This chapter introduces the existing risk-analysis system for biotechnology products, surveying agency authorities as they relate to future biotechnology products anticipated over the next 5–10 years. Consistent with this study’s statement of task, the focus is on the U.S. Environmental Protection Agency (EPA), the U.S. Food and Drug Administration (FDA), and the U.S. Department of Agriculture (USDA) but not limited to these agencies. This discussion highlights major statutes that authorize these agencies either to conduct risk analysis or to require other entities—such as product developers—to conduct it.
The regulatory agencies carry out two closely interrelated but distinct regulatory functions that together protect public health, safety, and the environment and which form the major topics of this chapter. The first is consumer- and occupational-safety regulations that protect members of the public who directly expose themselves to biotechnology products through their decisions to consume or use them or to enter a workplace where biotechnology products or biotechnological means of production are in use. Examples of possible risks associated with these products are injuries consumers may suffer when using a biotechnology-based product or injuries to industrial workers caused by exposure to a biotechnological means of production. The other function is environmental regulation to address non–human health risks (that is, ecological risks) and human health risks to members of the public that are exposed to future biotechnology products regardless of their individual decisions. Examples of these possible risks include contamination of the surrounding environment and introduction of a pernicious species.
The broad, environmental impacts of biotechnology products have historically been a focus of concern and this can be expected to continue in the future. The expanding array of products identified in Chapter 2 suggests, however, that consumer- and occupational-safety issues may assume growing importance within the time frame of this study. The 2017 update to the Coordinated Framework (EOP, 2017) devotes less attention to these issues than to environmental risks, so the committee opted to examine consumer- and occupational-safety issues in depth in this chapter before introducing the key statutes related to environmental risks, which lay groundwork for more detailed discussion of environmental risk analysis that follows in Chapters 4 and 5 of this report.
The temporal limitation of this study’s scope necessarily implies a focus on legal authorities conferred by existing federal statutes. Major shifts in federal agencies’ approach to risk analysis often evolve over a time scale longer than 5–10 years. Even after Congress enacts a new statute—a process that itself takes time—the process of implementing a new statute may include legal challenges and requires agencies to promulgate implementing regulations. Because regulatory change is a long process, some of the new biotechnology products described in Chapter 2 will likely challenge federal agencies to protect the public’s health, welfare, safety, and environment using the legal tools they already have. This chapter describes key features of the risk-analysis frameworks provided by statutes enacted at the time the committee was writing its report, including the 2016 amendments1 to the Toxic Substances Control Act (TSCA),2 and touches on scientific capabilities, tools, and expertise that may be useful to the agencies as they face this challenge; these matters are discussed in more detail in Chapter 4. The broader task of identifying potentially beneficial statutory amendments was outside the scope of this study, but this chapter does, when appropriate, highlight some of the costs, limitations, gaps, and redundancies that may arise as agencies attempt to regulate future biotechnology products using the legal authorities conferred by their existing statutes.
In January 2017, the federal government released an update to the Coordinated Framework (EOP, 2017), which provided a detailed overview of the responsibilities of EPA, FDA, and USDA within the Coordinated Framework and the major statutes these agencies enforce. Consequently, this chapter directs its attention to aspects of these statutes that are central to the report’s statement of task. One important question concerns the breadth of jurisdiction conferred by these statutes: Will all of the new biotechnology products expected over the next 5–10 years fit within the categories of products that EPA, FDA, and USDA can regulate? If not, which (if any) federal agencies will regulate the product? What authorities does each responsible agency have to conduct (or require) risk analysis, and what scientific capabilities, tools, and expertise may be useful to the agencies as they confront the new biotechnology products identified in Chapter 2? Finally, how much flexibility do the agencies have under their existing statutes to address any gaps that threaten to leave new products with inadequate regulatory oversight?
After a brief overview of the origins and evolution of the Coordinated Framework, the chapter addresses the statutory authorities and associated agency responsibilities for accomplishing the Coordinated Framework’s objectives with regard to safety: protection of human health—including consumer and occupational safety—and protection of the environment. It identifies the capacity of the agencies to regulate future biotechnology products under their existing authorities and points out areas where the limits of their authorities may leave gaps in oversight.
The purpose of the U.S. regulatory system is to “protect public health, welfare, safety, and our environment while promoting economic growth, innovation, competitiveness, and job creation” (EOP, 2011:3821). To strike this balance, risk in the U.S. system has been understood to pertain to consumer safety and environmental protection; however, the term can be defined more broadly (Box 3-1). This section provides a brief history and evolution of the Coordinated Framework, which was established to provide oversight for risks to human health and the environment. It also reviews, in more general terms, the considerations that go into balancing safety through regulations with innovation.
1 Frank R. Lautenberg Chemical Safety for the 21st Century Act, P.L. 114-182 (2016).
2 15 U.S.C. § 2601 et seq.
The Coordinated Framework
Federal involvement in the oversight of biotechnology is generally viewed as originating in the 1970s. Responding to concerns raised by scientists engaged in recombinant DNA research, the National Institutes of Health (NIH) published a set of research guidelines in 1976, which have been updated many times over the years (NIH, 2016). The NIH guidelines represent a formal research
governance approach that applies to all research with recombinant or synthetic nucleic acid molecules conducted or sponsored by public and private institutions that receive any NIH funding for such research, and many other federal agencies and private research sponsors also require compliance with the NIH guidelines in research that they fund.3 The NIH guidelines govern standards for protection of researchers, the public, and the environment.4 NIH-funded research at institutions in the United States and abroad that conduct basic and clinical research involving recombinant or synthetic nucleic acid molecules must adhere to safety practices and containment procedures described in the NIH guidelines through the oversight of Institutional Biosafety Committees.5 Even though the NIH guidelines may not govern all government-funded and privately funded research, they are a tool for the entire research community to understand the potential biosafety implications of recombinant or synthetic nucleic acid research.
Later in the 1970s and early 1980s, amid growing prospects that DNA research would produce a flood of new products, Congress considered but did not adopt various proposals to enact unified biotechnology legislation. In 1984, the White House Cabinet Council on Natural Resources and the Environment formed a Working Group on Biotechnology, which proposed a Coordinated Framework that would clarify regulatory responsibility to federal agencies acting under their existing statutory authorities (OSTP, 1986).
The Coordinated Framework was published in July 1986 after an 18-month period for public comment (OSTP, 1986). It orchestrated the biotechnology-related responsibilities of multiple federal agencies, with prominent roles assigned to NIH, EPA, FDA, USDA, and the U.S. Department of Labor’s Occupational Safety and Health Administration (OSHA). The biotechnology-related responsibilities of each agency were conferred by statutes already in effect as of 1986, meaning that statutes enacted before the biotechnology revolution were interpreted to cover biotechnology. For example, “chemicals” under TSCA were interpreted as including biotechnology products (described in more detail below) (EPA, 1997).
In addition to regulating biotechnology as required by their respective enabling statutes, these agencies also comply with generally applicable federal statutes including the National Environmental Policy Act (NEPA), the Endangered Species Act (ESA), and the Administrative Procedure Act (APA). These latter statutes, while often characterized as procedural in nature, require agencies to conduct certain risk-analysis activities or, in the case of APA, facilitate public deliberation by subjecting agency activities to transparency and due-process requirements.
The Coordinated Framework was updated in 1992 to provide further policy guidance to agencies. That guidance stated that products intended for use in the environment should not be regulated on the basis of the process by which they were made; instead, the criteria would be “characteristics of the organism, the target environment, and the type of application” (OSTP, 1992:6755). In January 2017, the federal government published an update to the Coordinated Framework, the first in more than 20 years (EOP, 2017). That update provided a basic survey of statutory authorities of EPA, FDA, and USDA to regulate environmental and human health and safety risks related to biotechnology products (EOP, 2017). At the time a proposed update to the Coordinated Framework was put forward for public comment (September 2016)—before publishing the final update in January
3 See “Product-Development Research” below for discussion of the impacts that anticipated shifts in the funding of biotechnology research may have on the continued applicability of the NIH guidelines.
4 NIH Office of Science Policy. Biosafety. Available at http://osp.od.nih.gov/office-biotechnology-activities/biosafety. Accessed December 6, 2016.
5 The responsibilities of the Institution Biosafety Committees extend to research involving material transfers among laboratories and field releases of genetically engineered organisms to governance of emerging technology applications, such as genome editing, or the design of gene-drive experiments and containment plans specific for research with gene drives. However, their responsibilities do not extend to biotechnology products.
2017—the federal government also published the National Strategy for Modernizing the Regulatory System for Biotechnology (EOP, 2016).
Table 3-1, originally published in the 2017 update to the Coordinated Framework, summarizes the statutes under which EPA, FDA, and USDA currently regulate biotechnology products. Under these statutes, the Coordinated Framework agencies carry out the two interrelated but distinct regulatory functions described earlier: (1) consumer- and occupational-safety regulation and (2) environmental regulation.
After considering the way regulations take into account safety and innovation, this chapter delves into the following two topics: (1) whether the statutes in Table 3-1 provide the agencies with adequate tools to support robust risk assessment to protect human health and the environment and (2) whether the agencies have sufficient statutory powers to address the special challenges raised by new products expected during the next 5–10 years.
Regulation to Promote Safety and Innovation
When the Coordinated Framework was established, one of its stated purposes was to find a balance between safety regulation and innovation (OSTP, 1986; Box 3-2). The two are not necessarily at odds: innovation has the potential to enhance safety, for example, by replacing high-risk products with newer, safer products. Moreover, regulatory frameworks that are suitably designed and implemented have the potential to foster innovation; for example, fuel economy standards have improved the average fuel economy of U.S. vehicles. Thus, it is incorrect to assume that regulation inevitably creates barriers to innovation. One valid area of concern, however, is that regulations have the potential to impede or delay the introduction of innovative products to the market, if the regulations add substantial up-front costs and delays to the process of developing and marketing a new product. These costs and delays can also provide incentives for developers to create products that are not considered regulated articles (such as in the example of using biolistics to transform a grass species described in Chapter 2). A related concern is that regulation can encourage developers to imitate products that have charted a path through the regulatory system, rather than pursue more innovative products that may have unclear paths and thus run the risk of taking a long time in regulatory review. The intent of the Coordinated Framework is to provide mechanisms to assess the safety of biotechnology products while simultaneously offering a framework for advancing innovation and increasing transparency, coordination, efficiency, and predictability. This balance is sought in the interpretation of the statutory authorities that make up the Coordinated Framework.
It is simplistic to characterize an entire statute as either precautionary or conducive to innovation, as these concepts have meaning only at the level of specific statutory provisions. Consumer- and occupational-safety statutes generally address risks through a complex mix of provisions that include some precautionary and some permissive elements. Together, a statute’s provisions balance the need to be cautious against the benefits people may gain as innovative new products enter the marketplace. Among the features that are important in accessing the risk characteristics of a specific statutory framework are
- The allocation of duties to develop an information base to support regulatory decision making.
- Where the burden of proof is placed in regulatory decisions.
- The mix of premarket and post-market safety information.
- The provisions that foster private-sector participation in data and evidence generation for risk analysis.
- The provisions for managing risks that are revealed during a risk assessment.
TABLE 3-1 Statutes and Protection Goals Related to the U.S. Environmental Protection Agency (EPA), the U.S. Food and Drug Administration (FDA), and the U.S. Department of Agriculture (USDA) for the Regulation of Biotechnology Products
|EPA||Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)||
Prevent and eliminate unreasonable adverse effects on the environment
|EPA||Federal Food, Drug, and Cosmetic Act (FDCA)||Ensure that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.|
|EPA||Toxic Substances Control Act (TSCA)||Prevent the manufacture, processing, distribution in commerce, use, or disposal of chemical substances, or any combination of such activities with such substances, from presenting an unreasonable risk of injury to health or the environment, including an unreasonable risk to a potentially exposed or susceptible population, without consideration of costs or other nonrisk factors.|
|FDA||FDCA||Ensure human and animal food is safe, sanitary, and properly labeled. Ensure human and animal drugs are safe and effective. Ensure the reasonable assurance of the safety and effectiveness of devices intended for human use. Ensure cosmetics are safe and properly labeled.|
|FDA||Public Health Service Act||Ensure the safety, purity, and potency of biological products.|
|USDA||Animal Health Protection Act (AHPA)||Protect livestock from animal pest and disease risks.|
|USDA||Plant Protection Act (PPA)||Protect agricultural plants and agriculturally important natural resources from damage caused by organisms that pose plant pest or noxious weed risks.|
|USDA||Federal Meat Inspection Act||Ensure that the United States’ commercial supply of meat, poultry, and egg products is safe, wholesome, and correctly labeled.|
|USDA||Poultry Products Inspection Act||Ensure that the United States’ commercial supply of meat, poultry, and egg products is safe, wholesome, and correctly labeled.|
|USDA||Egg Products Inspection Act|
|USDA||Virus-Serum-Toxin Act||Ensure that veterinary biologics are pure, safe, potent, and effective.|
SOURCE: EOP (2017:9).
Allocation of Duties to Develop an Information Base to Support Regulatory Decision Making
In order to make sound regulatory decisions that protect the public and the environment, regulators need a base of reliable information about the risks a product may pose. Statutes provide various mechanisms to facilitate creation of this information base. First, the regulatory agency (or group
of agencies) needs to know that the product exists; then, the regulatory agency needs information about the product in order to make a regulatory decision.
With regard to learning about products still in development, one option is for the statute to require product sponsors6 to make their activities and new products known to the regulator via a notification or other registration requirement so as to facilitate rapid detection and response if safety problems later arise. If there is not a statutory requirement for such notification, then the regulator must instead conduct market surveillance to discover the existence of new products and the identities of their manufacturers.
Statutes also allocate responsibilities surrounding generation of safety information, by identifying who is responsible for conducting studies to assess risks and resolve the scientific uncertainties that can surround regulatory decisions involving novel biotechnology products. A statute may foster safety studies by the product sponsors (manufacturers, distributors, or sellers) who wish to benefit commercially from the new product and provide for investigational use of unapproved products under regulatory oversight. It may also require product sponsors to conduct (and fund) safety studies and require sponsors to submit data at key points during the product life cycle, such as first open release in the environment, initial market entry, or after consumer-safety incidents occur. Alternatively, a statute (or lack thereof) may require the regulatory agency to conduct its own studies (or rely on publicly funded research) to evaluate product safety. The nature of the statute dictates the distribution of responsibilities for generating safety data between the private product sponsor and federal agencies.
Requiring product sponsors to bear heavy evidence-generation burdens in the premarket period can raise the barriers to entry and the cost of bringing new products on to the market and thus may deter innovation, especially if the projected future market value of the product is estimated to be less than the combined costs of discovery, product development, and safety evaluation. Yet regulators and public-research funding agencies may lack resources to finance all the risk assessment that is needed to evaluate the public’s safety in a time of fast-paced introduction of novel products. How statutes allocate responsibilities to generate evidence between private and public actors is therefore a critical parameter affecting the balance between innovation and safety.
Placement of the Burden of Proof for Regulatory Decision Making
A closely related question is where a statute places the burden of proof in key regulatory decisions, such as the decision to allow commercial sale of a new product or to add a new safety warning or restrict sales of an existing one. Faced with scientific uncertainty and evolving safety information, a regulator’s ability to manage safety risks may hinge on where the burden of proof is placed and on the implicit presumptions embedded in the law: is the product presumed dangerous until proved safe, or is it treated as safe until proved dangerous (Charo, 2015)? When data are insufficient to prove either danger or safety, where that presumption falls often is determinative (Charo, 2015).
Where this burden of proof is placed also affects the cost of new product development and, therefore, may affect the pace of innovation. When the regulator bears the burden of proving products to be unsafe, this relieves product developers of the cost of proving their products safe, but it implies that the regulator’s budget (or governmentally funded research) must bear primary responsibility for ensuring consumer, occupational, and environmental safety. Federal budgetary constraints may at times make it difficult to generate all of the data necessary to promote optimal levels of safety. Enacting statutes that require product developers to prove their products safe shifts
6 In its discussion of FDA’s authority, the committee has used the term sponsor to be consistent with language in the statutory authorities that pertain to the agency. The committee uses this term as it has used product developer elsewhere in the report, which can refer to a person, corporation, or agency that has brought a new product to a regulatory agency for oversight or regulatory approval.
this cost to them, but may also make products more costly if developers add research costs into pricing. Thus, there are delicate tradeoffs among statutory burdens of proof, required federal research budgets, the pace of innovation, and the cost and public accessibility of innovative new products.
Premarket Versus Post-Market Safety Information
In assessing whether a statute strikes a healthy balance between innovation and safety regulation, another key feature is when the statute requires evidence of safety to be developed. If products must be shown safe before they go on the market, this seemingly enhances safety but the costs and delays of developing premarket safety data may prevent the entry of innovative, lower-risk products. A robust program of post-marketing risk detection and analysis can relieve pressure to achieve certainty about safety prior to new product entry, thus facilitating innovation while promoting safety through rapid risk detection and response. Even when a statute requires premarket risk analysis, post-marketing risk assessment adds an important layer of protection because some risks cannot be detected in small-scale, short-duration premarket studies and can only be evaluated in the post-marketing period after products move into wide commercial use (Evans, 2009). When assessing a statute, key questions are as follows:
- Does the statute emphasize premarket safety studies, post-marketing safety surveillance and studies, or both?
- After new products enter the market, does the regulator bear the ongoing burden of detecting safety problems through inspections and testing or is there a framework for sponsors or users to report safety incidents7 to the regulator?
- Are there mandatory requirements for product sponsors to report safety incidents after a product enters the market or is the framework voluntary?
- Does the statute equip the regulator with data infrastructure or foster the creation of data resources to support the use of observational methodologies as a tool for proactive, continuous detection of emerging risk signals (active safety surveillance) after a product enters the market?8
- Can the regulator require product sponsors to conduct safety studies and clinical trials in the post-marketing period to clarify signals of new safety risks?
Provisions to Foster Private-Sector Participation in Creating Evidence and Data Infrastructure for Risk Analysis and Setting Safety Standards
In regulatory frameworks, the participation of private-sector actors goes beyond simply requiring product sponsors and developers to generate risk information about their own commercial products. The work of ensuring consumer, occupational, and environmental safety at times requires broader public–private collaborations in which governmental and private actors join forces to tackle problems that are too complex for either to address alone. A host of tools already exists for orchestrating public–private collaborations that merge the activities of governmental bodies and private organizations in inventive ways (Kettl, 2002; Salamon, 2002; Yescombe, 2007). These tools include traditional instruments such as governmental grants and contracts that enable the government to engage private actors (for-profit and nonprofit) in tasks, such as risk analysis, that promote regula-
7 Incident reporting allows the regulator to conduct passive surveillance by monitoring the reports it receives.
8 An example of such data resources would be FDA’s post-market risk identification and analysis system (Sentinel System), a very large-scale data resource FDA developed via a public–private collaboration for use in active post-marketing drug safety surveillance, using authorities Congress granted in the Food and Drug Administration Amendments Act of 2007 (21 U.S.C. §§ 355(k)(3), (4)).
tory objectives. However, they also include tax incentives, insurance, and loan guarantees to mobilize private capital and a wide array of other mechanisms through which governmental regulators can harness private-sector resources and know-how (Salamon, 2002) to address challenges, such as how to finance and develop large-scale, industry-wide data infrastructures that support post-marketing product safety surveillance and continuous learning or how to assemble “knowledge commons” (shared data resources) to promote innovation and rapid dissemination of best practices within an industry (Frischmann et al., 2014). In the 20th century, regulation via hierarchical governmental bureaucracy was the predominant organizational model for fulfilling public-policy goals (Goldsmith and Eggers, 2004), and this model is reflected in many of the 20th-century statutes that authorize federal agencies to seek to regulate the safety of novel biotechnology products. Alongside these statutes, however, there is a decades-long trend toward greater integration of private actors—both commercial firms and nonprofit organizations—into the day-to-day work of these agencies through public–private partnerships and other modes of collaboration (Goldsmith and Eggers, 2004).
Provisions for Managing Risks Revealed During Risk Assessment
Many statutory provisions affect risk management more than risk assessment. For example, what powers does the regulator have to respond to an emerging safety problem? Does the regulator have a nuanced set of tools that allow safety problems to be resolved while keeping beneficial products available to consumers—for example, powers to require labeling changes or to restrict use, sale, or distribution of the product as opposed to banning it? How nimble is the agency’s authority to act? Are there cumbersome procedural requirements (such as having to promulgate a regulation in order to investigate or respond to a safety concern) or formal procedural requirements (such as having to conduct hearings or other formal processes before taking action)?
Diverse, new types of biotechnology products entering the market may pose new consumer- and occupational-safety challenges. The important questions for a specific product are as follows:
- Does any federal regulatory agency have jurisdiction to regulate it and, if so, which agency (or agencies)?
- Do the regulatory agencies have adequate tools to analyze the types of risk the product may present?
Multiple federal agencies are responsible for consumer and occupational safety. Under the Food, Drug, and Cosmetic Act (FDCA), FDA is a major product safety regulator. EPA is mandated to ensure safety of chemicals across a number of uses, including consumer products, occupational exposures, and manufacturing. Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)9 and Section 408 of the FDCA, EPA regulates consumer safety with respect to pesticides and pesticide residues in food and occupational safety with respect to uses of pesticides in the workplace. As shown in Table 3-1, USDA plays a crucial role in consumer safety with respect to various food products, such as meat and poultry.
Federal oversight of consumer and occupational safety is not limited to the three agencies discussed in the 2017 update to the Coordinated Framework (EOP, 2017). In addition to EPA, FDA, and USDA, the Consumer Product Safety Commission (CPSC) has residual jurisdiction to regulate consumer products not regulated by the other agencies, so biotechnology products that are
9 7 U.S.C. § 136 et seq.
not regulated by one or more of the statutes listed in Table 3-1 may fall under CPSC’s jurisdiction. Under FIFRA, EPA is completely responsible for all pesticide risks, including in the workplace. Under TSCA, EPA and OSHA share responsibility for chemical safety in the workplace; EPA evaluates and manages the chemical risk, and OSHA establishes and enforces workplace exposure limits and safety practices. In coming years, OSHA may confront novel issues in workplaces where biotechnology is used as a means of production in diverse industrial, commercial, and agricultural settings. Agencies concerned about consumer and occupational safety have to be attuned to assessing not just the types of new products but also the characteristics of the anticipated users because the safety of some future biotechnology products depends on the skill and intent of the user along with the product design (Box 3-2).
Additional agencies may need to become involved when specific biotechnology products fall within their jurisdiction—for example, the National Highway Traffic Safety Administration (NHTSA) may be called upon to address safety issues related to future biotechnology-based car batteries. This section does not attempt to identify every agency, such as NHTSA, that may occasionally encounter new biotechnology products and instead focuses on agencies—FDA, CPSC, OSHA, EPA, and finally USDA—with broad jurisdiction over consumer and occupational safety.10
U.S. Food and Drug Administration
FDA has various general powers to protect public health and safety, such as the authority FDA shares with the Centers for Disease Control and Prevention (CDC) under the Public Health Service Act to control the spread of communicable diseases (Hutt et al., 2014). However, FDA’s authority to protect consumer safety under the FDCA is determined “almost entirely by the list of product categories over which it has jurisdiction” (Hutt et al., 2014:77); FDA protects consumers by regulating products that fall within definitions that Congress establishes. Since the 1992 update to the Coordinated Framework was issued, Congress has enacted new statutes affecting FDA’s jurisdiction, including the Dietary Supplement Health and Education Act of 1994 (DSHEA)11 affecting dietary supplements and the Family Smoking Prevention and Tobacco Control Act of 200912 authorizing FDA to regulate tobacco products.
For this discussion, the important FDA-regulated product categories are conventional foods (including various subcategories such as raw agricultural commodities), food ingredients that are generally recognized as safe (GRAS), food additives, medical foods, infant formula, pesticide and environmental contaminants in food, dietary supplements, cosmetics, tobacco products, new animal drugs, and animal food. Appendix D presents the statutory definitions of these terms. Whether a future biotechnology product will be regulated by FDA—and, if so, the specific risk assessment and management tools FDA can apply to that product—is determined by whether the product fits within one of these definitions. FDA makes the threshold decision whether a product fits into one of its regulated product categories, and U.S. federal courts largely—but not always13—defer to FDA’s decisions.
Congress has granted FDA a distinct set of statutory powers to analyze and manage product safety risks for each product category. Table 3-2 summarizes the risk assessments Congress has prescribed for the various FDA-regulated categories. The discussion that follows focuses on a
10 The Federal Trade Commission (FTC) plays a central role in consumer safety through its efforts to ensure that people’s choices are well informed by truthful advertising and risk disclosures, but FTC is not discussed further because FTC does not directly regulate product safety or analyze product risks.
11 Dietary Supplement Health and Education Act of 1994, P.L. 103-417.
12 Family Smoking Prevention and Tobacco Control Act of 2009, P.L. 111-31.
13 See, for example, FDA v. Brown & Williamson Tobacco Corp., 529 U.S. 120 (2000) (rejecting FDA’s assertion that cigarettes could be regulated as a medical device).
TABLE 3-2 Premarket and Post-Market Statutory Risk Assessment for Examples of Different Product Categories Regulated by the U.S. Food and Drug Administration (FDA)
|Product Category||Premarket Risk Assessmenta||Post-Market Risk Assessment|
|Cosmetic||Cosmetics must be safe for their intended use and properly labeled, but no premarket evidentiary review of safety by FDA is required.||FDA regulates cosmetics through post-market risk-assessment processes (e.g., inspections, analysis of samples, and enforcement of its provisions on adulteration and misbranding) and can react to safety problems, but the burden is on FDA to establish that a safety problem exists.|
|Food||Food does not require FDA’s premarket approval, and no premarket evidence of food safety is required. FDA does not review food labels prior to marketing but has regulations that require certain types of information to be disclosed.||Congress authorizes FDA to regulate food safety mainly through post-marketing mechanisms (e.g., inspections, testing, and enforcing adulteration and misbranding standards and good manufacturing practices). FDA bears much of the burden of detecting food-safety problems, but its regulations call for food manufacturers to report certain types of safety incidents to FDA. Once a food-safety problem is detected, FDA has multiple tools to manage the problem (e.g., seizures, injunctions, criminal sanctions, warning letters, and publicity).|
|Food Additive||New food additives cannot be sold until FDA determines they are safe, and product sponsors (manufacturers and distributors) must produce evidence of safety. Ingredients that are generally recognized as safe (GRAS) do not require premarket approval as food additives.||Regulated as food (see above).|
|Dietary Supplement||Manufacturers and distributors (sponsors) must notify FDA 75 days before a new product enters the market. They must include information explaining the basis for concluding that the product is reasonably expected to be safe, but they do not have to await affirmative approval by FDA before marketing the product.||Regulated as food (see above). FDA monitors adverse event information and conducts its own research to monitor safety following approval.|
|Medical Foods||No premarket approval by FDA is required, but any claims in the product’s labeling must be truthful and nonmisleading.||Regulated as food (see above).|
|Infant Formula||FDA does not approve infant formulas before they are marketed, but manufacturers must register with FDA and notify the agency before they introduce a new product, and they must comply with nutrient requirements and other regulations directed at ensuring product safety.||Regulated as food (see above).|
|Tobacco Productb||Manufacturers are subject to registration and product listing requirements. New tobacco products that make claims about modified risks are subject to FDA review and clearance or approval prior to marketing. Authority to regulate tobacco products includes related products such as e-cigarettes.c||FDA can set and enforce standards for adulterated and misbranded tobacco products and can restrict distribution, promotion, and advertising of tobacco products.|
|Product Category||Premarket Risk Assessmenta||Post-Market Risk Assessment|
|New Animal Drug||New animal drugs cannot be marketed until FDA affirmatively approves them. The burden of proof is on the manufacturer to show that the drug is safe and effective for the animal and—for drugs used in food-producing animals—that food products derived from treated animals are safe for consumption.||FDA performs inspections and requires reporting of certain safety problems by sponsors and manufacturers as well as encouraging reporting by veterinarians and animal owners of safety problems with approved animal drugs.d FDA has a broad array of enforcement powers to address safety problems once they are detected.|
|Drug (relevant insofar as it sets boundaries on other product definitions)||New drugs cannot be marketed until FDA affirmatively approves them based on evidence of safety and effectiveness. The burden of proof is on the product sponsor (the manufacturer) to provide evidence of safety and effectiveness, generated at the sponsor’s expense via a three-phase premarket clinical study process that is itself regulated by FDA.||FDA has strong post-marketing regulatory powers and a broad range of tools to evaluate and manage post-marketing safety risks, and can require sponsors to report safety information and, under some circumstances, can require post-marketing studies and clinical trials. FDA has data infrastructure for both passive and active safety surveillance.|
|Device (relevant insofar as it sets boundaries on other product categories)||FDA uses a risk-stratified approach for clearing or approving new devices. High-risk devices must be affirmatively approved by FDA, and manufacturers face evidentiary burdens similar to those required for drugs. Moderate-risk devices must be cleared by FDA prior to marketing, but manufacturers only must show that they are substantially equivalent to a device already on the market. Many low-risk devices are exempt from premarket evidentiary review.||FDA has strong post-marketing powers to detect and manage safety risks, including general controls applicable to all devices plus additional controls aimed at higher-risk devices. Safety surveillance is primarily passive although efforts are under way to develop infrastructure to support active safety surveillance.|
aU.S. Food and Drug Administration. Is It Really FDA Approved? Available at http://www.fda.gov/forconsumers/consumerupdates/ucm047470.htm. Accessed September 30, 2016.
cSottera, Inc. v. FDA, 627 F.3d 891 (D.C. Cir. 2010).
dU.S. Food and Drug Administration. How to Report Animal Drug Side Effects and Product Problems. Available at http://www.fda.gov/animalveterinary/safetyhealth/reportaproblem/ucm055305.htm. Accessed October 3, 2016.
select group of these categories that may pose special risk-assessment challenges or arouse high public concern and concludes with a review of FDA’s role in product-development research. FDA’s regulation of human drugs and medical devices lies outside the scope of this report. Nevertheless, drugs and devices are relevant in two situations: (1) when FDA’s discretionary decision to treat a product as a drug or device removes the product from regulation as a food, food additive, cosmetic, or other FDA-regulated category and (2) when FDA’s discretionary decision to categorize a product as a drug or a device removes the product from CPSC’s jurisdiction.
Cosmetics are “the least intensively regulated of all the products under FDA’s jurisdiction” (Hutt et al., 2014:110). Congressional legislation was proposed in 2016 to strengthen FDA’s framework for cosmetics, but no amendments had been adopted or implemented at the time the committee
was writing its report. Thus, this discussion explores whether FDA could effectively regulate novel biotechnology cosmetics with the powers it had at the start of 2017.
Because its existing framework for cosmetics risk assessment is weak, FDA has regularly used its discretion to deem cosmetics to be drugs or devices. The mere fact that a cosmetic poses a safety risk does not itself place the product within FDA’s drug or device definitions. FDA can, however, regulate a cosmetic as a drug or device if the product sponsor displays intent for the cosmetic to be used for the “cure, mitigation, treatment, or prevention of disease” or if the cosmetic is “intended to affect the structure or any function of the body” (see Appendix D). These concepts are broad enough to encompass many future biotechnology-based cosmetics.
Deeming a cosmetic to be a drug lets FDA require premarket proof of safety and effectiveness and subjects the product to all of FDA’s strong pre- and post-marketing drug regulatory powers. A problem with this approach is that FDA’s drug regulation is not risk stratified; that is, it requires product sponsors to bear the costs and delays of going through FDA’s premarket clinical trial process for all new drugs, regardless of the level of risk they pose. This lack of differentiation could deter the development of innovative cosmetic products. There is no middle ground between FDA’s cosmetic regulation (which provides no premarket regulatory review) and FDA’s drug regulation (which subjects all drugs to the same premarket review process FDA requires for high-risk cancer therapies).
Some biotechnology-based cosmetics may qualify as medical devices rather than drugs. A product can be categorized as a device, rather than a drug, if the product “does not achieve its primary intended purposes through chemical action within or on the body . . . and is not dependent upon being metabolized” (see Appendix D). When applicable, FDA’s device regulations offer a nuanced, risk-stratified review process that could ensure consumer safety with fewer impacts on beneficial innovation.
FDA noted in a 2011 draft guidance that many products lend themselves to characterization either as a drug or a device (FDA, 2011), which will often be the case with future biotechnology products, especially those that achieve their effects at a genomic or microscopic scale where the mode of action could legitimately be characterized as either chemical/metabolic (drug) or mechanical/electrical (device) (Evans, 2015a). This guidance provides FDA with significant discretion to categorize particular products variously as cosmetics, drugs, or devices. Through careful exercise of this discretion, the agency has significant power to position products under the risk-assessment framework best suited to the task of protecting human safety while still fostering beneficial innovation.
Biotechnology Foods, Food Additives, and Dietary Supplements
Food products derived from genetically engineered (GE) or genome-engineered plants and animals (“biotechnology foods”) were already foreseen in the 1980s, and FDA has policies in place to address such products, which were discussed in the 2017 update to the Coordinated Framework (EOP, 2017). Future biotechnology products may include an additional array of new products, for example, synthesized foodstuffs produced directly in industrial and fermentation facilities without the intermediation of plants or animals (such as egg-white protein produced from GE yeast) or cultured food products like yogurt containing GE microorganisms. Some of these future foodstuffs may fit within FDA’s existing policies, but others may present challenges. This discussion examines the flexibility of FDA’s statutes to cope with such products.
Consumer Information. One matter of public concern is whether consumers will receive information to guide their decisions about exposing themselves to biotechnology food. FDA shares responsibility with the other Coordinated Framework agencies to ensure safety of the human food
supply. Food is circularly defined in the FDCA as “articles used for food or drink” and components thereof (see Appendix D). Courts often follow a commonsense approach when assessing whether a product is a food.14 In the early and mid-20th century, FDA aggressively required manufacturers of imitation foods to label their foods as such to prevent consumer deception. Since the 1970s, however, FDA has required substitute or synthetic foods to be labeled as imitations only if they are nutritionally inferior to the food they resemble (Hutt et al., 2014).15 Thus, synthetic biotechnology foods would not be required to disclose “imitation” status if nutritional equivalency is established.
With respect to foods derived from GE plants, FDA does not consider the mere fact of a modification to be a “material fact” that must be disclosed in food labeling,16 even if consumers have a strong desire to know. FDA requires disclosure only if there is a food quality or safety issue, and FDA bears the burden of substantiating such issues (FDA, 1992).17 Thus, FDA’s food labeling statutes do not ensure consumers will be informed when they are exposing themselves to biotechnology food products.
In July 2016, President Obama signed a bill amending the Agricultural Marketing Act of 1946 to require USDA to establish labeling requirements for food products containing bioengineered or genetically modified organisms (Fama, 2016). Labeling would apply to many, but not necessarily all, types of future biotechnology food. Legal commentators have noted that the law may not cover some bioengineered foods, for example, foods that are the product of genetic deletions (Elliott, 2016). USDA was given 2 years to promulgate regulations and determine the thresholds for biotechnology-derived ingredients in food that would trigger a disclosure requirement. Once promulgated, these federal regulations will preempt the biotechnology food labeling requirements that some states have enacted.
Premarket Safety Review. A second matter of public concern is whether biotechnology-derived foods will receive premarket safety review. FDA regulates food safety mainly through post-marketing mechanisms, such as inspections, testing, issuing good manufacturing practice regulations, and enforcing FDA’s prohibitions on commerce in adulterated and misbranded foods. Once a safety problem is detected with a marketed food product, the agency has strong enforcement tools such as product seizure, injunctions, civil and criminal sanctions, or issuing warnings and publicity. However, FDA bears much of the burden to detect food-safety problems, although the FDCA imposes some duties for food manufacturers and suppliers to report safety issues under some circumstances.
As a general matter, FDA does not subject food to any premarket safety review or require manufacturers to submit evidence of safety before new products can be sold. The FDCA does, however, define several subcategories of food—medical foods, infant formula, food additives, and dietary supplements—that are subject to special regulatory requirements. For food additives and dietary supplements, at least some premarket evidence of safety is required:
- Food additives. New food additives cannot be sold until FDA determines they are safe, and product sponsors must produce evidence of safety and await FDA approval before they can be marketed. Ingredients that are GRAS do not require premarket approval as food additives. The FDCA provides a strong evidence-forcing mechanism that places the burden
14 See, for example, Nutrilab, Inc. v. Schweiker, 713 F.3d 335 (7th Cir. 1983) (discussing the statutory definition of food).
15 See also Federal Food, Drug, and Cosmetic Act § 403(c), 21 U.S.C. § 343(c) (providing that “a food shall be deemed to be misbranded if it is an imitation of another food unless its label bears, in type of uniform size and prominence, the word ‘imitation’ and, immediately thereafter, the name of the food imitated”) but see 21 C.F.R. § 101.3(e) (focusing FDA’s inquiry on whether a substitute food is nutritionally inferior).
16 21 U.S.C. § 321(n).
17 See also Alliance for Bio-Integrity v. Shalala, 116 F.Supp.2d 166 (D.D.C. 2000).
- of proof on food additive manufacturers to prove their food additives are safe. FDA’s 1992 Statement of Policy on Foods Derived from New Plant Varieties (FDA, 1992) deemed foods from GE plants to be GRAS, thus ceding the agency’s strong statutory evidence-forcing mechanism with regard to biotechnology foods, including food additives produced through biotechnology. FDA reasoned that the addition of genetic material (nucleic acids) to foods is GRAS because nucleic acids already exist in all plant and animal foods used by humans. Concerns could arise only if the added genetic material expresses a protein or substance that differs significantly from substances already found in the food. Thus, this GRAS presumption is rebuttable, and FDA can still require a sponsor to submit a food additive petition and require premarket approval if the genetic manipulation transfers genes from a species that is a known food allergen or causes the food product to contain a novel protein that arouses safety concerns. Without an evidence-forcing mechanism, however, the burden is largely on FDA to develop evidence with which to rebut its GRAS presumption. FDA has implemented a process for voluntary consultation prior to market entry for such products (FDA, 1997) and reports wide industry adherence to the process (EOP, 2017).
- Dietary supplements. Manufacturers wishing to market “new” dietary ingredients (that is, ingredients not already marketed in the United States before 1994 and which have not previously been in the food supply as articles used for food without chemical alteration) must give notice to FDA at least 75 days before introducing the product. This notice must include information that supports the conclusion that a supplement containing the ingredient can reasonably be expected to be safe (Levitt, 2001). This evidence-forcing mechanism requires sponsors to provide some evidence of safety, but they do not have to await affirmative approval by FDA before marketing the product once the 75-day notice period has expired, which “makes it essential for public health protection that FDA have the resources to review the notifications in a timely manner” (Levitt, 2001). Once on the market, a dietary supplement is subject to FDA’s broad prohibition on the sale of adulterated food. A supplement is considered adulterated if it (or one of its ingredients) presents “a significant or unreasonable risk of illness or injury” when used in accordance with its label, or under normal conditions of use if there are no directions in its label. “The burden of proof is on FDA to show that a product or ingredient presents such a risk” (Levitt, 2001).
Even though there is no general requirement for FDA premarket safety review of food, the statutes just described allow at least some premarket safety review of food additives and dietary supplements. FDA thus has various tools, under its existing statutes, to address safety concerns that novel biotechnology food products may present in the coming 5–10 years. First, if FDA determines that it needs to adapt its 1992 policy and consultation process for food derived from GE or genome-engineered plant varieties, the agency can do so without any further congressional action. Second, the 1992 policy, which deemed many biotechnology foods to be GRAS, only applies to foods derived from GE plant varieties. Some of the new biotechnology foods coming to market may lie outside that policy and, thus, outside the 1992 GRAS presumption. For example, a synthesized spice or flavoring ingredient or a synthetic egg used as an ingredient in processed foods may fit within FDA’s general definition of a food additive (see Appendix D), requiring a food additive petition and premarket safety review. The 1994 DSHEA defines dietary supplements as including, in addition to vitamins and minerals, “a dietary substance for use by man to supplement the diet by increasing the total dietary intake” (see Appendix D, 21 U.S.C. § 321(ff)(1)(e)). This broadly worded clause may allow FDA to treat some novel biotechnology foods as dietary supplements, requiring sponsors to notify FDA of their plans to market the product and explain their basis for concluding that the
product can reasonably be expected to be safe. FDA thus has various existing tools for fashioning case-by-case solutions that protect consumer safety without unduly burdening innovation.
Validity of Nutritional and Health Claims. FDA regards safety as a balance of benefits and risks. If false or unsubstantiated claims about nutritional and health benefits are made about biotechnology food products, this potentially poses a consumer-safety risk. An important part of risk assessment, therefore, is to ensure that any nutritional and health claims about biotechnology foods are accurate—or, if they are scientifically uncertain, to ensure the uncertainty is properly disclosed. FDA has several ways to protect consumers from false or misleading claims about foods and dietary supplements, including those that are derived from or produced through biotechnology.18 First, the 1990 Nutrition Labeling and Education Act (NLEA) authorized FDA to review evidence to support health claims about foods and dietary supplements. Product sponsors can submit a health claim petition to FDA and supply evidence to support the claim, or FDA can initiate a review on its own. Second, the 1997 Food and Drug Administration Modernization Act allows health claims that are supported by an authoritative statement by the National Academy of Sciences or a scientific body of the U.S. government with responsibility for public health protection or nutrition research. Food and supplement manufacturers can make such claims after a 120-day notification to FDA, unless FDA indicates the notification is deficient. There is a third pathway for claims that do not meet FDA’s “significant scientific agreement” standard for validity of health claims. The First Amendment prevents FDA from blocking such claims entirely, but FDA can require disclosure that the claims are uncertain. FDA has published guidance about appropriate disclosures (FDA, 2003). Finally, FDA has authority to deem a food or supplement to be a drug if the product makes therapeutic claims that display the sponsor’s intent to market the product as a drug (see Appendix D). By enacting NLEA and DSHEA, Congress struck a balance between safety and innovation that constrains FDA’s authority to subject foods and dietary supplements to the full rigor of FDA’s premarket drug-approval process.19 Still, the agency is not without power to deem a novel biotechnology product to be a drug if the claims made about it and other circumstances make that course appropriate. Thus, FDA has multiple risk-assessment tools available to protect consumers from false or misleading claims about the health benefits of new biotechnology foods.
Summary of FDA’s Authorities for Food-Safety Risk Assessment. The trends identified in Chapter 2 present challenges and counsel a need to ensure that FDA’s Center for Food Safety and Applied Nutrition and Center for Veterinary Medicine receive adequate resources for the task ahead. Some of these trends, such as accelerated product development and increased scale of new product entry, may affect the volume of workload. The premarket notification framework of the dietary supplement statute, as noted above, only protects consumers if FDA is adequately staffed to review and respond to notifications in a timely way.
An additional concern is the growth of do-it-yourself biology (DIYbio), small-scale, and decentralized product development. FDA’s safety oversight framework relies, in substantial part, on having compliance-oriented regulated companies that can meet the agency halfway in ensuring consumer safety. In future years, FDA may face the challenge of regulating small product developers that lack internal regulatory compliance resources and require an added level of consultation and education by the agency. For example, will FDA’s voluntary consultation process for GE crops and food derived from GE crops, which has attracted a high level of participation by traditional manufacturers, elicit similar rates of participation by individual DIYbio and small manufacturers? Will
18 U.S. Food and Drug Administration. Label Claims for Conventional Foods and Dietary Supplements. Available at http://www.fda.gov/food/ingredientspackaginglabeling/labelingnutrition/ucm111447.htm. Accessed September 30, 2016.
19 As noted by Hutt et al. (2014:103), “the most important aspect of DSHEA is that it permits a dietary supplement to make a structure/function claim without rendering itself a food, even if the supplement is not a ‘common sense’ food.”
FDA’s traditional inspection processes be strained as a growing decentralization of food-product development allows individual growers to harness DIYbio to modify their own small crops? Additional outreach and leveraging of FDA’s own regulatory resources—including but not necessarily limited to measures already envisioned in the 2017 update to the Coordinated Framework—will be important to meet such challenges.
FDA currently regulates most GE animals under the FDCA’s new animal drug provisions by treating genetic material that is integrated into the animal as a new animal drug (FDA, 2015a, 2017a).20 FDA’s new animal drug risk assessment considers a drug’s safety and effectiveness to the animal and, in the case of food-producing animals, whether food derived from the animal is safe for consumption. The 2017 update to the Coordinated Framework describes FDA’s programs for protecting consumers from risks from eating food derived from GE animals (EOP, 2017).
Biotechnology-altered animals of the future may include nonfood animals, such as pets or species brought back from extinction. In addition to environmental risks, these animals may pose consumer-safety risks. For example, a biotechnology-altered pet could have altered susceptibility to zoonotic diseases or aggressive traits that pose injury risks to humans. According to the FDCA, the term safe, as used in the new animal drug provisions, “has reference to the health of man or animal.”21 While this is sometimes conceived as an authority merely to ensure the safety of foods derived from food-producing animals, it actually carries a broader authority to consider human-safety impacts of new animal drugs. Thus, if an alteration to an animal results in human risks that go beyond food-safety risks, FDA has authority to take these other risks into account as part of a user-safety evaluation.
The specific risks are, however, difficult to foresee in advance and a critical dimension of consumer protection is to have robust post-marketing systems for prompt detection of emerging problems and rapid response if they arise. FDA and CDC share authorities under the Public Health Service Act, unrelated to FDA’s regulation of new animal drugs, that empower them to respond to outbreaks of communicable diseases caused by familiar and exotic species. An example was their coordinated response to an outbreak of monkeypox caused by traffic in exotic species in 2003 (Crawford, 2003). The first line of defense is CDC’s regular public health surveillance activities, which monitor communicable disease outbreaks, including zoonotic diseases, and which also monitor injuries to humans caused by animals (CDC, 2003). FDA and CDC then have powers to coordinate a response to protect the public. Upon detecting the monkeypox outbreak, FDA and CDC issued a joint order to other federal agencies, including the U.S. Department of Transportation, and to state agriculture and health agencies including state and public health veterinarians and state fish and wildlife officials, among others (Crawford, 2003).
A more speculative concern is the possibility that biotechnology might be used to engineer deleterious traits into animals or that deleterious traits might be introduced as a side effect of genetic manipulation. CDC, joined by the American Society for the Prevention of Cruelty to Animals,22 has taken the position that species- or breed-specific regulations (for example, regulation of pit bulls) are an ineffective way to address problems such as human injuries caused by animals. They suggest that a more effective approach is to address underlying societal concerns, such as the existence of industries (for example, dog fighting) that promote the inappropriate enhancement of deleterious
20 In addition to FDA’s authority to regulate new animal drugs under the Federal Food, Drug, and Cosmetic Act, USDA has authority to regulate biologic medicines used in animals under the Virus-Serum-Toxin Act of 1913 and related statutes.
21 21 U.S.C. § 321(u).
22 See American Society for the Prevention of Cruelty to Animals, Breed Specific Legislation. Available at http://www.aspca.org/animal-cruelty/dog-fighting/what-breed-specific-legislation. Accessed September 30, 2016.
traits in animals. For animals that are the products of biotechnology, a similar approach may be appropriate: protecting the public will require an appropriate dedication of resources for CDC to conduct surveillance for rapid detection of animal-related injuries as well as zoonotic disease outbreaks traceable to new varieties of biotechnology-altered animals. If signals of a problem are detected, FDA, CDC, and other state and federal agencies have powers to address them through existing legal approaches. Underlying social problems that may cause people to engineer animals for inappropriate goals will need to be tackled directly using means such as publicity, education, and public engagement to forge consensus around norms that protect animals as well as the people exposed to them.
FDA regulates new drugs and devices as an Investigational New Animal Drug (INAD),23 Investigational New Drug (IND),24 or Investigational Device Exemption (IDE)25 to allow the agency to restrict the distribution and use of unapproved animal drugs, human drugs, and medical devices. Human drug and device regulation is outside the scope of this report, yet these regulations deserve mention for two reasons. First, as already discussed, the definitional lines are such that some cosmetics, foods, and other consumer products may, at times, fall within FDA’s drug or device definitions. When this is so, product-development research may lie within the reach of the IND and IDE regulations. Second, the INAD, IND, and IDE regulations may have growing importance in the face of a trend, described in Chapter 2, toward diversification of the financing sources for biotechnology-product development. Diffusion of research to DIYbio and smaller, noninstitutional research settings potentially may move research outside the centralized, NIH-led research oversight process that has been a central pillar of the Coordinated Framework.
The NIH guidelines detail safety practices and containment procedures for basic and clinical research involving recombinant or synthetic nucleic acid molecules, including the creation and use of organisms and viruses containing recombinant or synthetic nucleic acid molecules. The NIH guidelines apply to research funded by NIH and various other federal agencies but are voluntarily followed by some other research organizations. Even when the 1992 update to the Coordinated Framework was first published, contemporary commentators expressed concern about the possibility that “unregulated organisms” might fall outside USDA and EPA’s authorities and might also escape the NIH guidelines if developed at a research institution or with funding not subject to those guidelines. The evolving structure and financing of biotechnology research refresh this concern.
FDA’s INAD, IND, and IDE regulations offer potentially important pathways to ensure appropriate federal regulatory oversight of some categories of research that may fall outside the NIH guidelines. For example, FDA’s IND and IDE regulations define “sponsor-investigators” as individuals who both initiate and conduct (alone or with others) an investigation and under whose direction the experimental product is administered, dispensed, or used.26 Many at-home or DIYbio enthusiasts fit within this concept. Sponsor-investigator studies are thought to present special risks to humans exposed to non-FDA-approved products because merging the sponsor and investigator roles removes a layer of checks and balances that ordinarily exist in research (TPG, 2005). Because of this concern, FDA’s training materials suggest that an FDA-approved IDE or IND may be required for any sponsor-investigator study of an unapproved product, “even if no marketing application is planned” (Henley, 2013)—that is, even if the sponsor-investigator has no plans to commercialize the product for wider sale. The structure and function clauses of FDA’s drug and
23 21 C.F.R. § 511.1.
24 21 C.F.R. § 312.
25 21 C.F.R. § 812.
26 21 C.F.R. § 812.3(o) [devices]; 21 C.F.R. § 312.3 [drugs].
device definitions, as already discussed, grant the agency significant authority to deem products to be investigational drugs or devices if they are intended to affect the structure or function of the body (see Appendix D). Requiring at-home and DIYbio enthusiasts to obtain an IND or IDE for certain categories of research is one possible mechanism to ensure that the protocols and human-subject protections receive external oversight by FDA (Evans, 2015b). Statutory authority thus may exist for FDA to oversee some categories of at-home and DIYbio experiments that otherwise threaten to escape federal research oversight. This role would, however, imply a significant expansion of workload for FDA and would require an appropriate expansion of staffing and resources.
Consumer Product Safety Commission and the U.S. Food and Drug Administration
The growing list of product categories potentially transformed by biotechnology requires a discussion of how FDA’s consumer product regulation interacts with CPSC’s regulatory role. The CPSC has jurisdiction over “consumer products,” which broadly encompass articles sold and distributed to consumers.27 The statutory definition of CPSC-regulated products expressly excludes products regulated by FDA, EPA, and USDA. CPSC’s jurisdiction to regulate biotechnology consumer products thus is a residual, gap-filling jurisdiction over products that fail to fall under the jurisdiction of other Coordinated Framework agencies. CPSC does not regulate pesticides,28 tobacco products,29 drugs, devices, or cosmetics subject to FDA regulation,30 or food.31 As a result, FDA’s decisions about whether products fit into its own jurisdiction can have the effect of shrinking or expanding the list of products that CPSC regulates.
A frequently discussed example is FDA’s power to deem a product to be a medical device if it is “intended to affect the structure or any function of the body of man or other animals” (Appendix D, 21 U.S.C. § 201(h)(3)). Construed broadly, this definition would allow FDA to assert jurisdiction over a wide range of consumer products like air conditioners, shoes, and sporting goods that arguably affect the structure and function of the human body. FDA has traditionally construed the definition narrowly, limiting itself to products that have a medical or therapeutic impact and leaving other products to CPSC. Nevertheless, a former FDA chief counsel stated that “if Section 201(h)(3) of the [FDCA] were interpreted to give FDA jurisdiction over any product foreseeably having an effect on the structure or a function of the body, then regulatory authority would shift from the CPSC to FDA for a host of non-health-related products.”32
This fact may provide a useful safety valve, working within existing statutes, to protect consumer safety as the array of new biotechnology products expands to encompass household goods, computing products, clothing, cosmetics and personal care products, recreational products and
27 See 15 U.S.C. § 2052(a)(5), providing, “The term ‘consumer product’ means any article, or component part thereof, produced or distributed (i) for sale to a consumer for use in or around a permanent or temporary household or residence, a school, in recreation, or otherwise, or (ii) for the personal use, consumption or enjoyment of a consumer in or around a permanent or temporary household or residence, a school, in recreation, or otherwise.”
28 15 U.S.C. § 2052(a)(5)(D), excluding pesticides as defined by the Federal Insecticide, Fungicide, and Rodenticide Act, 7 U.S.C. § 136 et seq.
29 15 U.S.C. § 2052(a)(5)(B). See P.L. 111-31 (Family Smoking Prevention and Tobacco Control Act of 2009) placing tobacco products under FDA’s jurisdiction.
30 15 U.S.C. § 2052(a)(5)(H), excluding drugs, devices, and cosmetics as defined in section 201(g), (h), and (i) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 321(g), (h), and (i).
31 15 U.S.C. § 2052(a)(5)(I), excluding food as defined in section 201(f) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 321(f); excluding poultry and poultry products as defined in section 4(e) and (f) of the Poultry Products Inspection Act, 21 U.S.C. § 453(e) and (f); excluding meat, meat food products as defined in section 1(j) of the Federal Meat Inspection Act, 21 U.S.C. § 601(j); and excluding eggs and egg products as defined in section 4 of the Egg Products Inspection Act, 21 U.S.C. § 1033.
32 See letter from Daniel E. Troy, FDA Chief Counsel, to Jeffrey N. Gibbs, concerning Applied Digital Solutions VeriChip products (Oct. 17, 2002), reprinted in Hutt et al. (2014:125–128).
toys, and pet-care products. Scholars question whether CPSC has an adequate set of statutory tools under the Consumer Product Safety Act to cope with future biotechnology consumer products (see, for example, Lin, 2013). CPSC’s authorities are weak, with heavy reliance on information disclosure and standard setting as tools of consumer protection. The agency first must rely on voluntary standards but can impose mandatory safety standards when “reasonably necessary” to address unreasonable consumer safety risks,33 and CPSC ultimately can ban a dangerous product (Lin, 2013). The “reasonably necessary” threshold for taking mandatory action places CPSC under a burden to develop evidence of a safety problem before it can act—a burden “at least as difficult to meet as the standards imposed by the [pre-2016] TSCA” (Lin, 2013:92). CPSC has no authority to require premarket safety testing and generally finds itself in a reactive posture of responding to reports of product-related injuries after products already are in wide use. Commentators also express concern about CPSC’s resources and expertise to regulate products incorporating new and emerging technologies (Felcher, 2008).
A broad reading of FDA’s product definitions offers a potential pathway—under existing statutes—to bring high-risk biotechnology consumer products under FDA’s jurisdiction on a case-by-case basis. FDA could continue to interpret its definitions conservatively, as it has been doing, with respect to traditional products, but might justify a broader reading for novel biotechnology consumer products where CPSC’s risk-assessment tools are inadequate to protect the public. FDA does not, of course, have unlimited discretion to deem a product to lie within FDA’s jurisdiction; the product must reasonably fit into one of the available FDA product categories (see Appendix D). However, as Hutt et al. (2014:125) noted, the full breadth of the structure and function clause of FDA’s device definition “remains an open issue.” FDA thus may have unutilized authority to expand its reach to protect the public from novel biotechnology consumer products that call for more risk assessment than CPSC is able to provide.
Occupational Safety and Health Administration
Many future biotechnology products are intended not as final consumer products but instead would be used as means of production in diverse industrial, commercial, and agricultural settings. Such products may pose risks primarily to workers rather than to consumers of the final marketed products, in which case OSHA would be the primary safety regulator. As previously discussed, EPA shares jurisdiction with OSHA to regulate occupational safety, and OSHA was part of the 1986 Coordinated Framework. When the Coordinated Framework was originally developed in 1986, OSHA concluded that it had an adequate and enforceable basis to protect the safety and health of biotechnology workers under the general duty clause, which requires employers to provide a place of employment that is “free from recognized hazards that are causing or likely to cause death or serious physical harm.”34
Several concerns surround OSHA’s ability to regulate the safety of industrial biotechnology applications (Lin, 2013). OSHA has authority to set and enforce standards for workplace safety by setting permissible exposure limits (PELs) for hazardous materials and by establishing measures (for example, requiring protective equipment or engineering controls) to help comply with PELs.35 However, key court decisions, by placing the burden of proof on OSHA, including the quantification of risk, have made it difficult for OSHA to set standards in situations where there is uncertainty
33 15 U.S.C. § 2057.
34 See Section 5(a)(1) of the Occupational Safety and Health Act (29 U.S.C. § 651 et seq.) (29 U.S.C. § 654(a)(I), see also §§ 651–678).
35 29 U.S.C. § 655(b)(5), (7).
or limited information about the potential risks, as will often be the case when regulating future industrial biotechnologies.36
Another concern is whether the processes required by the Occupational Safety and Health Act may be too cumbersome to support nimble response to emerging risks. For example, with regard to nanomaterials in the workplace, some commenters have questioned whether the formal process of establishing exposure limits “could overwhelm” the capabilities of the National Institute for Occupational Safety and Health and OSHA (Bartis and Landtree, 2006). Because of these various judicial, procedural, and political constraints, some commenters feel that regulation under the Occupational Safety and Health Act will have difficulty protecting workers effectively from risks related to novel biotechnology products (Mendeloff, 1988; Shapiro and McGarity, 1989; Lin, 2013).
In summary, the Supreme Court interprets the Occupational Safety and Health Act as placing the burden of proof on OSHA, and OSHA’s process of setting exposure limits is, by law, procedurally cumbersome. Existing statutes thus may make it difficult for OSHA to respond nimbly to new risks arising in the biotechnology-enabled workplace of tomorrow, and this concern is exacerbated when there is uncertainty or incomplete information about emerging risks.
U.S. Environmental Protection Agency
As discussed above, EPA’s authority as it relates to consumer and occupational safety is granted under FIFRA, FDCA, and TSCA. EPA regulates consumer safety with respect to pesticides and pesticide residues in food37 and occupational safety with respect to uses of pesticides in the workplace under FIFRA. TSCA straddles the boundaries among consumer-safety, occupational-safety, and environmental regulation, promoting all three objectives. A key point is that the regulation of “new chemical substances” described by TSCA before the commercialization of biotechnology products now includes biotechnology products, such as GE and genome-engineered organisms (EPA, 1997). TSCA authorizes EPA to regulate a diverse array of consumer, commercial, and industrial biotechnology products, to the extent these are not otherwise regulated by FDA or by EPA under FIFRA. EPA regulates the importation, production, distribution, use, and disposal of “new chemical substances,” with the goal of protecting human health and the environment from unreasonable risk of injury. As enacted in 1976, the “old” TSCA had defects that caused it to be widely viewed as a dysfunctional risk-assessment framework (Culleen, 2016; Rothenberg et al., 2016). It provided for premarket notification of new chemical substances and certain significant new uses of chemicals. Products did not have to await affirmative approval and could enter the market unless EPA could bear the evidentiary burden of finding significant risk. EPA could require manufacturers to test chemicals for health and environmental effects, but EPA was hamstrung by a requirement to use notice-and-comment rulemaking (a cumbersome and slow procedure) to require such testing (Duvall et al., 2016). Moreover, the 1976 TSCA circularly required EPA to develop evidence that a chemical posed a risk before the agency could require manufacturers to conduct testing to discover what the risks were.38 EPA could require periodic reporting of certain information, but TSCA protected the confidentiality of trade secrets in ways that blocked information flows that could have informed the public and enhanced public safety (Culleen, 2016). The 1976 TSCA
36Industrial Union Department, AFL-CIO v. American Petroleum Institute (448 U.S. 607 (1980)) placed the burden of proof on OSHA to show that regulation is “reasonably necessary and appropriate to remedy a significant risk of material health impairment” before it can promulgate a new standard. That case held that OSHA needed to quantify the risk of and show that it surpassed a numerical threshold of significance before OSHA could justify regulating a known carcinogen, benzene.
37 Federal Food, Drug, and Cosmetic Act § 408, codified at 21 U.S.C. § 346a.
38 Environmental Defense Fund. A new chemical safety law: The Lautenberg Act. June 22, 2016. Available at https://www.edf.org/health/new-chemical-safety-law-lautenberg-act. Accessed January 31, 2017.
had provisions to preempt state regulation, but they were seldom used because EPA did not enact many regulations under the original TSCA. The act’s principal risk management provision (Section 6) was so unworkable that EPA proposed no rulemakings under it after a court invalidated EPA’s attempt to regulate asbestos in 1991 (Duvall et al., 2016). As a result, some states implemented more stringent protections, resulting in nonuniform requirements that have been burdensome for business and innovation (Rothenberg et al., 2016).
The 2016 TSCA amendments seek to improve the risk-assessment framework. They expand EPA’s authority under Section 5 of TSCA to order testing to review premarket notifications or notices of significant new uses—providing a more workable evidence-forcing mechanism than the past requirement to use rulemaking. They require EPA to make an affirmative determination that new chemicals do not present unreasonable risk of injury before they can enter commerce. The amendments also strengthen EPA’s post-market authorities. They call on EPA to conduct a risk evaluation of all chemicals already existing in commerce and allow the agency to do so without first having to make legal findings that, in the past, impeded such review. The amendments tasked EPA to quickly (within a few years) promulgate regulations to govern the risk-evaluation process and to identify high-priority substances (10 within 6 months and 20 within 3.5 years) for evaluation. Once initiated, evaluations must be completed in 3 years. The statutory standard for evaluation has been modified to focus on risks of injury to humans or the environment, without having to balance costs or benefits. At the point of deciding how to manage risks, however, costs and benefits can be considered, and the earlier requirement to adopt the “least-burdensome” regulatory restrictions has been eliminated. The amendments allow EPA to collect higher fees to defray up to 25 percent of the costs of the new programs. They also promote greater transparency by allowing EPA to share confidential business information with state and tribal governments, health and environmental professionals, and first responders, although the security procedures required of recipients may still limit transparency. They implement a partial preemption scheme that grandfathers some past state laws and regulatory actions—thus leaving some ongoing lack of uniformity but moving to a higher level of uniformity prospectively.
The effects of the 2016 TSCA amendments will be felt during the 5–10-year time frame addressed in this report, but it would be incorrect to assume a sudden transformation. The roster of companies affected by TSCA will expand from traditional chemical manufacturers and processors to “potentially any manufacturer that incorporates chemicals in its products,” such as manufacturers of personal care products, automotive components, computer and electronics, toys, and clothing (Sidley, 2016). Thus, developers of biotechnology-derived chemicals will feel the effects of the amended TSCA, but the question is how soon. Legal commentators caution that “it may take years for EPA to fully implement the amended law’s numerous new requirements” (Culleen, 2016). At the time the committee was writing its report, key parameters still had to be worked out in series of rulemakings that were likely to span several years. Attorneys suggested that “the industry should carefully monitor new EPA regulations and decisions that may warrant judicial review” (Sidley, 2016), raising the prospect of legal challenges that could delay implementation further.
Commentators also expressed concern that TSCA’s new fees and enhanced premarket review requirements could adversely affect innovation by slowing the time to market for new products, “given how few people EPA has working in the new chemicals program, and how overwhelmed they are already” (Culleen, 2016). Appropriate staffing and resources are thus crucial, both to reap the full benefits that the 2016 amendments offer and to avoid regulatory bottlenecks that threaten to slow innovation as the flood of new products anticipated in Chapter 2 confronts TSCA’s new premarket-notification requirements.
U.S. Department of Agriculture
USDA’s authority for consumer safety39 rests within the Federal Meat Inspection Act,40 the Poultry Products Inspection Act,41 and the Egg Products Inspection Act.42 Pursuant to these statutes, USDA’s Food Safety and Inspection Service (FSIS) inspects meat, poultry, processed eggs, and certain fish moving in interstate commerce. USDA and FDA have a long history of coordinating their complex shared jurisdiction to regulate food safety. Thus, for example, FDA has exclusive regulatory jurisdiction over live animals intended to be used for food, but USDA oversees slaughter and processing of meat and poultry, and USDA has ceded jurisdiction to FDA for food products containing less than 2 percent of meat and poultry content (Hutt et al., 2014). The agencies also coordinate with respect to food products that fall within their shared jurisdiction, which would continue under the 2017 update to the Coordinated Framework (EOP, 2017). According to that update, FDA will apprise FSIS of reviews concerning the safety of meat, poultry, eggs, and fish of the Order of Siluriformes from GE animals if there is intent to use the animals for food production. FDA also will advise FSIS about FDA’s assessments concerning the safety of substances added to food animals via genetic engineering. FSIS will evaluate whether the addition of such substances is permissible under its own statutes and will communicate with the public and other stakeholders. Synthetic food products, such as synthesized meat and eggs produced without the intermediation of animals, appear to fall outside the definitions of non-GE meat and egg products that FSIS regulates and responsibility for the safety of such products would lie primarily with FDA.
U.S. Environmental Protection Agency
EPA regulates the sale, distribution, and use of pesticides under FIFRA, and these responsibilities include products produced through biotechnology. Thus, a plant-incorporated protectant (for example, a Bt toxin) is subject to EPA’s pesticide regulations. EPA regulates the market entry of new pesticides by requiring registration of new products. Registration requires an evidence-based premarket review in which product sponsors submit evidence to demonstrate that the product will not cause unreasonable adverse effects on the environment under its proposed conditions of use. EPA facilitates the development of information to support product registration by allowing unregistered products to be field tested under Experimental Use Permits (EUPs). EUPs allow limited distribution and use of the product, under EPA oversight, for the purpose of generating data to support product registration. EPA can register products with unrestricted or restricted use or marketing based on the determined potential risk, and it has the authority to address concerns that arise after a product is already on the market.
Under TSCA, EPA has the authority to regulate the commercial use of intergeneric microorganisms, which are formed from organisms in different genera or with synthetic DNA not from
39 USDA does not have authority to address occupational safety.
40 21 U.S.C. § 601 et seq.
41 21 U.S.C. § 451 et seq.
42 21 U.S.C. § 1031 et seq.
43 FDA is not directly involved in environmental regulation. Thus, for example, FDA only regulates biopharming—the modification of plants to express pharmaceutical products—to ensure that the resulting drug products are safe and effective. Regulating the uncontained testing and use of the modified plant itself is the responsibility of USDA.
TABLE 3-3 Environmental Protection Responsibilities of the U.S. Environmental Protection Agency (EPA) and the U.S. Department of Agriculture (USDA) for Biotechnology Products
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)
Federal Food, Drug, and Cosmetic Act (FDCA)
EPA approves small-scale field trials and commercialization. Pesticides cannot have “unreasonable adverse effects on the environment”; as defined by FIFRA, this means “any unreasonable risk to man or the environment, taking into account the economic, social, and environmental costs and benefits of the use of any pesticide.” This analysis is based on explicit risk–benefit tradeoffs; when any significant hazard is identified (which has been rare for biotechnology pesticides such as plant-incorporated protectants or microbial pesticide products), analyses include economic benefits and comparisons to current pesticides, how they are used, and their environmental effects.
Post-market oversight is strong with monitoring and reporting requirements, and by statute, products must be reevaluated at least every 15 years; however, EPA has been reevaluating biotechnology products every 5–6 years. EPA also has the flexibility under FIFRA to reassess a registration decision at any time if new information suggests the probability of adverse effects may be greater than what was originally estimated.
|EPA||Intergeneric microorganism||Toxic Substances Control Act (TSCA)||
For field trials, product developers submit a TSCA Environmental Release Application for approval. The product cannot have “unreasonable risk of injury to human health or the environment.” This analysis is based on risk–benefit tradeoffs. If some hazard is identified (which has been rare in EPA’s experience as of 2016), then the risks relating to that hazard are quantified and compared with expected benefits. Such benefits can include economic analyses and environmental benefits accrued from replacing previous generations of technology. EPA is time-limited to 60 days for its analysis, but product developers often agree to a time extension to gather necessary data.
For commercial use, a product developer submits a Microbial Commercial Activity Notification. EPA then must find that the product has “unreasonable risk” or the product will move forward after 90 days. Again, product developers often agree to a time extension.
Once a microorganism is in commerce, the manufacturer is required to report any adverse-effect information through Section 8(e) of TSCA.a
|EPA||New chemical (including some RNAi)||TSCA||
For commercial use, a product developer submits a PreManufacture Notice. EPA then must find that the product has “unreasonable risk” or the product will go to market after 90 days. If environmental exposure is likely, EPA has certain data requirements that must be met.
Once a chemical is in commerce, the manufacturer is required to report any adverse-effect information through Section 8(e) of TSCA.a
|USDA–APHIS||Plant pest or regulated article (GE plant)||Plant Protection Act||
Products are regulated by USDA–APHIS while under experimentation and can subsequently be deregulated for unconfined release, which for many types of products is a necessary practical step for commercial use. Permitting for a field trial requires that the organism is adequately confined in transport or field environments so that it is unlikely to spread or cross with native species and does not pose concerns for threatened or endangered species. For pharmaceutical-producing crops, USDA–APHIS has explicit guidance for permitted field trials.
A product developer submits a petition for deregulation, providing evidence that the article shows no more of a plant-pest risk than an equivalent non-GE organism; it needs to be unlikely to pose a plant-pest risk. This analysis is based only on risk.
Once a product has been deregulated, there is virtually no post-market monitoring or oversight. However, some products remain under permit even when commercialized (e.g., plants that produce pharmaceuticals) and in those cases, USDA–APHIS maintains oversight.
aReporting a TSCA Chemical Substance Risk Notice. Available at https://www.epa.gov/assessing-and-managing-chemicals-under-tsca/reporting-tsca-chemical-substantial-risk-notice. Accessed September 14, 2016.
SOURCE: Based on a white paper prepared for the committee by S. Carter, Science Policy Consulting, 2016, which is available upon request from the National Academies’ Public Access Records Office at PARO@nas.edu.
the same genus. Examples would be algae engineered to produce biofuels or microorganisms engineered to extract metal from ore. TSCA grants EPA the authority to test and assess potential risks of the microorganism before it is brought to market. At the time the committee was writing its report, EPA had reached agreements with all product developers for regulated products the use or marketing of which the agency decided to restrict in some way. EPA has the authority under the amended TSCA to reevaluate a previously approved product; however, it is not clear how high biotechnology products will be prioritized compared to other chemicals for which EPA may wish to conduct reevaluation.
U.S. Department of Agriculture
USDA’s Animal and Plant Health Inspection Service (APHIS) regulates biotechnology products under the Plant Protection Act (PPA), which protects plants and plant products from plant pests and noxious weeds, and under the Animal Health Protection Act (AHPA), which regulates products
that are pests to or could cause disease in livestock. Less relevant to this discussion is that veterinary biologics are subject to regulation by USDA rather than by FDA under the Virus-Serum-Toxin Act.
With regard to the Plant Protection Act, USDA–APHIS oversight extends to those biotechnology plants that have been genetically engineered using a donor organism, a recipient organism, or a vector or vector agent that is listed in 7 C.F.R. Part 340 and meets the definition of a plant pest. The agency’s oversight also applies to an unclassified organism or one whose classification is unknown. Oversight extends to products that contain an organism produced through genetic engineering via the use of a plant pest.44
Under the Animal Health Protection Act (7 U.S.C. § 8302), USDA–APHIS has oversight authority for biotechnology products that could directly or indirectly cause disease or damage to livestock. Its application is limited to pests that impact livestock (defined as farm-raised animals, including horses, cattle, bison, sheep, goats, swine, cervids, poultry and others, and farm-raised fish) and not to wildlife or fish that are not farm raised. Dissemination of livestock pest products or animal vectors that carry them can be restricted by limiting movement across state lines or import into the United States. USDA’s assessment of whether a product poses a risk to livestock is triggered by processes such as the application for permit for interstate movement of a product. Genetically engineered insects are not treated differently than other insects under this authority; rather, the assessment is based solely on whether the insect carries any contagious, infectious, or communicable disease of livestock.
As of 2016, USDA authority over GE insects that are plant pests has been exercised under the PPA, but the AHPA authority has not been exercised over GE insects that are animal pests. USDA has reviewed and approved field trials of diamondback moth genetically engineered with population suppression genes under the PPA. FDA has also reviewed and approved field trials for mosquitoes (Aedes aegypti) genetically engineered for population suppression under the FDCA.45
Jurisdictional Gaps and Redundancies
Jurisdictional gaps are one of the major challenges that future biotechnology products pose to the existing scheme of environmental regulation under FIFRA, TSCA, PPA, and AHPA. Gaps occur if a biotechnology organism falls outside the definitions of products that can be regulated under those statutes and, therefore, does not receive premarket or post-market oversight and fails to receive environmental assessment (Box 3-3).46
Because the use of a plant pest to transform an organism has been a key feature of the regulations used by USDA–APHIS since 1987 to oversee products of biotechnology, the agency typically has not regulated biotechnology plants that are not engineered using a plant-pest vector or those plants that do not contain any plant-pest DNA. This potential gap in jurisdiction was identified as far back as 2000 in a National Research Council report (NRC, 2000) and has been discussed in the literature (see, for example, Kuzma and Kokotovich, 2011). Since 2011, USDA–APHIS has seen an increasing number of GE crops, plants, and plant products that do not fall within its jurisdiction (Camacho et al., 2014; Kuzma, 2016).
To provide clarity for product developers on whether a product is considered a regulated article by USDA–APHIS, the agency has begun soliciting and answering letters of inquiry from product developers on a case-by-case basis. The letter from the product developer contains information
44 7 C.F.R. § 340.1.
45 In January 2017, FDA issued a draft guidance to clarify that its definition of nonfood regulated articles no longer included those “intended to function as pesticides by preventing, destroying, repelling, or mitigating mosquitoes for population control purposes. FDA believes that this interpretation is consistent with congressional intent and provides a rational approach for dividing responsibilities between FDA and EPA in regulating mosquito-related products” (FDA, 2017b:6575).
on the host organism, the intended phenotype, whether there is an intention to move or release the product, the intended genetic change in the final product (for example, insertion, deletion, or substitution of genetic material), a description of the vector or vector agent used to induce genetic change in the organism (for example, biolistic delivery, Agrobacterium-mediated, or site-specific nuclease), the identity of the gene construct, and information on all elements of the gene construct (type, name, source, and function). As of 2016, USDA–APHIS had considered several cases of crops engineered with genome-editing technology to cause directed insertions or deletions of one to several bases. Several instances involving directed deletions or insertions have been deemed not regulated under 7 C.F.R. Part 340.47 USDA–APHIS has made similar decisions to not regulate GE crops and plants engineered through biolistics if the resulting crop does not contain plant-pest sequences. However, some genome-edited crops have been regulated if they incorporated insertions with plant-pest sequences. USDA–APHIS responses to letters of inquiry often contain language with recommended actions for developers to ensure that plant-pest genetic sequences will not be present in the final product. In these situations, USDA has not required premarket testing, reported a risk finding, or undertaken a NEPA analysis.
In January 2017, USDA–APHIS issued a proposed rule (USDA–APHIS, 2017), which clarified that GE organisms in which the sole modification was a deletion or a single base-pair substitution that could otherwise be obtained through mutagenesis would not fall under the agency’s regulatory purview. A modification that introduces only naturally occurring sequences from sexually compatible relatives that could be achieved through conventional-breeding methods also would fall outside USDA–APHIS’s oversight. The same would be true for null segregants, that is, the progeny of organisms with introduced DNA that have not inherited the introduced sequences. Organisms that contained recombinant DNA or synthetic DNA would be subject to oversight. The proposed rule was open for public comment at the time the committee’s report was published.
47 See Submission Process for Am I Regulated Letters of Inquiry, https://www.aphis.usda.gov/aphis/ourfocus/biotechnology/am-i-regulated/regulated+article+letters+of+inquiry/regulated+article+letters+of+inquiry. Accessed October 11, 2016.
Even when products fall within an agency’s jurisdiction, the product still may not receive premarket or post-market oversight. The sponsors of GE crops and plants regulated by USDA–APHIS can petition the agency for nonregulated status, which allows for commercialization. At the time the committee was writing its report, once a GE crop or plant is deregulated, the agency has virtually no monitoring or reporting requirements. However, some GE crops or plants that are not regulated by USDA–APHIS may fall under other authorities, including EPA’s FIFRA (if the crop or plant contains a plant-incorporated protectant such as Bacillus thuringiensis). Under FIFRA, these crops or plants may be subject to post-market monitoring as a condition of registration; at the time the committee wrote its report, EPA required insect resistance management plans to delay the development of resistance by insect pests to the plant-incorporated protectant.
With regard to microorganisms altered or created by biotechnology, gaps in regulation exist depending on how the product is commercially used and what the genetic composition is. EPA’s authority over such microorganisms applies to those that are intergeneric and are sold or distributed; products produced and only used within the home may not be regulated under TSCA.
One way to address these sorts of gaps is for EPA to exercise authority under TSCA. In the 1986 Coordinated Framework, TSCA was described as a “back-stop” authority that could be applied to any biotechnology organism that did not fall under other authorities. EPA’s authority under TSCA over a variety of biotechnology organisms, including plants and animals, was reaffirmed in 2001 with the Executive Office of the President’s Office of Science and Technology Policy and Council on Environmental Quality’s biotechnology case studies (CEQ and OSTP, 2001). However, at the time the committee was writing its report, EPA had not exercised its authority under TSCA in this way; whether this is due to insufficient resources or interpretations of authority is not clear. It would be helpful if the federal government would make a policy determination as to whether EPA will serve this gap-filling role.
Another way to address the gap is through the rulemaking process to update regulations. USDA–APHIS began such a process in early 2016 to address the gap pertaining to GE crops and plants. USDA published a Notice of Intent (NOI) to perform a programmatic environmental impact statement to capture not only GE crops and plants posing plant-pest risk but also those that pose potential noxious-weed risks. The definition of a noxious weed broadly covers potential harms such as “damage . . . to the natural resources of the United States, the public health, or the environment.”48 At the time the committee was writing its report, USDA–APHIS had routinely interpreted these authorities in a limited way to plants that are aggressively invasive, have significant negative impacts, and are extremely difficult to manage or control once established. Under the NOI, USDA–APHIS proposed four options (USDA–APHIS, 2016a):
- Take no action and continue to regulate GE organisms as it historically has done.
- Revise regulations to implement a two-step process that would first analyze the potential of a product of biotechnology to pose plant health risks and then determine the use of any regulatory action as appropriate or needed.
- Revise regulations to not only regulate products of biotechnology developed using a plant pest but also to regulate products of biotechnology that pose a risk as noxious weeds.
- Cease regulation and implement a voluntary, nonregulatory consultative service for developers.
USDA–APHIS solicited public comments on the four options over the course of about 3 months to inform the scope of analysis in its subsequent environmental impact statement. The proposed rule issued in January 2017 followed the third option: regulation of products of biotechnology on the
48 7 C.F.R. § 360.100.
basis of the use of a plant pest or on the basis of the product’s noxious-weed risk (USDA–APHIS, 2017). Under this proposal, GE crops and plants would be subject to a mandatory regulatory status evaluation by USDA–APHIS only if the agency had not evaluated previously the plant-pest risk or noxious-week risk posed by the submitted trait–crop combination or if the trait–crop combination has received DNA from a donor organism in a taxon known to contain plant pests and the introduced DNA was sufficient to produce a plant-disease property in the trait–crop combination. The agency would also have the ability to reevaluate its decision on a deregulated article if new information became available that indicated the organism may cause a plant or noxious-weed risk. The proposed rule was open for public comment at the time the committee’s report was published.
An additional challenge with regard to environmental protection is that agencies may be able to identify environmental effects in their assessments of the products but lack the jurisdictional authority to address these effects. FDA and USDA, like most other federal agencies, are responsible for assessing environmental effects of its major federal actions under NEPA (Box 3-4) and must
consider impacts of their decisions on endangered species under the ESA (Box 3-5). However, they are restricted by their authorities from considering certain risk-assessment endpoints.
There is also the potential for jurisdictional redundancy; for instance, all agencies receive plant composition and agronomic performance data for GE crops, and these data are reviewed for various overlapping concerns in relation to risks to agriculture, health, and the environment. Findings could vary among the agencies based on differing assessment considerations. Neither the lack of oversight nor redundancy necessarily indicates a risk, but either may erode public confidence and confuse developers. The risks would depend on the products; at the time the committee was writing its report, most risks had been successfully managed under the Coordinated Framework on a case-by-case basis.
The Coordinated Framework for Regulation of Biotechnology is a complex collection of statutes and regulations that provide the basis for federal oversight of biotechnology products. The Coordinated Framework appears to have considerable flexibility to cover a wide range of biotechnology products, although in some cases the agencies’ jurisdiction has been defined in ways that
potentially may leave gaps or overlaps in regulatory oversight. Even when the statutes technically do allow agencies to regulate these products, the current statutes equip the regulators with tools that may, at times, make it hard for them to regulate the products effectively. For example, the statutes may not empower regulators to require product sponsors to share in the burden of generating information about product safety, may place the burden of proof on regulators to demonstrate that a product is unsafe before they can take action to protect the public, or may require cumbersome processes or procedures the regulators must follow before they can act, and almost all of the statutes lack adequate legal authority for post-marketing surveillance, monitoring, and continuous learning approaches. Thus, although the products of future biotechnology are often likely to be within the jurisdiction of existing regulators, they may struggle to regulate these products effectively and to respond nimbly to the products that will be coming. Clearly gaps in the process will emerge as novel products are brought forward in future years, but they cannot be anticipated in any regulatory system, so they must be addressed as they emerge within the system.
The diversity of open-release products under development continues to expand, as described in Chapter 2, but it is not clear how many new products per year are likely to be submitted to federal agencies for premarket review or post-market oversight during the next decade. It is, however, reasonable to assume the number of products per year that will require federal oversight will increase
and the complexity of future assessments for these products, and the associated level of effort required on the part of appropriate regulatory authorities, will also increase.
Conclusion 3-1: The diversity of biotechnology consumer products anticipated over the next decade confronts consumer- and occupational-safety regulators with two related challenges: (1) to find jurisdiction under existing statutes to regulate all the products that may pose risks to consumers and (2) to utilize the risk-assessment tools available under those statutes to provide oversight that protects consumers while allowing beneficial innovation.
Existing statutes offer promising pathways to meet these challenges, although there may be cases when a novel product falls outside the jurisdiction of EPA, FDA, or USDA and is either in a jurisdictional gap (where no regulator has authority to address potential safety concerns) or under the jurisdiction of another agency, such as CPSC, that has fewer statutory authorities and capabilities to conduct rigorous, timely risk assessment. For this reason, EPA, FDA, and USDA may at times need to make use of the flexibility available under their statutes to minimize gaps in jurisdiction and to position novel products under the statutory framework most suited to each product’s characteristics and level of risk. Specifically, a federal policy determination as to whether EPA will exert a gap-filling role under TSCA would reduce uncertainty.
Even in cases when EPA, FDA, and USDA interpret their jurisdiction as widely as courts will allow them to do, it is still true that a growing number of future biotechnology products may fall into gaps in these agencies’ jurisdiction. For example, some biotechnology products, such as toys or domestic products manufactured in the home for domestic use, may not be covered by EPA, FDA, or USDA and may fall mainly under CPSC’s jurisdiction, while other biotechnology products used in the workplace as means of industrial production may fall mainly under OSHA’s jurisdiction.
Conclusion 3-2: The Consumer Product Safety Act and the Occupational Safety and Health Act do not provide CPSC and OSHA with legal authorities and tools that are well tailored to the challenges of regulating novel biotechnology-based consumer products and means of production.
CPSC lacks authority to conduct premarket safety analysis of biotechnology-based consumer products and has limited tools for responding to risks emerging after products are marketed. The Occupational Safety and Health Act has limitations that may make it difficult for OSHA to respond nimbly to novel uses of biotechnology as a means of production.
Conclusion 3-3: The shifting structure and financing of biotechnology-product development and manufacturing may place strains on existing systems for research oversight, timely response to premarket notifications, and post-marketing inspections and product testing.
Appropriate staffing of the regulatory agencies is critical, as is careful planning to maximize the reach of available research regulations (INAD, IDE, IND, and EUP) for research not subject to the NIH guidelines. Federal oversight of biotechnology products can take place at a number of phases in the product-development cycle, depending on the product and its intended use. Under current statutes, regulators’ power to require product manufacturers to submit premarket safety studies and post-marketing safety information varies, depending on the product type.
Conclusion 3-4: Under existing statutes, much of the burden to generate evidence of consumer safety falls on regulators and public funding agencies; this implies that adequate federal support for research will be crucial to protect consumer and occupation safety.
Under many of the statutes that the committee reviewed, regulators have only limited authority to require product sponsors to conduct (and thus to fund) studies to generate information about the safety of their products, and some statutes require regulators to bear the burden of establishing that a human safety or environmental problem exists before the regulator can take steps to manage the risk. Such policies foster innovation by reducing the barriers to entry and costs of bringing new products onto the market, but they imply a corresponding obligation for regulators and public funding agencies to generate safety information through inspections, product testing, information gathering, and research to identify and analyze potential risks. These policies reflect a balance Congress has struck between the benefits of innovation and the burdens of assuming major federal responsibilities to generate information that is necessary to protect the public and the environment. As a profusion of diverse biotechnology products enters the market during the next 5–10 years, maintaining this balance will require adequate federal support for the research, inspection, testing, and other activities that Congress has confided to federal government agencies under the existing statutes. There are examples, however, that suggest that the federal investment in information-gathering activities can be leveraged through public–private partnerships, public engagement, and other measures that mobilize data and know-how already existing within industry and the product-consuming public.
Conclusion 3-5: Post-market risk identification, analysis, and safety surveillance are important tools for supporting beneficial uses of innovative products and ensuring public and environmental safety.
For the product categories covered in this report, existing statutes do not provide regulators with a complete set of modern tools, such as authorization to develop active surveillance systems and shared data resources to support regulatory science and continuous learning. Therefore, publicly funded research has an ongoing role to play throughout the entire product life cycle, although public–private partnerships offer promise for both mobilizing know-how and leveraging public investments.
Conclusion 3-6: For some product categories considered in this report, consumer-safety regulatory agencies have little or no authority to restrict the receipt, use, sale, or distribution of products to address risks that otherwise-safe products may pose in the hands of unqualified or malicious users.
Existing programs to restrict shipments of biological agents (the Federal Select Agent Program administered by USDA–APHIS and CDC, U.S. Department of Commerce restrictions, and U.S. Department of Health and Human Services voluntary screening programs) are neither focused nor scaled to address concerns that may arise in connection with future consumer products.
The future industry structure will include new players, such as do-it-yourself and at-home biotechnology enthusiasts and product developers, nontraditional manufacturers, and those entering the biotechnology space with support from nontraditional funding sources for research. Protecting public safety may, at times, call for controls over who can access and use certain types of products—for example, to restrict the use of the product to qualified users or to ensure the product is used only in facilities that agree to implement certain safety measures. The regulatory agencies of the Coordinated Framework, such as FDA, OSHA, and CPSC, have little authority to restrict sales, distribution, and use of products. The federal frameworks currently in place for limiting access to biological agents (the Federal Select Agent Program administered by USDA–APHIS and CDC, U.S. Department of Commerce restrictions on transactions, and voluntary screening programs administered by the U.S. Department of Health and Human Services) are geared toward controlling
small numbers of highly dangerous or strategically significant products, rather than a wider array of biotechnology products that may require qualified users in order to be safe.
Conclusion 3-7: Definitions of what constitutes a product of biotechnology under different statutes lead to jurisdictional gaps and redundancies in the assessment of the environmental effects of biotechnology products.
EPA, FDA, and USDA may not have authority to conduct an environment risk assessment of a future biotechnology product if the product does not fall within the parameters of their authorizing statutes. Even when FDA and USDA identify environmental effects through the NEPA process or through ESA consultations with the U.S. Fish and Wildlife Service or the National Marine Fisheries Service, they do not have the authority to make regulatory decisions based on the findings of the environmental assessment or environmental impact statement. As of 2016, most existing biotechnology products have been used in contained environments or open environments in managed systems, but with more biotechnology products designed for released into open environments with minimal or no management, this disconnect may be more acute.
Jurisdiction redundancy also exists; for example, all three agencies can receive composition and agronomic performance data for GE crops. Each agency has a different approach to assessing risks related to agriculture, health, and the environment; therefore, the findings of each agency may differ slightly from the others and may create confusion for product developers.
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