On the basis of its assessment of the trends in biotechnology as of 2016, the likely products of biotechnology in the next 5–10 years, and the current authorities and capabilities of the regulatory agencies, the committee identified a set of broad themes regarding future opportunities for enhancement of the U.S. biotechnology regulatory system:
- The bioeconomy is growing rapidly and the U.S. regulatory system needs to provide a balanced approach for consideration of the many competing interests in the face of this expansion.
- The profusion of biotechnology products over the next 5–10 years has the potential to overwhelm the U.S. regulatory system, which may be exacerbated by a disconnect between research in regulatory science and expected uses of future biotechnology products.
- Regulators will face difficult challenges as they grapple with a broad array of new types of biotechnology products—for example, cosmetics, toys, pets, and office supplies—that go beyond contained industrial uses and traditional environmental release (for example, Bt or herbicide-resistant crops).
- The safe use of new biotechnology products requires rigorous, predictable, and transparent risk-analysis processes whose comprehensiveness, depth, and throughput mirror the scope, scale, complexity, and tempo of future biotechnology applications.
- In addition to the conclusions and recommendations from this report, the U.S. Environmental Protection Agency (EPA), the U.S. Food and Drug Administration (FDA), the U.S. Department of Agriculture (USDA), and other agencies involved in regulation of future biotechnology products would benefit from adopting recommendations made by previous National Academies committees related to future products of biotechnology, which are consistent with the findings and recommendations in this report.
In this final chapter, the committee has summarized its major conclusions, organized against the statement of task, and made selected recommendations for next steps to be taken to enhance the capabilities of the U.S. regulatory system to protect human health and the environment.
The committee’s statement of task requested that the committee “describe the major advances and the potential new types of biotechnology products likely to emerge over the next 5–10 years.” In reviewing the technologies that are currently being explored in industry, academia, and government, the committee concluded:
Conclusion 6-1: The scale, scope, complexity, and tempo of biotechnology products are likely to increase in the next 5–10 years. Many products will be similar to existing biotechnology products, but they may be created through new processes, and some products may be wholly unlike products that exist today.
Driven by advances in biotechnology such as lowered cost of gene synthesis and sequencing, intelligent design tools for building gene constructs, readily accessible and affordable standardized biological parts, and the increasing accessibility of those technologies to a broad array of agents, the committee anticipates a significant profusion of biotechnology products in the next 5–10 years. Many of these products will be for contained use or otherwise map to existing product categories, but the committee expects that there will be significantly more products designed to exist in the open environment under low-management conditions that will be also developed. Some of these products, like the mosquito engineered to produce sterile offspring (deployment of which was under discussion in Florida at the time the committee was writing its report), will be designed to mitigate an identified environmental problem, a public health issue (for example, reducing populations of mosquitoes that transmit malaria, dengue, and Zika), or both. In addition, new processes for making genetic modifications will be introduced, moving from Agrobacterium-mediated transformation to biolistics to genome-editing techniques such as CRISPR, and beyond this to novel advances in genome engineering, including the possibility of genomically recoded organisms that are largely or wholly created via synthetic DNA.
These advances in technology will lead to new products that range from an expansion of the familiar set of organismal hosts and genetic pathways to those that use rapid design-build-test-learn cycles to enable more complex designs of genetic pathways in a wider variety of host organisms to those in which multiple organisms may be used in complex microbial communities, such as microbiome engineering. As biotechnology products become less similar to existing products and more complex, there will be fewer comparator products to use in risk analyses; consequently, there will be a need to develop new approaches to analyze risks. The number of actors who are involved in product development will also increase and diversify beyond just companies and academia, creating the additional regulatory challenge of product developers who may have little familiarity with risk analysis and with the regulatory system.
The committee was also asked to “describe the existing risk analysis system for biotechnology products including, but perhaps not limited to, risk analyses developed and used by EPA, USDA, and FDA, and describe each agency’s authorities as they pertain to the products of biotechnology.” In carrying out this charge, the committee reviewed the Coordinated Framework for Regulation of Biotechnology, including the 2017 update to the Coordinated Framework (EOP, 2017) as well as the 2016 National Strategy for Modernizing the Regulatory System for Biotechnology Products (EOP, 2016). The committee reached the following conclusions:
Conclusion 6-2: The Coordinated Framework for Regulation of Biotechnology appears to have considerable flexibility to cover a wide range of biotechnology products, though in some cases the jurisdiction of the agencies has the potential to leave gaps in regulatory oversight.
The Coordinated Framework for Regulation of Biotechnology is a complex collection of statutes and regulations that provides 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 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 developers 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. 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 often are within the jurisdiction of existing regulators, they will struggle to regulate these products effectively and to respond nimbly to the profusion of products that will be coming.
Conclusion 6-3: The current biotechnology regulatory system is complex and fragmented, resulting in a system that can be difficult for individuals, nontraditional organizations, and small- and medium-sized enterprises to navigate, that might cause uncertainty and a lack of predictability for developers of future biotechnology products, and that has the potential for loss of public confidence in regulation of future biotechnology products.
As was pointed out in the public comments received as part of developing the 2017 update to the Coordinated Framework, the U.S. regulatory system can be difficult to navigate. Future product developers will include new players, such as do-it-yourself biotechnology enthusiasts, nontraditional manufacturers, and entities whose research or product development is funded through nontraditional sources. 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 have little authority to restrict sales, distribution, and use of products that do not cross state lines or are made and used in domestic settings (individuals’ homes). The federal frameworks currently in place for limiting access to biological agents—the Federal Select Agent Program administered by USDA’s Animal and Plant Health Inspection Service (APHIS) and the Centers for Disease Control and Prevention (CDC), the U.S. Department of Commerce’s restrictions on transactions, and voluntary screening programs administered by the U.S. Department of Health and Human Services—are presently geared to 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. In addition, many developers of early-stage biotechnology products or biological technology (that may eventually lead to products for commercial use) do not consider regulatory issues and the potential need for data to support risk analyses during technology (and sometimes product) development. Failure to anticipate regulatory requirements creates the potential to complicate developers’ business plans and delay the risk analyses associated with the decisions to allow future biotechnology products to enter the market.
Regarding future products of biotechnology, the committee was asked to “determine whether potential future products could pose different types of risks relative to existing products and organisms. Where appropriate, identify areas in which the risks or lack of risks relating to the products of biotechnology are well understood.” As described in Chapter 4, in carrying out this portion of its statement of task, the committee distinguished between risk-assessment endpoints and the complexity of risk assessments and also interpreted “well understood” to mean that the uncertainty in estimates of risk does not preclude a formulation of risk-management options. The committee reached the following conclusions:
Conclusion 6-4: The risk-assessment endpoints for future biotechnology products are not new compared with those that have been identified for existing biotechnology products, but the pathways to those endpoints have the potential to be very different in terms of complexity.
The biotechnology products emerging in the next 5–10 years pose a diverse array of environmental, health, and safety risks that vary widely in terms of their potential impacts, likelihood of occurrence, spatial and temporal dimensions, and the appropriate regulatory policies for their assessment. Although the nature of human health and environmental risk-assessment endpoints that will need consideration are similar to those identified with existing products, the pathways to these endpoints will differ in complexity; therefore, advances in regulatory science will be needed for effective and appropriate evaluation. The number of products poised to enter the marketplace in the coming years will likely outpace the means and capacity for voluntary- or regulatory-based assessment processes to inform decision making. This imbalance, if not addressed in the near term, could impede the development of new biotechnology products in the long term. The profusion of future biotechnology products poses a significant potential stress to the existing regulatory system. Regulatory agencies are likely not prepared with sufficient staff, appropriate risk-assessment approaches, and corresponding guidance for development and evaluation of product data packages.
Conclusion 6-5: The profusion of future biotechnology products anticipated in coming years will challenge the federal agencies’ ability to handle significant increases in the rate of biotechnology product innovation, the number of biotechnology products, the complexity of interactions, and the diversity of actors (and their experience with the regulatory process).
Based on the information gathered as part of this study, there is a strong possibility that 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. The committee saw this not as a transient event at this point in time, but rather as part of a sustained increase in the development of new products of biotechnology that will be driven by increased understanding of the biological sciences and increased capabilities in the underlying biological engineering technologies. New tools for government oversight in the face of this expansion may be required.
Conclusion 6-6: To enable effective regulation of the safe use of future biotechnology products, it would be beneficial to have a single point of entry into the regulatory system with a decision-making structure aimed to assess and manage product risk, to direct
products to their appropriate regulatory agencies, and to increase transparency for developers and society.
In order to be prepared for the potential profusion of future products of biotechnology, it will be important that the U.S. regulatory system has the capacity and capability to efficiently assess their potential human health and environmental risks. A revised strategy for regulatory oversight with increased public participation, transparency, and predictability, when possible under current statutes, can improve public confidence in the regulatory process for future biotechnology products. A rigorous, transparent regulatory oversight system can ensure that risk-analysis efforts are proportional to the level of regulatory agencies’ familiarity with the product and the degree of complexity required in the associated risk assessment. The need to balance the many different demands from federal agencies, developers, and interested and affected parties will make the current case-by-case assessment of new products of biotechnology increasingly challenging. Furthermore, it will be important that the routes of decision making be consistently applied across the different classes of products described in Chapter 2. The committee notes that the ability to provide a consistent regulatory route that depends on product function and use may be limited by the jurisdiction of the agencies and the differences in the authorities that govern them.
As described in the 2017 update to the Coordinated Framework and the National Strategy, individual federal agencies have already taken significant steps toward providing information to a variety of stakeholders in their individual processes. The committee concluded that, in addition to these initial steps, a single point of entry that allows better understanding and selection of the regulatory route would further enhance the ability of the regulatory system to handle anticipated products of biotechnology and the diverse array of developers of such products.
Finally, the committee was asked to “indicate what scientific capabilities, tools, and expertise may be useful to the regulatory agencies to support oversight of potential future products of biotechnology.” The committee reviewed the current expertise within EPA, FDA, and USDA and analyzed the investments that those agencies and others are making in areas related to risk analyses. The committee concluded:
Conclusion 6-7: The staffing levels, expertise, and resources available in EPA, FDA, USDA, and other agencies that have interests related to future biotechnology products may not be sufficient to handle the expected scope and scale of future biotechnology products.
Although the regulatory agencies have access to a number of external advisory committees, the number of in-house experts and the responses to the committee’s request for information indicate that there may not be sufficient scientific capability, capacity, and tools within and across the agencies to address the risk-assessment challenges for future biotechnology products. The agencies need to maintain or build the capacity and the level of expertise within agencies required to assess the anticipated profusion of biotechnology products and have access to the most current tools for technology assessment. Some resources may also need to go into research. The specific areas of scientific capabilities, tools, and expertise that are likely to be required are described in the committee’s recommendations in the next section.
On the basis of the conclusions of this report, the committee recommends the following actions be taken to enhance the ability of the biotechnology regulatory system to oversee the consumer safety and environmental protection required for future biotechnology products.
Recommendation 1: EPA, FDA, USDA, and other agencies involved in regulation of future biotechnology products should increase scientific capabilities, tools, expertise, and horizon scanning in key areas of expected growth of biotechnology, including natural, regulatory, and social sciences.
Future biotechnology products will be more complex in terms of their internal and external interactions, and it is critical that the agencies involved in regulation of biotechnology develop and maintain scientific capabilities, tools, and expertise in relevant areas. Furthermore, it will be essential that the agencies stay apprised of technology trends so that they can engage in meaningful discussions with technology and product developers early in the product-development cycle, where there is often the best opportunity to affect future technologies. Thus, it will be also important to maintain the capability to perform horizon scanning through participation in technical meetings, outreach to universities and companies, and engagement with the public and international partners.
Determination of the key areas of scientific capability will need to adapt to the emerging technologies that underlie future products of biotechnology. On the basis of the current level of federal investments, some of the key research areas in regulatory science related to the products of biotechnology likely in the next 5–10 years include comparators, off-target gene effects, and phenotypic characterization; gene fitness, genetic stability, and horizontal gene transfer; impacts on nontarget organisms; control of organismal traits; modeling (including risk-analysis approaches under uncertainty) and life-cycle analyses; monitoring and surveillance; and economic and social costs and benefits.
In maintaining an active list of relevant areas of expertise that should be developed and maintained, federal agencies should partner with or otherwise engage the developer sector to ensure that the regulatory-science priorities are informed by the nature of biotechnology products in discovery, research, and development pipelines.
To support this broad recommendation, the committee developed several more specific recommendations on opportunities for increasing the capabilities of the regulatory system.
Recommendation 1-1: Regulatory agencies should build and maintain the capacity to rapidly triage products entering the regulatory system that resemble existing products with a history of characterization and use, thus reducing the time and effort required for regulatory decision making, and should be prepared to focus questions on identifying new pathways to risk-assessment endpoints associated with products that are unfamiliar and that require more complex risk assessments.
To encourage innovation, execute diligence in risk analyses, and instill confidence in the process and outcomes of regulating future products of biotechnology, it is important that regulatory agencies make use of a stratified approach to identify those products that require the most attention. Although the risk-assessment endpoints from biotechnology products have been considered in the past and existing processes for risk assessment can be applied, processes need to be advanced to provide quantitative risk estimates and address the dimensionality of more complex assessments. In some areas, decades of work and review of multiple products are available, and future products that are similar to those with a history of characterization and use should be able to take advantage
of these existing risk analyses to bridge existing information and focus exposure or hazard data to specific, identified areas of uncertainty unique to a new product. It will be important to focus resources on those products of biotechnology in which novel traits and more complex interactions are present because these are the types of products for which detailed scientific understanding may not yet be available and with which regulatory agencies may be less familiar. Even in these situations, risk-analysis frameworks should encourage the use of clearly articulated conceptual models based on best available information to identify critical exposure pathways and risk-assessment endpoints to guide information needs. In some cases, an iterative approach to information gathering can support a more efficient and focused risk analysis (for example, the approach described in the National Academies report on gene drives [NASEM, 2016a]).
It is likely that increased staffing, training, and expertise in new disciplines will be needed to deal with the coming profusion of new biotechnology products to support timely regulatory decisions that are based on the best available science tailored to the complexity of a given risk analysis. Analysis of capabilities in the regulatory agencies over the period 2011–2015 indicates that in some cases there is a decrease in the number of personnel available for nonhealth-related regulatory activities.
Recommendation 1-2: In order to inform the regulatory process, federal agencies should build capacity to scan the horizon for new products and processes that could present novel risk pathways, develop new approaches to assess and address more complex risk pathways, and implement mechanisms for keeping regulators aware of the emerging technologies they have to deal with.
In order to be prepared for future products of biotechnology that will enter the regulatory pipeline, regulatory agencies should have an informed view of the underlying technologies that will lead to those advancements. Regulatory agencies should provide training programs to continually maintain technical expertise commensurate with the scope, scale, and complexity of future biotechnology products and may wish to consider annual or biannual training at technical workshops to learn and apply state-of-the-art technologies. Regulatory agencies should also critically assess existing expertise and develop a strategic plan to hire personnel (permanent or contract employees) capable of assessing future biotechnology products.
In addition to building and maintaining internal expertise, regulatory agencies should make use of external resources for horizon scanning. This could include the use of external advisory groups such as EPA’s Science Advisory Board and Scientific Advisory Panel, and extramural research to identify and study emerging risks. EPA’s futures network may also provide insights into new methods for effective horizon scanning. Agencies such as the U.S. Department of Energy, the U.S. Department of Defense, the National Institute of Standards and Technology, the National Aeronautics and Space Administration, and the National Science Foundation could assist the regulatory agencies in their horizon-scanning efforts.
Recommendation 1-3: EPA, FDA, USDA, and other relevant federal agencies should work together to (1) pilot new approaches for problem formulation and uncertainty characterization in ecological risk assessments, with peer review and public participation, on open-release products expected during the next 5 years; (2) formulate risk–benefit assessment approaches for future products, with particular emphasis on future biotechnology products with unfamiliar functions and open-release biotechnology products; and (3) pool skills and expertise across the government as needed on first-of-a-kind risk–benefit cases.
There is a significant amount of expertise available across the various federal agencies involved with the regulation of biotechnology products, and the increasingly complex interactions between traits, functions, and the environment that are likely with future products of biotechnology motivate increased collaboration between the agencies. A potential mechanism to increase cooperation would be to use a “community of practice”—comprised of representatives from the agencies’ community of risk assessors and risk managers—that could explore approaches to advance science-based assessments of new products, especially in those areas where products cut across traditional areas of regulatory oversight by individual agencies. As an example, the U.S. Fish and Wildlife Service has a conservation genetics community of practice with a mission “to serve as an interactive forum to facilitate the growth, application and exchange of conservation genetics expertise, information, and technology among members” (FWS, 2011). Regulators of biotechnology products could form a similar community of practice to share and build knowledge about new biotechnology processes and new ways to evaluate the risks of biotechnology products.
In developing this “community of practice,” the federal agencies could consider the entire life cycle of biotechnology products as well as approaches to engage interested and affected parties in governance and oversight of risk analysis and regulation of those products. Risk analyses will vary by statutory requirements, the regulatory agencies’ familiarity with the product, and manufacturing processes and use patterns of the products; hence, governance and oversight approaches should be tailored to the regulatory context. Federal agencies should explore the implementation of principles of responsible research and innovation and should provide public confidence in development and use of new biotechnology products.
In many cases, biotechnology-sector regulators need to consider not only the risks posed by future products but also the potential societal benefits that may be gained with a new product. Working through a “community of practice,” regulatory agencies could explore opportunities to apply their discretionary powers to focus information needs tailored to products and use patterns, which will inform timely and robust risk–benefit analyses and regulatory decisions. For example, agencies may choose an area of current technology investment (for example, engineered microbial consortia) and begin to examine scenarios and seek external input that would inform future risk analyses.
The agencies could also consider expanding a “community of practice” to include product developers, risk-analysis consultants, state agencies, and other interested and affected parties. This approach has been employed by EPA for other areas of environmental risk assessment and research, as noted in Chapter 4.1
Recommendation 1-4: EPA, FDA, USDA, and other relevant federal agencies should create a precompetitive or preregulatory review “data commons” that provides data, scientific evidence, and scientific and market experience for product developers.
A key element in future regulation of biotechnology products will be increased scientific understanding of the complex interactions between a variety of traits and functions that will form the core of future products of biotechnology and the increasingly complex interactions between products of biotechnology and their host environments. To accelerate the advancement of this scientific understanding, appropriate “data commons” could be established and run by the federal government, perhaps based at a national laboratory. These data commons could make use of data produced by government, industry, or academic researchers at a variety of stages of product devel-
1 See, for example, Computational Toxicology Communities of Practice, available at https://www.epa.gov/chemical-research/computational-toxicology-communities-practice, and Pesticide Environmental Modeling Public Meeting–Information, available at https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/environmental-modeling-public-meeting-information. Both accessed January 10, 2017.
opment. Examples of existing databases include Allergen Online, the International Life Sciences Institute crop composition database, and the CRISPR Genome Analysis Tool.
If properly developed, these data commons could have multiple uses that benefit the capability and capacity of the regulatory system. Regulators could use the data commons as a source of comparative data and quantitative measures of long-term effects. Applicants, especially small- and medium-sized enterprises and entrepreneurs, could use the shared data commons to minimize burdens, promote quality control, and speed up their “time to market” and understanding of societal benefits of biotechnology. Researchers could both tap into these resources to identify gaps in understanding and conduct new studies that enrich the shared pool of knowledge.
Funding for these resources could rely on industry funding or modest user fees to support their development and curation.
Recommendation 1-5: Consistent with the goals and guidance stated by the Office of Science and Technology Policy in the Executive Office of the President in a July 2015 memo, the Biotechnology Working Group should implement a more permanent, coordinated mechanism to measure progress against and periodically review federal agencies’ scientific capabilities, tools, expertise, and horizon scanning as they apply to the profusion of future biotechnology products.
In July 2015, the Biotechnology Working Group (BWG) under the Emerging Technologies Interagency Policy Coordination Committee was established with representatives from the Executive Office of the President, EPA, FDA, and USDA (EOP, 2015). The BWG developed the 2017 update to the Coordinated Framework to clarify the current roles and responsibilities of the agencies that regulate the products of biotechnology (EOP, 2017); it also wrote the National Strategy (EOP, 2016). In the National Strategy, the BWG is charged with producing an annual report on specific steps that agencies are taking to implement that strategy and any other steps that the agencies are taking to improve the transparency, coordination, predictability, and efficiency of the regulation of biotechnology products.
The committee supports the initial steps of the BWG and encourages it to establish more permanent mechanisms to measure progress against and periodically review federal agencies’ scientific capabilities, tools, expertise, and horizon scanning as they apply to the profusion of future biotechnology products.
Recommendation 2: EPA, FDA, USDA, and other relevant agencies should increase their investments in internal and external research and their use of pilot projects to advance understanding and use of ecological risk assessments and benefit analyses for future biotechnology products that are unfamiliar and complex and to prototype new approaches for iterative risk analyses that incorporate external peer review and public participation.
Risk governance of future biotechnology products must be capable of adapting and responding to the rapid pace of changes in technology and information that are driving the development of those products. Just as the design-build-test-learn cycle is an important trend that is driving much of the biotechnology field, the use of pilot projects as a means to explore new methods of performing scientifically driven risk analysis can provide an opportunity to rapidly explore the “design space” of regulatory science relevant to future products of biotechnology.
Examples of areas where pilot projects should be considered are given in the detailed recommendations below. The recommendations highlight some of the broad areas where new approaches might be particularly fruitful, but they are not intended to be exhaustive. One key area where the committee believes that advances can be fruitful is in new techniques for iterative risk assessments
that link to the design-build-test-learn cycle and also to the scaled release of biotechnology products (from laboratory scale to small field trials, larger field trials, and eventually full-scale deployment). This conceptual approach has been articulated for decades, but the employment of field studies and computational models to inform risk assessments at the population, community, or ecosystem level is often not used or, when used, has generally failed to reduce uncertainties in risk assessments and in some cases raised more questions than answers. In this regard, pilot efforts could be undertaken to evaluate, and develop new approaches as appropriate, open-release products, using physical models (for example, mesocosms or field studies) and computational models to assess population, community, and ecosystem effects.
Another is the use of stratified approaches that focus the most attention on those products for which there is the least familiarity within the regulatory agencies and for which the most complexity is required in the associated risk assessment. These approaches are common practice for regulation of open-release products but could be applied more broadly to contained products and biotechnology platforms. Pilot efforts could be used to develop new, high-throughput comparative risk-assessment methods to ensure a risk-based approach that identifies products with the greatest potential of risk but does not inadvertently become a bottleneck in the regulatory pipeline.
In the area of external participation in the regulatory process, pilot projects can also be used to explore new ways of incorporating expert advice through peer review and providing public participation and input in the regulatory decision-making process. Issues to be addressed through the pilots might include how external, independent peer reviewers are chosen, how the public is identified and engaged, who decides the external participants, and how the external, independent peer review and public participation are integrated into the decision-making process. It may also be possible to further explore how early engagement of external input affects the pace of regulatory approval by encouraging more deliberation in the early stages of the regulatory process rather than post-decision litigation. An example of existing pilot programs that is representative of what could be done is the long-running Pseudomonas fluorescens bioremediation project (Trögl et al., 2012; Ji et al., 2013), which could be used to drive future pilots for release of biosensors, modified consortia, and other similar products. Another example is the case of genetically engineered algae and the launch of EPA’s algal biotechnology project (EPA, 2015).
To support this broad recommendation, the committee developed several more specific recommendations on potential pilot projects that might be considered.
Recommendation 2-1: Regulatory agencies should create pilot projects for more iterative processes for risk assessments that span development cycles for future biotechnology products as they move from laboratory scale to prototype or field scale to full-scale operation.
The pilot projects could address iterative assessments within design cycles for future biotechnology products by adapting the approach outlined in the National Academies report on gene drives (NASEM, 2016a), which described a path from product-development research through open environmental release with post-release monitoring. Risk analyses could inform decisions at each of five steps in an idealized development scheme that includes preparation for research (step 1), laboratory-based research (step 2), pilot-plant manufacturing or field-based research (step 3), staged market entry or environmental release (step 4), and post-market or post-release surveillance, when appropriate (step 5). Although described as a linear process, development cycles typically involve feedback loops with refined understanding based on new findings and data generated during the course of product research and risk assessments. These pilot projects would benefit from active participation of product developers and interested and affected parties to explore approaches for
efficiently integrating risk analyses and options for public engagement within product-development cycles.
Recommendation 2-2: Government agencies should pilot advances in ecological risk assessments and benefit analyses for open-release products expected in the next 5–10 years, with external, independent peer review and public participation.
The biotechnology products emerging in the next 5–10 years pose a diverse array of potential environmental risks that vary widely in terms of their potential impacts, likelihood of occurrence, spatial and temporal dimensions, and the appropriate regulatory policies for their assessment. Although the nature of environmental risk-assessment endpoints that will need consideration are similar to those identified with existing biotechnology products, the pathways to these endpoints will differ in complexity. Regulatory agencies are likely not prepared with sufficient staff, appropriate ecological risk-assessment approaches, and corresponding guidance for development and evaluation of associated product data packages. Public confidence in government oversight of emerging technologies may be eroded to the extent there is a lack of transparency and clarity as to how regulatory authorities are undertaking ecological risk assessments, including identifying societal values in addition to taking input from biotechnology developers in formulating regulatory decisions. Possible pilot efforts could address open release of bioengineered microorganisms or microbial consortia with multiple modifications (for example, for use in bioremediation). Other pilots could address risk assessments for biocontrol agents and the release of non-native organisms (bioengineered or otherwise) designed to suppress and or enhance a species, which reflect a high degree of dimensionality and entail a diversity of risk-assessment endpoints at varying levels of biological organization and temporal scales. Considerations of this scale of complexity may necessitate rethinking of both regulatory processes and risk-assessment approaches.
Recommendation 2-3: Government agencies should initiate pilot projects to develop probabilistic estimates of risks for current products as a means to compare the likelihood of adverse effects of future biotechnology products to existing biotechnology and nonbiotechnology alternatives.
There are many opportunities for increased use of quantitative analyses in risk assessment and, in particular, the use of probabilistic estimates of risks as part of larger conceptual models. Even when data are missing, expert and stakeholder elicitation can be used to identify high-priority areas (Murphy et al., 2010; Hayes et al., 2014; Murray et al., 2016). Such analyses would help identify high-priority information needs to reduce uncertainty in risk estimates and inform the classification of comparable products (including possible alternatives that do not rely on biotechnology approaches) based on the nature of risk-assessment endpoints, dimensionality of risk assessments, and the probabilities of adverse effects. The scenarios discussed in Chapter 4 could be used as a starting point for selecting possible pilot projects. Pilots would be particularly helpful for products intended for wide-area environmental release in low-management conditions.
Recommendation 2-4: Regulatory agencies should make use of pilot projects to explore new methods of outreach to the public and developer community as a means of horizon scanning, assessing need areas for capability growth, and improving understanding of the regulatory process.
One example of a potential pilot in this area would be for one or more regulatory agencies to follow the lead of the Federal Bureau of Investigation (FBI) in making outreach part of its activi-
ties to help small companies, the international Genetically Engineered Machine (iGEM) teams, the do-it-yourself biology (DIYbio) community, and others to better understand the regulatory process.
Policy, decision, and social-science research to improve risk-analysis processes is also needed. Research areas could include
- Experiments with governance systems to test ways to anticipate and prepare for future technologies in governance systems with side-by-side comparisons of different features for these systems and to explore alternatives for engaging interested and affected parties within these systems;
- Methods to handle uncertainty and ambiguity in governance to improve upstream methods for exploring a broad range of harms and benefits, to characterize uncertainty, and to improve decision-science and future-studies approaches (for example, scenario planning, Bayesian approaches, or systems mapping) in governance systems; and
- Improved methods to explore claims and counterclaims in contested areas to develop balanced and more inclusive approaches for determining “weight of evidence” to understand and mitigate bias in interpretations of evidence, to acknowledge values behind multiple perspectives and interpretations of evidence, and to explore assumptions, contradictions, and correlation arguments on multiple sides of controversies.
Recommendation 2-5: EPA, FDA, and USDA should engage with federal and state consumer- and occupational-safety regulators that may confront new biotechnology products in the next 5–10 years and make use of pilot projects, interagency collaborations, shared data resources, and scientific tools to pilot new approaches for risk assessment that ensure consumer and occupational safety associated with new biotechnology products, particularly those that may involve novel financing mechanisms, means of production, or distribution pathways.
As described in Chapters 3 and 4, biotechnology regulators will face difficult challenges as they grapple with new product categories that go beyond contained industrial uses and traditional environmental release (for example, Bt or herbicide-resistant crops). It will be necessary to engage with other federal agencies to develop appropriate regulatory oversight frameworks for such products. The interagency dialogue should primarily engage agencies such as the Consumer Product Safety Commission, the Occupational Safety and Health Administration, and CDC that have broad responsibility for consumer and occupational safety and public health, but the diversity of future biotechnology products may, on a case-by-case basis, implicate the safety oversight roles of a much longer list of agencies (for example, the National Highway Traffic Safety Administration for automotive applications) that also need effective pathways for engagement in the Coordinated Framework.
Rapid post-marketing risk identification, analysis, and safety surveillance are crucial tools to ensure consumer and occupational safety in an environment that promotes rapid innovation. Agencies should aggressively explore options (for example, public–private partnerships, consumer engagement mechanisms, or anonymous reporting mechanisms such as those that have been effective in airline safety) to enhance timely information flows about the safety of biotechnology products in real-world use.
In addition, as nontraditional research funding mechanisms and do-it-yourself or small-scale uses of biotechnology challenge traditional regulatory enforcement mechanisms, the regulatory agencies could maximize their impact on public safety through their powers to publicize risks and educate the public, their power to convene public workshops and to engage stakeholders in address-
ing emerging problems, and their power to promote compliance with good practices and codes of conduct via policies that link enforcement discretion to voluntary compliance.
Finally, the safety of some future biotechnology products may call for restrictions on sale, distribution, and use that EPA, FDA, and USDA presently lack statutory authority to implement. The agencies should engage with other concerned agencies (the Federal Select Agent Program administered by USDA–APHIS and CDC, the U.S. Department of Commerce’s restrictions on transactions, and voluntary screening programs administered by the U.S. Department of Health and Human Services), with law enforcement (for example, FBI), and with Congress to explore appropriate solutions.
Recommendation 3: The National Science Foundation, the U.S. Department of Defense, the U.S. Department of Energy, the National Institute of Standards and Technology, and other agencies that fund biotechnology research that has the potential to lead to new biotechnology products should increase their investments in regulatory science and link research and education activities to regulatory-science activities.
There are substantial opportunities for the use of improved methods for scientific evaluation, risk assessment, and community engagement related to future products of biotechnology. In order to ensure that the regulatory framework is able to make use of the best available tools in performing its regulatory oversight responsibilities, it will be important to invest in those tools and make them available to regulators and product developers. Areas for consideration include stochastic methods, advances in uncertainty analysis, better ways to integrate and interpret both qualitative and quantitative data, and communication strategies.
In talking with small companies, university research, the DIYbio community, and others during its information-gathering activities, a common theme the committee heard was that early developers of technology that may lead to future biotechnology products are not considering the possible regulatory paths that their technologies and potential products may face. To help address this, federal agencies that fund basic and applied research related to biotechnology should consider funding research activities that close gaps and provide linkages to market-path requirements for regulatory success.
Finally, for those agencies that have a role in educational activities, it may be beneficial to find ways to increase the education that researchers receive regarding the regulatory system. In the same way that the National Institutes of Health (NIH) requires all universities that receive NIH funding to offer courses in biosafety and bioethics, the profusion of future biotechnology products would benefit from the inclusion of material on the regulatory process and risk-assessment frameworks and tools in textbooks, scientific literature, and regulatory agency websites.
To support this broad recommendation, the committee developed several more specific recommendations on how such investments might be targeted.
Recommendation 3-1: The federal government should develop and implement a long-term strategy for risk analysis of future biotechnology products, focused on identifying and prioritizing key risks for unfamiliar and more complex biotechnology products, and work to establish appropriate federal funding levels for sustained, multiyear research to develop the necessary advances in regulatory science.
As noted in Chapter 4, of the total $1.04 billion invested in biotechnology research during 2008–2015, federal research funding agencies invested approximately 7 percent on risk research. The federal government should establish a research program that is responsive to the nature and
extent of future challenges facing public- and private-sector risk assessors, risk managers, and other interested and affected parties.
The committee’s initial perspective on the highest priorities for increased investments is
- Comparators, off-target gene effects, and phenotypic characterization.
- Genetic fitness, genetic stability, and horizontal gene transfer.
- Impacts on nontarget organisms.
- Control of organismal traits.
- Modeling (including risk-analysis approaches under uncertainty) and life-cycle analyses.
- Monitoring and surveillance.
- Economic and social benefits and costs.
The federal government in coordination with developers should, in an open and transparent process, begin discussions on approaches to establish standards for assay methods, data, and information management. The national laboratories or public–private partnerships may be possible avenues to advancing activities in this area: the U.S. Department of Energy’s Bioenergy Research Centers and the Joint Initiative for Metrology in Biology supported by the National Institute of Standards and Technology are examples of relevant entities that are supported by similar strategic federal investments.
Finally, the committee notes that the financial resources needed to establish an adequate research portfolio for the United States need not fall solely on the federal government and the nation’s tax payers. The federal government should explore establishing open and transparent approaches to integrate and optimize public investments, private investments, and public–private partnerships to realize the needed resources to support development of a responsive risk-analysis paradigm.
The committee notes that this recommendation is supported by recommendations in the National Academies reports on gene drives and genetically engineered crops, which stated:
There is an urgent need for publicly funded research on novel molecular approaches for testing future products of genetic engineering so that accurate testing methods will be available when the new products are ready for commercialization. (NASEM, 2016b:236)
Researchers, regulators, and other decision makers should use ecological risk assessment to estimate the probability of immediate and long-term environmental and public health effects of gene-drive modified organisms and to inform decisions about gene drive research, policy, and applications. (NASEM, 2016a:128)
To strengthen future ecological risk assessment for gene-drive modified organisms, researchers should design experimental field trials to validate or improve cause-effect pathways and further refine ecological models. (NASEM, 2016a:128)
Recommendation 3-2: Federal agencies that fund early-stage biotechnology-related research and regulatory agencies should provide support to academic, industry, and government researchers to close gaps and provide linkages to market-path requirements for regulatory success.
Many future products of biotechnology build on advances from the research community that take place in environments that are far removed from a regulatory context. Nonetheless, early consideration of regulatory needs could be highly beneficial and could lead to collection of data and incorporation of features that provide substantial benefit to regulatory science and regulatory activities for products that build on that technology. Examples might include the development of quantita-
tive methodologies for risk assessment in biological products that involve consortia of engineered organisms, where much of the underlying understanding of long-term behavior is currently missing.
The committee notes that this recommendation is supported by recommendations in the National Academies reports on gene drives and on the industrialization of biology, which stated:
To facilitate appropriate interpretation of the outcomes of an ecological risk assessment, researchers and risk assessors should collaborate early and often to design studies that will provide the information needed to evaluate risks of gene drives and reduce uncertainty to the extent possible. (NASEM, 2016a:128)
Government agencies, including EPA, USDA, FDA, and NIST, should establish programs for both the development of fact-based standards and metrology for risk assessment in industrial biotechnology and programs for the use of these fact-based assessments in evaluating and updating the governance regime. (NRC, 2015:109)
Recommendation 3-3: Government agencies that fund biotechnology development, working together with regulatory agencies and each other, should also invest in new methods of understanding ethical, legal, and social implications associated with future biotechnology products.
As noted in Chapter 4, research on the ethical, legal, and social implications (ELSI) of biotechnology represented less than 1 percent of total in investment during 2008–2015. It is likely that the ethical, legal, and social implications of future products of biotechnology will increase, so it will be important for federal agencies to ensure that investments in new methods of understanding ELSI associated with biotechnology are appropriately determined. This is especially important in the context of risk analysis as values are embedded in the choices of models, endpoints, risks assessed, and methods used. Investments should include adequate funding to proactively address ethical, legal, and social implications linked to new product introductions. Possible agencies that could support such efforts include the National Science Foundation and the U.S. Department of Energy, and also EPA, FDA, and USDA if they are appropriated funds for biotechnology research.
Recommendation 3-4: Government agencies with an educational mission should identify and fund activities that increase awareness and knowledge of the regulatory system in courses and educational materials for students whose research will lead to advances in biotechnology products.
At the time of completion of their degrees and postgraduate training, many of the students and postdocs who will go on to make important contributions to the technology of future biotechnology products may not be aware of the Coordinated Framework and may not have been exposed to methods of risk assessment and risk management that are part of the Coordinated Framework. Encouraging the development and inclusion of educational materials that provide insights and context to the regulation of biotechnology, along with quantitative tools for measuring uncertainty that forms the basis of quantitative risk assessment, could substantially benefit the governance, oversight, and regulation of future biotechnology products. In addition, early introduction to these concepts might spawn innovation in regulatory science and in product design that takes into account risk-analysis processes.
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