’s assertion of drugs in the FD&C Act under section 201 (g) is not identifiable (GWU, 2017 p. 6). Furthermore, alteration of the genome can result from other conventional practices of breeding.
Genome editing allows faster growth of animal breeds compared to conventional animal breeding methods. The challenge that arises is that it would be difficult to scientifically distinguish between animals developed via genome editing and animals from conventional breeding practices (GWU, 2017 p. 7). The animals are identical except that the method used to create them might have been used many generations earlier. Intervention should, therefore, be on the basis of the method used to come up with the new strain or breed.
The GWU is also of the opinion that the regulations come with additional costs that are totally unnecessary. For instance, the guidance has listed certain requirements that need to be applied before market approval. They include labeling and shipping of animals, disposition of animals, and environmental considerations that must be adhered to. In addition, other responsibilities such as the provision of information on the source, and the identity and functionality of the edited genome could also be costly (GWU, 2017 p. 8). “The requirement for approval requirements such as drug registration, maintaining records and reports that are concerned with the approval of products come with additional costs,”( GWU, 2017 p. 9) All these factors have a high cumulative cost which might be detrimental in research and diminish the possibilities of propelling research.
Further observations by GWU show that the guidance is a departure from the already existing federal policies in the field of biotechnology regulation. The comment makes reference to President Clinton’s executive order number 12866 that was put into effect in 1993. The order states that agencies such as FDA should propose or adopt regulations only based on the intended benefits which also justify the cost (GWU, 2017 p. 11). Regarding the FDA guidance, there is no evidence of such a determination.
The analysis of the economic viability has also been a key issue. The guidance does not address risk reduction or justify the additional cost. Moreover, the FDA has not conducted any economic viability study of the benefits as well as the costs of the guidance (GWU, 2017 p. 13). The Bill Clinton executive order 12866 required such an analysis to be conducted before the implementation of new regulations. The analysis would involve the determination of the negative effect of the regulation that it might have on development, marketing, as well as the use of the genome edited animals. It, therefore, addresses issues in environmental protection, health, nutrition, and agriculture.
The organizations against intervention are of the opinion of that the animal drug should be treated as a new drug. And therefore the regulations by FDA are not countering existing law but rather, they are complementing them to ensure safe practices reign supreme. The comments by BIO, ITIF, and GWU analyze the key areas of the regulation of intentionally altered genomic DNA animals. The legal procedure was not followed in developing the regulations, For instance, President Clinton’s executive order number 12866 was not adhered to. The new regulations also differ with the guidelines of the EPA, the U.S regulation for biotechnology of 1986, as well as the principles of the Organization of Economic Cooperation and Development (OECD) of 1995. Consequently, the laws do not have a strong legal backing from the comments by the various organizations and stakeholders in the academia, it would be prudent and advisable for the government not to intervene.
The new regulations could water down the achievements made in biotechnology in the last three decades. They propose the limitation of genome editing methods which would have expanded research frontiers. Furthermore, research on the adverse effects of genome edited animals is not known to have any adverse effects on the health of human beings, animals or the environment. The new regulations would be retrogressive and may spell doom on the field of biotechnology. The three non-supporting organizations offered diversified viewpoints that have a solid backing of evidence against what the FDA is proposing. Consequently, the FDA needs to look into some of the comments that have been discussed along with those of other organizations and the academia before making any decisions on the legislation so that the concerns raised can be addressed.
BIO. (2017, June 19). Docket Number: FDA-2008-D-0394: Regulation of Intentionally Altered Genomic DNA in Animals; Draft Guidance for Industry; Notice of Availability. Retrieved from https://www.bio.org/sites/default/files/2017%20BIO%20comments%20FDA%20CVM%20GFI%20%23187.pdf
Eenennaam, A. V. (2018, January 12). Will – And Should – Gene Edited Animals Be Regulated?. Retrieved from https://geneticliteracyproject.org/2017/02/08/will-gene-edited-animals-regulated/
FDA. (2017). Guidance for Industry Regulation of Intentionally Altered Genomic DNA in Animals
GWU. (2017, June 19). How to Regulate Genome-Edited Animals? A Comment on FDA’s Proposed Guidance | Regulatory Studies Center | The George Washington University. Retrieved from https://regulatorystudies.columbian.gwu.edu/how-regulate-genome-edited-animals-comment-fda%E2%80%99s-proposed-guidance
Hansen, M. (2017). Comments of Consumers Union to the Food and Drug Administration on the Notice of Availability: Regulation of Intentionally Altered Genomic DNA in Animals; Draft Guidance for Industry Docket No. FDA 2008-D-0394.
ITIF. (2017). FDA Must Revise Current Regulatory Proposal for Gene-Edited Animals.
Robert, M., Califf, M. D., & Ritu, N. (2017, January 18). FDA’s Science-based Approach to Genome Edited Products | FDA Voice. Retrieved from https://blogs.fda.gov/fdavoice/index.php/2017/01/fdas-science-based-approach-to-genome-edited-products/