May 12, 2016

Gene-Edited Mushroom Is First CRISPR-Generated Product to Avoid Federal USDA Regulation

Genetic alteration since the beginning of the biotechnology age has largely relied on the introduction of new genetic material into an organism to create a genetically engineered (GE) bacterium, plant or animal (also known as a genetically modified organism, GMO). Regulatory schemes reflected that dominant paradigm. Now, however, the use of gene-editing technology for genetic manipulation in plants can result in genetically altered plants that bypass the regulatory requirements for the introduction of standard GE plants into the marketplace. The traditional genetic engineering of crops employed the introduction of foreign genetic material into the crop; such gene transfer generally triggered formal review of the altered product because of the phenotype conveyed by the introduced gene(s), or because of the use of a vector that had plant pest characteristics. A GE plant product would trigger review if the newly introduced trait posed environmental or other safety-related risks. The review was conducted by the Animal and Plant Health Inspection Service (APHIS) of the USDA, pursuant to its statutory authority under the Plant Protection Act of 2000. (Depending on the product, additional oversight by the FDA or EPA could be required). Today, genetic alteration has moved beyond simple gene transfer into more precise techniques for changing the genome of an organism. Now, in a regulatory first, APHIS has made a determination that a white button mushroom altered by CRISPR/Cas9 gene editing technology to exhibit reduced browning is an “unregulated article” that will not require the kind of formal review usually applied to traditionally genetically engineered products containing foreign DNA: 
APHIS does not consider CRISPR/Cas9-edited white button mushrooms as described in your October 30, 2015 letter to be regulated. 
Here, CRISPR/Cas9 gene editing technology was used to introduce a small deletion in a polyphenol oxidase gene in the mushroom, with the result that the altered enzyme cannot produce the browning that shortens shelf life. The final product has no foreign DNA and no plant pest characteristics. This decision by APHIS follows earlier determinations that have resulted in at least 10 genetically altered products being approved without requiring a formal review. These products have been produced with, e.g., techniques that did not rely on the introduction of new genetic material using any plant pest vector, or non-CRISPR gene editing technologies. This shift in regulation highlights how modern genetic alteration writ large encompasses multiple technologies, some of which fall into an existing regulatory mandate, and some of which do not. The central theme of biotechnology regulation to date has been to focus on the product, not the process. As far back as the introduction of the federal Coordinated Framework for Regulation of Biotechnology in 1986, the prevailing scheme ensured that genetically engineered products would not be singled out for heightened review simply because of the way they were produced. The product was the focus; more precisely, the actual phenotypes of the GE plants or insects were evaluated to identify traits that required additional oversight. The traditional dichotomy between product-based or process-based paradigms for regulation biotechnology products has been criticized as a poor fit for the realities of the biotech marketplace. Evidence for an evolution of the regulatory scheme has been provided by the Obama administration’s announcement of a deliberative process to overhaul and modernize the regulation of biotech products, with the recruitment of the FDA, EPA, and USDA in the process (see earlier post). This regulatory renewal will no doubt eliminate a strict focus on gene transfer as the only genetic technology producing altered organisms, and strive to broaden the definition of the field of genetic alteration to reflect new realities, such as CRISPR and other gene-editing technologies. Then the calculus of risk/benefit analysis will need to be applied, in the context of emerging genetic technologies where risk profiles are not yet established.

April 29, 2016

Zika Virus Outbreak: Research Funding, Commercial Test, U.S. Risk Map

In the ongoing outbreak of Zika virus infection across parts of North and South America, there are several developments which signal increasing concern over the exact impact and geographic reach of the virus (the first death in the U.S. linked to the virus has been reported). At least 55 countries report Zika outbreaks, according to the World Health Organization. The virus is spread by mosquitos, specifically the Aedes aegypti. In the U.S., 426 cases of Zika-infected individuals have been reported. Although a course of infection may be mild and easily resolved in most individuals, Zika has become a high-profile infectious disease because viral infection in pregnant women has been linked to an increased risk of microcephaly in offspring. There are suspicions that more developmental risks to the child of an infected mother may exist, possibly unknown and only seen as development unfolds. In general, the mosquito thrives in warm and tropical climates, but seasonal weather patterns can shift the field of exposure. NASA scientists and other colleagues have published an Aedes aegypti risk map of the U.S., showing that a wide swath of the eastern U.S. is potentially susceptible to mosquito (and thus virus) spread, especially in the upcoming summer of 2016; the potential spread goes north as far as New York City. A commercially available test for detection of the Zika virus received an Emergency Use Authorization (EUA) from the FDA (the Quest Diagnostics Zika RT-PCR test). A current legislative battle over possible increased funding for public health responses to Zika reached a stalemate before Congress adjourned. One bill calls for $1.6 billion in supplemental funding for dedicated Zika virus research and public health capabilities, but is encountering Republican opposition. Some of the political infighting over a federal response to the Zika outbreak recalls earlier conflicts during the Ebola virus crisis. However, the Zika virus is already in the U.S., cases are officially documented, and the upcoming summer portends more infections, not less. The 2016 Summer Olympics in Brazil this summer have already caused concern among attending athletes; the current understanding of transmission suggests that Zika virus cases in the U.S. are largely explained by travel to countries with high risk of infection; that fact will also impact the Olympics participation. No effective treatment or vaccine for the Zika virus is yet developed; increased NIH funding would certainly allow research to expand. Another target for intervention is to reduce the Aedes aegypti mosquito population; already, a British biotechnology has produced a genetically engineered (GE) mosquito that is reproductively crippled and is hoping to conduct trials in the U.S. An upcoming post will examine that option in more detail.

April 7, 2016

Major Overhaul of Federal Biotechnology Regulation is Underway; National Academy of Sciences Invites Public Participation

The federal regulation of biotechnology products is grounded in a design that was first announced in 1986 as the Coordinated Framework (CF) for the Regulation of Biotechnology, later updated in 1992. Those documents have largely shaped the the federal regulatory regime for biotechnology. A key concept in this original framework was that products produced through genetic engineering (or recombinant DNA) techniques would not receive special oversight because of the processes used to produce them. Instead, a risk-based approach was instituted that focused on the characteristics of actual products, not underlying production techniques. In 2015, the White House, through its Office of Science and Technology (OSTP), announced that it would launch an overhaul of the 1992 policy. In the memorandum, the OSTP provided a definition of “biotechnology products” to be included in the review: 
For the purpose of this memo, “biotechnology products” refers to products developed through genetic engineering or the targeted or in vitro manipulation of genetic information of organisms, including plants, animals, and microbes. It also covers some of the products produced by such plants, animals, and microbes or their derived products as determined by existing statutes and regulations. Products such as human drugs and medical devices are not the focus of the activities described in this memorandum. 
Since the 1980’s, the existing coordinated framework has divided the primary regulation of biotechnology products among three agencies: the U.S. Environmental Protection Agency (EPA), the U.S. Department of Agriculture (USDA), and the U.S. Food and Drug Administration (FDA). The OSTP is involved in a more general role as overseer of the regulatory design, rather than as a formal regulatory body. In the memorandum sent to the heads of the EPA, FDA and USDA, the OSTP alludes to the regulatory overlap, redundancy and confusion that has arisen with the multi-agency design: 
Each of the Federal regulatory agencies with jurisdiction over the products of biotechnology has developed regulations and guidance documents to implement its authority under existing laws, resulting in a complex system for assessing and managing health and environmental risks of the products of biotechnology. While the current regulatory system for the products of  biotechnology effectively protects health and the environment, in some cases unnecessary costs and burdens associated with uncertainty about agency jurisdiction, lack of predictability of time frames for review, and other processes have arisen.
As part of the modernization initiative, the Administration held 3 meetings organized by the relevant agencies to receive feedback on the proposed overhaul. Two documents were issued that are helpful to understanding the current climate that is precipitating calls for redesign: a table of current agency responsibilities, and a series of case studies illustrating how a singular GE product can be subject to multi-agency review. Pursuant to the OSTP charge, a committee formed by the National Academy of Sciences, Medicine and Engineering was commissioned to conduct a formal study, “Future Biotechnology Products and Opportunities to Enhance Capabilities of the Biotechnology Regulatory System.” This committee has set the following objectives:
Describe the major advances and the potential new types of biotechnology products likely to emerge over the next 5-10 years. 
Describe the existing risk analysis system for biotechnology products including, but perhaps not limited to, risk analyses developed and used by EPA, USDA, and FDA, and describe each agency’s authorities as they pertain to the products of biotechnology. 
Determine whether potential future products could pose different types of risks relative to existing products and organisms. Where appropriate, identify areas in which the risks or lack of risks relating to the products of biotechnology are well understood. 
Indicate what scientific capabilities, tools, and expertise may be useful to the regulatory agencies to support oversight of potential future products of biotechnology. 
The first public meeting of the NAS committee will be held on April 18, 2016. The agenda for the meeting is posted here.

March 31, 2016

Lawsuit Challenges FDA Approval of Genetically Engineered Salmon

This week, a coalition of environmental, food safety and consumer groups has filed suit against the FDA for its 2015 approval of a genetically engineered (GE) salmon product in 2015 (following several decades of review). The product is AquaAdvantage, made by Aqua Bounty, Inc.  This is the first transgenic animal to be approved by the FDA for food consumption. To produce the GE salmon, Atlantic salmon is engineered to contain the growth hormone gene from Pacific Chinook salmon, which causes the fish to grow in less time; the gene is placed under the control of a promoter from ocean pout, which causes elevated expression of the hormone. The fish are to be only sterile females. The production plans submitted to the FDA describe the preparation of the GE fish eggs in Canada, and the actual production of the fish in Panama (with eventual location in the U.S. as well). Following the approval, Alaska Sen. Lisa Murkowski, an opponent of the FDA's actions (see here), inserted a legislative provision into the 2015 omnibus spending bill, requiring the FDA to develop a labeling scheme for the GE salmon before they enter the market. As a result of that maneuver, the FDA is in the process of complying with that mandate, and the GE salmon is not yet commercially available.

In their press release, the plaintiffs assert several grounds on which the agency’s action does not comply with existing federal law: 
The lawsuit challenges FDA’s claim that it has authority to approve and regulate GE animals as “animal drugs” under the 1938 Federal Food, Drug, and Cosmetic Act. Those provisions were meant to ensure the safety of veterinary drugs administered to treat disease in livestock and were not intended to address entirely new GE animals that can pass along their altered genes to the next generation. The approval of the GE salmon opens the door to other genetically engineered fish and shellfish, as well as chickens, cows, sheep, goats, rabbits and pigs that are reportedly in development. 
The lawsuit also highlights FDA’s failure to protect the environment and consult wildlife agencies in its review process, as required by federal law. U.S. Atlantic salmon, and many populations of Pacific salmon, are protected by the Endangered Species Act and in danger of extinction. Salmon is a keystone species and unique runs have been treasured by residents for thousands of years. Diverse salmon runs today sustain thousands of American fishing families, and are highly valued in domestic markets as a healthy, domestic, “green” food.
The lawsuit was filed in the Northern District of California. The suit could directly test the applicability of the FDA's determination that the insertion of new genetic material amounts to a kind of "veterinary  drug" and thus applications for approval of food from GE animals require a new drug application under the Federal Food, Drug, and Cosmetic Act. According to the FDA: 
FDA regulates GE animals under the new animal drug provisions of the law, and the agency must approve them before they are allowed on the market. Food and animal feed from GE animals will undergo FDA review before the food or feed can be marketed. The Federal Food, Drug, and Cosmetic Act defines a drug as "an article (other than food) intended to affect the structure or any function of the body of man or other animals." Therefore, the rDNA construct intended to change the structure or function of the body of the GE animal is a drug.
The suit also challenges the legitimacy of the FDA's determination that the GE salmon posed no environmental risk, based on an Environmental Assessment; the plaintiffs argue that the FDA is required to perform the more rigorous Environemntal Impact Statement (EIS). The food and restaurant industries had earlier indicated some resistance to selling the GE salmon; Red Lobster and Costco have already announced that the product will not be carried.

March 30, 2016

Vermont Law Requiring Labeling of Genetically Engineered Foods Set to Take Effect as Congressional Opposition Fails

Vermont is on track to implement the nation’s first law requiring the labeling of foods with genetically engineered (GE) ingredients, whether raw or processed. (The term "genetically modified organism" (GMO) is often seen in discussions as well). The state’s Act 120, passed in 2014, was enacted to advance several objectives related to “public health and food safety, environmental impacts” and avoidance of “consumer confusion and deception.” The law states: 
[F]ood offered for sale by a retailer after July 1, 2016 shall be labeled as produced entirely or in part from genetic engineering if it is a product:
(1) offered for retail sale in Vermont; and 
(2) entirely or partially produced with genetic engineering. 
The law further describes the labeling: 
[I]n the case of any processed food that contains a product or products of genetic engineering, the manufacturer shall label the package in which the processed food is offered for sale with the words: “partially produced with genetic engineering;" “may be produced with genetic engineering;" or “produced with genetic engineering.” 
In the two years since its passage, there have been several efforts in Congress to enact a federal law that would reassert federal jurisdiction over the labeling issue and preempt any state labeling laws. The House considered bills in 2015, and the Senate just this month considered its own version. Although a House bill passed, the attempts to establish a federal counterweight to state labeling efforts failed as a similar bill was defeated in the Senate. Efforts to mandate the labeling of GE food products at the national level have consistently failed in Congress, and the FDA has resisted all calls for a national mandate on labeling. Now, as Vermont’s law will take effect on July 1, 2016, preparations for compliance are evident on a number of fronts. The Attorney General has issued a memorandum detailing its enforcement strategy which states: 
Our Office expects that most GE foods on Vermont grocery store shelves will be properly labeled by July 1, 2016. Out of recognition that some food products have longer shelf lives, CP (Consumer Protection Rule) 121 creates a six-month “safe harbor” for foods distributed before July 1, 2016, and offered for retail sale through December 31, 2016. During this six-month period, unless there is evidence that a manufacturer distributed a mislabeled product after July 1, 2016, we will not bring an enforcement action or seek fines for those products. 
Beyond these developments in Vermont, Connecticut and Maine have also passed mandatory GE labeling laws; however, their implementation will only be triggered when a number of states join the effort (see here). On the commercial front, with the Vermont mandate looming, major food manufacturers are releasing plans to add labeling labeling regarding the “genetically engineered” attributes of their food products. General Mills issued a statement
As the discussions continue in Washington, one thing is very clear: Vermont state law requires us to start labeling certain grocery store food packages that contain GMO ingredients or face significant fines. We can’t label our products for only one state without significantly driving up costs for our consumers and we simply will not do that. The result: consumers all over the U.S. will soon begin seeing words legislated by the state of Vermont on the labels of many of their favorite General Mills products. 
Other major companies following suit include Kellogg’s, ConAgra Foods, and Campbell’s Foods. In a departure from other manufacturers, Campbell’s has called for a federally mandated labeling system to systematize labeling, and the company formally withdrew from food industry efforts to oppose GE food labeling laws and initiatives. The effect of the Vermont law is now being realized across the food industry; however, a lawsuit filed against Vermont's law by the Grocery Manufacturers Association (GMA) is still working through the federal courts: the trial judge denied summary judgment and a preliminary injunction for GMA; an appeal of the district court's injunction ruling is on appeal at the Second Circuit.