Regulations for the Bioeconomy

In “Racing to Be First to Be Second” (Issues, Spring 2023), Mary E. Maxon ably describes the regulatory challenges to the emerging bioeconomy in the United States. The Biden administration has recognized explicitly the transition from a “chemical” economy to one in which inputs, processes, and products are largely the result of “biology,” and has chosen to help facilitate that transition.

The United States regulates products, not technologies. The regulatory paths these products take are defined by their intended use or “regulatory trigger” (i.e., the legal concept determining whether and how a product is regulated) regardless of manufacturing method. Intended use has generally been a good guide in determining which agency has primacy of regulatory oversight, as envisioned in the federal government’s Coordinated Framework for the Regulation of Biotechnology, first issued in 1986.

Almost 40 years on, one questions if that is still the case. To paraphrase the Irish playwright and political activist George Bernard Shaw, regulators and the regulated communities are divided by a common purpose—the safe, effective, and yet efficient introduction of products into commerce. Some of these have traversed the regulatory system slowly, but under the aegis of one agency; others have been shuttled among agencies asking approximately the same risk questions. Duplicative regulation rarely provides additional protection; instead, it can make a mash of policy that can undermine public confidence. It further poses enormous costs to manufacturers and the chronically under-resourced and over-burdened regulatory agencies. And we have yet to find a way to estimate the direct costs and externalities of not developing the bioeconomy.

The examples that Maxon and others cite are products first developed over 20 years ago. What fate will befall products still “on the bench” or yet to occur in their inventors’ minds? Many participants in the field, me included, have advocated for the creation of a “single door,” possibly placed in a proposed bioeconomy Initiative Coordination Office, through which all (or almost all) products of the bioeconomy would be directed to the appropriate lead agency. Additionally, proposals have been floated to cross-train regulators, developers, funders, and legislators, possibly via mid-career sabbaticals or fellowships, about the various facets of the bioeconomy so that all are better prepared for regulatory oversight. These two steps could provide a mechanism for charting an efficient and transparent regulatory path. They will, of course, require nontrivial effort and coordination among and within agencies known more for their siloed behaviors than their cooperative interactions.

But a larger question lingers: Should we continue to regulate the products of the bioeconomy the same way we regulate the products of the chemical economy? Emerging technologies and their products can often require reframing risk pathways: it’s not that the endpoints (risks) are all that different; rather, the nature and kind of questions that characterize those risks can be more nuanced. Fortunately, we have also developed powerful, more appropriate tools to supplant the often irrelevant assays traditionally used to evaluate risks. We have also begun to understand that products posing minimal risks may not require the same regulatory scrutiny as products not yet seen by regulatory systems; these may require different and more complex hazard characterizations. Perhaps in addition to improving administrative paths, we should put some of the nation’s best minds toward the continued development of risk and safety assessment paradigms to be used simultaneously with product development so that regulation becomes—and is seen as—part of efficient, relevant, and responsible innovation and not just an unnecessary burden or box-checking exercise.

Larisa Rudenko

Mary E. Maxon advocates for a coordinated regulatory system as a critical need toward building the biotechnology ecosystem of the future. She’s exactly right, but coordination is just one piece of the regulatory puzzle and could be taken a step farther still.

The products that will drive the next century of paradigm-shifting economic growth defy easy definition or jurisdiction. Having witnessed the discussions that take place on products that cross boundaries of agency jurisdiction, I have heard each entity’s lawyers and regulatory experts make a clear and cogent case about why their agency has jurisdiction and why the risks of the technology are relevant to their mission to protect the public.

The problem is, they are all right in their arguments, which makes reaching consensus a challenge. Navigating their disagreements is particularly difficult when it comes to emerging biotechnologies, where the risk space is uncertain and agencies vary in their comfort level with different types of risk, whether to human health or innovation. In the federal context, this can be paralyzing; lack of consensus creates endless wheel-spinning or logjams, particularly when the parties involved do not share a common executive decisionmaker below the level of the president.

In an ideal world, this wouldn’t matter. Each regulatory agency has a vigorous regulatory process and the ability to bring in additional subject matter expertise when needed. That suggests a flexible process would be best, with a common regulatory port of entry and a fixed amount of time, as Maxon recommends, to determine a cognizant agency. Unfortunately, one person’s flexibility is another’s ambiguity, and this does not solve the issue of the regulated community of developers who understandably want to shape their data collection around the culture and requirements of the agency with whom they’ll be dealing so they can most easily navigate the regulatory process. Moreover, this will lead to inconsistency, as Maxon notes in the case of the genetically modified mosquitos, in which agencies, based on their own cultural norms around risk assessment, will operate under very different timelines and come to different conclusions.

How do you overcome this quandary? What’s needed is a third-party arbiter who has the authority to cut through disagreement to establish clear precedents and an evidence base for future decisionmaking that gives industry more certainty about regulatory pathways. The arbiter could also serve as a pre-submission advisory group for developers and agencies. This arbiter could be a White House-based Initiative Coordination Office (ICO), as Maxon suggests, but I would argue that more heft is needed to ensure resolution. One possibility would be a small council, administered by the ICO, with representation at a senior level from the agencies and appropriate White House offices, such as the Office of Science and Technology Policy, the Domestic Policy Council, and the Office of Information and Regulatory Affairs, with clearly delegated authority from the president. When decisions are made, the resulting deliberations could be made public, to give a set of “case law” to the developer and regulatory community and assure the public of the integrity of safety assessments. This would be a very different model than the current and ineffective voluntary approach emphasizing the soft diplomacy of coordination between agencies. Congress could also consider establishing a clear arbiter in future legislation that has power to determine which agency has final decisionmaking responsibility on any individual product. As the various parties work through options, however, one thing remains certain. New paradigm-shifting biological products will continue to emerge from the US innovation ecosystem, and Maxon is correct that it is time for a parallel shift in thinking about regulation and governance.

Carrie D. Wolinetz

For nearly 40 years academic and industrial laboratories have been working on “industrializing” biology, usually referred to as biotechnology. As Mary E. Maxon points out, the process has been extremely successful, but it has been halting and selective. The future potential is enormous and has implications for many sectors of the US economy. To date the vision of a wide bioindustry has been hampered, in part by what can be politely called regulatory confusion. Maxon proposes an ambitious regulatory reform that would clarify and accelerate the regulatory process under the oversight of a new entity, an Initiative Coordination Office that would work with the various agencies identified in President Biden’s Executive Order launching a National Biomanufacturing and Biotechnology Initiative. Based on past experience with biotechnology regulation, this suggestion is what is often described as necessary but not sufficient.

It is amazing that the core structure for the nation’s current regulatory process is still the 1986 Coordinated Framework for the Regulation of Biotechnology. Maxon describes the weakness of that structure, but misses two important elements that must be considered in the development of any new structure. First, the Coordinated Framework places a major emphasis not on the product under review but on how the product was produced. She cites an excellent example of that problem in the case of laboratory-grown mosquitoes where Oxitec failed and MosquitoMate succeed based on how essentially the same product was produced.

The second weakness of the Coordinated Framework is the promise of cooperation between the various agencies that had no strong commitment at the top management level. Each agency official responsible for coordination had very little incentive to “share their turf” with another regulator, often citing the constraints of the enabling legislation. The Coordinated Framework was endorsed unanimously at the Cabinet level, but the message never was heard in the ranks. If the proposed new Initiative Coordination Office is to have any impact, more than new rules are needed. Strong leadership and the articulation of the value and urgency of the bioeconomy to the country is essential. Regulators must realize that their job is not to block new products but to work with their customers to quickly identify any problems and move things through the pipeline smoothly. How a product is produced is an anachronism.

The distressing element related to the continued development of the bioeconomy is not just the absence of a functional and meaningful regulatory framework. Without public confidence in the results, even approved products will not be successful in the marketplace. Over the past few years, we have seen an alarming degradation of public confidence in government guidance and in scientific information, even that produced by highly qualified experts. Reversing this trend is going to be an enormous challenge, but may be far more important than the development of a robust regulatory framework. Initiatives such as BioFutures, created and administered by the philanthropy Schmidt Futures, can play a significant role in this process, but they need to stand back and look at the whole pipeline of the biofuture transformation.

David T. Kingsbury

Mary E. Maxon packages nearly 30 years of biotechnology governance into a call for action that cannot be ignored, centered on aligning regulations with the times. Indeed, of all the issues that plague the future of the US bioeconomy, a regulatory structure that no longer suits its regulatory context is worthy of special consideration.

Maxon presents examples of biotechnologies that have been delayed or even lost, ultimately due to deficits in “biocoordination.” While I second Maxon’s suggestion that the Initiative Coordination Office, if established in the White House Office of Science and Technology Policy, should support agency collaboration on horizon-scanning, transparency, and guided processing for future biotechnologies, coordination needs to be central to the framework, not an accessory to it. As long as its individual regulatory elements (the Environmental Protection Agency, Department of Agriculture, and Food and Drug Administration, among others) lack the infrastructure to “share regulatory space,” the current federally established Coordinated Framework for the Regulation of Biotechnology will continue to present gaps in coordination that threaten the bioeconomy.

Moreover, in considering ways to establish a regulatory framework that scales with future biotechnology, it will be essential to incorporate more public input and community reflection into the regulatory process. Maxon recommends the use of enforcement discretion as a strategy to fast-track new products that agencies consider low risk. This raises broader questions, however, of who determines safety and who determines risk? People and communities perceive risk differently, based on their lived experiences and their perceptions of what they have to lose. The same is true for safety, which also needs a collective definition that is grounded by social considerations. Creating a transparent decisionmaking process for biotechnology that integrates public input starts with redefining of risks and safety as a collective.

To put it plainly, if the nation maintains a collaboration that is built upon poor communication, then we ought not expect coordination. While collaborative governance is found throughout the US regulatory system, advancement will require acknowledgement of the regulatory problems that result from such governance strategies. In 2012, the Administrative Conference of the United States released a report titled Improving Coordination of Related Agency Responsibilities. When addressing the concept of shared regulatory space, the report states: “Such delegations may produce redundancy, inefficiency, and gaps, but they also create underappreciated coordination challenges.” As Maxon cleverly points out, this coordination challenge is petitioning for the creation of a regulatory framework for the bioeconomy—not just biotechnology.

To build on the author’s observations, concerted and deliberate policy action is crucial for fostering a regulatory ecosystem that advances the bioeconomy—subject, of course, to public trust—and increases national competitiveness, both now and in the future.

Christopher J. Gillespie

Mary E. Maxon argues for the establishment of a bioeconomy Initiative Coordination Office that could facilitate interagency collaboration, cross-train regulators, conduct horizon-scanning, and establish a single point of contact for guiding developers of biotechnology products through the regulatory process. This may seem like an impossibly long list of activities, especially in the area of biotechnology regulation, but I believe they are achievable, given the right support from the White House and Congress.

I say this because, as part of a team of Obama administration officials, I worked with dozens of experts from across the federal government, and I saw firsthand that it is possible to address the complexity and confusion in the biotechnology regulatory system. We delivered two public-facing policy documents: the 2017 Update to the Coordinated Framework for the Regulation of Biotechnology (2017 Coordinated Framework), which represented the first time in 30 years that the government had produced a comprehensive summary of the roles and responsibilities of the Food and Drug Administration (FDA) , the Environmental Protection Agency (EPA), and the Department of Agriculture with respect to regulating biotechnology products; and the National Strategy for Modernizing the Regulatory System for Biotechnology Products (2016 Strategy), which described a set of steps those agencies were planning to take to prepare for future products of biotechnology.

These documents were not cure-alls, but they represented progress. And don’t take just my word for it. The Trump administration, hardly known for cheerleading Obama-era policies, issued an Executive Order in 2019 stating that the 2017 Coordinated Framework and the 2016 Strategy “were important steps in clarifying Federal regulatory roles and responsibilities.”

To further support my contention that progress is possible (and to clarify one detail that Maxon discusses), I point to one of the policy changes that came out of the Obama-Trump Biotechnology Regulatory Modernization effort. This change specifically addresses the case studies of laboratory-grown mosquitos that Maxon describes. As she stated, the Oxitec mosquito, which was developed with genetic engineering, and the MosquitoMate mosquito, which was infected with a bacteria called Wolbachia, were both products with very similar mosquito population control (i.e., pesticidal) claims. However, one mosquito (Oxitec) was regulated by the FDA and the other (MosquitoMate) was regulated by the EPA.

The interagency team that developed the 2016 Strategy and the 2017 Coordinated Framework recognized this inconsistency and addressed it. In the 2016 Strategy, the EPA and the FDA committed to “better align their responsibilities over genetically engineered insects with their traditional oversight roles.” In October 2017, the FDA issued a final policy, clarifying that the EPA will regulate mosquito-related products intended to function as pesticides and the FDA will continue to have jurisdiction over mosquito-related products intended to prevent, treat, mitigate, or cure a disease. Since this clarification, Oxitec has received the green-light from the EPA to conduct field trials of its genetically engineered mosquitos in Florida and California.

A quarter of a century passed between the 1992 and 2017 updates to the Coordinated Framework for the Regulation of Biotechnology, during which time advances in biotechnology altered the product landscape. This mismatch between the regulatory system and technological progress made it difficult for the public to understand how the safety of some biotechnology products was evaluated, and also made it challenging for biotechnology companies to navigate the regulatory process. In the past eight years progress has been made, and there is clearly now momentum in Congress and in the White House to advance that momentum.

Robbie Barbero

Mary E. Maxon argues convincingly that the White House Office of Science and Technology Policy (OSTP) should establish a bioeconomy Initiative Coordination Office (ICO) as mandated in the CHIPS and Science Act of 2022. Although Maxon focuses on its key role in the biotechnology regulatory system, it is important to think broadly and strategically about the many activities that a bioeconomy ICO should lead and coordinate governmentwide. The office should work not only to support the biotechnology regulatory system but also to coordinate strategic planning of federal investments in the bioeconomy; to facilitate interagency processes to safeguard biotechnology infrastructure, tools, and capabilities; and to serve as a focal point for government engagement with industry, academia, and other stakeholders across the bioeconomy.

This broad purview is supported by the language in the CHIPS and Science Act and would also encompass many of the activities included in President Biden’s Executive Order 14081 on “Establishing a National Biomanufacturing and Biotechnology Initiative.” Indeed, a recent bipartisan letter confirms Congress’s intent that the ICO described in the legislation incorporate this broader initiative. A bioeconomy ICO would be analogous to other congressionally mandated Coordination Offices at OSTP that drive effective interagency coordination and outreach, including those for the US Global Change Research Program, the National Nanotechnology Initiative, and the Networking and Information Technology Research and Development Program.

A public-facing bioeconomy ICO will make an ideal home for the biotechnology regulatory system’s “single point of entry” for product developers, and Maxon rightly places this issue as a top priority. To establish this approach, the ICO should work closely with the principal regulatory agencies to define ground rules for this process that will support efficient decisionmaking while also reflecting and protecting each agency’s autonomy in interpreting its own statutes and responsibilities. As experience is gained, the ICO should work to address bottlenecks to decisionmaking and help distill generalizable principles and useful guidance.

Another critical role for the ICO should be to support and coordinate a project-based fellowship program that brings together individuals with a wide range of perspectives from government agencies, industry, academia, the legal profession, and other sectors to focus on issues of relevance to the biotechnology regulatory system. In addition to providing fresh eyes and new perspectives, a program of this type would present opportunities for training and cross-sectoral engagement for regulators and would improve understanding of the biotechnology regulatory system across the bioeconomy.

Executive Order 14081 and the CHIPS and Science Act have kicked off a flurry of activity within the federal government related to the bioeconomy, and the regulatory system will need additional tools to keep up. Now is the time for OSTP to establish a bioeconomy ICO as a foundation for robust and durable interagency coordination that can lead in transforming the range of possible beneficial outcomes into reality.

Sarah R. Carter