On May 8, 2024, the U.S. Environmental Protection Agency (EPA), U.S. Food and Drug Administration (FDA), and the U.S. Department of Agriculture (USDA) released a plan to update, streamline, and clarify their regulations and oversight mechanisms for products of biotechnology. The Coordinated Framework for the Regulation of Biotechnology: Plan for Regulatory Reform under the Coordinated Framework for the Regulation of Biotechnology (the Plan) provides a roadmap for actions the agencies will take, individually and collaboratively, to improve regulatory clarity, streamline regulatory oversight, reduce regulatory redundancies and gaps, and increase regulatory coordination for specific product categories and across the Coordinated Framework. The Plan identifies regulations and guidance documents that can be updated, streamlined, or clarified and identifies potential new guidance or regulations, where needed. These actions will focus on the following areas of biotechnology product regulation: modified plants; modified animals; modified microorganisms; human drugs, biologics, and medical devices; and cross-cutting issues.

Background

As reported in our September 13, 2022, blog item, on September 12, 2022, President Joseph Biden signed an Executive Order creating a National Biotechnology and Biomanufacturing Initiative to accelerate biotechnology innovation and grow America’s bioeconomy across multiple sectors in industries such as health, agriculture, and energy. On December 20, 2022, the White House Office of Science and Technology Policy (OSTP) issued a request for information (RFI) on behalf of the primary agencies that regulate the products of biotechnology — USDA, EPA, and FDA — requesting relevant data and information, including case studies, that may assist in identifying any regulatory ambiguities, gaps, inefficiencies, or uncertainties in the Coordinated Framework for the Regulation of Biotechnology, particularly with regard to new and emerging biotechnology products. 87 Fed. Reg. 77900.

On November 13, 2023, USDA, EPA, and FDA posted the following documents on the Unified Website for Biotechnology Regulation:

• Report on Stakeholder Outreach Related to Ambiguities, Gaps, Uncertainties in Regulation of Biotechnology Under the Coordinated Framework (Report on Stakeholder Outreach) (Mar. 11, 2023); and
• The Coordinated Framework for the Regulation of Biotechnology: Plain language information on the biotechnology regulatory system (Plain Language Document) (Nov. 2023).

According to the Report on Stakeholder Outreach, in reviewing the comments on the RFI, several themes emerged: (1) requests for greater regulatory clarity; (2) requests for greater regulatory coordination and harmonization; (3) requests for regulatory reform or revision; and (4) comments on regulatory resources. The Report on Stakeholder Outreach summarizes comments representing each area.

Modified Plants

According to the Plan, commenters expressed various agency-specific and cross-agency concerns about the regulation of modified plants and plant products, including: cumbersome and lengthy regulatory processes; the scope of plant-incorporated protectants (PIP); lack of harmonization of approaches to the regulation of genome-edited plants and new varieties of previously reviewed plants; lack of alignment of timelines for reviews of products subject to regulation by more than one agency; food crops engineered to produce substances that could cause food safety concerns if they inadvertently enter the general food supply; duplicative regulation of genetically modified plants; and a need for recognition by agencies of each other’s expertise to promote predictability, reduce redundancy, and enable synchronous agency decisions.

The Plan states that agencies will identify ways to streamline review processes, including:

• USDA will identify ways to streamline its Regulatory Status Review (RSR) process: Modified plants that do not meet the criteria for exemption from USDA regulations have an opportunity for a regulatory off-ramp through the RSR process. To improve the predictability of this process (which is important for developers making business plans and decisions), in fiscal year (FY) 2024, USDA will review the RSR process to identify improvements that will bring processing times into greater alignment with the target timeframes specified in its biotechnology regulations. Following its review, USDA will continue implementing process improvements and track progress in shortening the time taken to complete reviews until it reaches full alignment with the timeframes specified in the biotechnology regulations.
• EPA will identify ways to streamline and ensure consistency across its PIP registration reviews: To improve the quality of materials received and the predictability of reviews of PIP registration applications under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), EPA is developing guidance documents on common data needs for PIPs for each of the three components of the risk assessment: molecular characterization, human health assessment, and ecological assessment. EPA will also develop internal guidance for PIPs related to technical screen checklists, study evaluation templates, and risk assessment templates to ensure consistency across reviews.
• FDA intends to develop procedural guidance for participants in its voluntary consultation program as resources allow. The guidance would provide clarity for stakeholders, making for a more efficient and timely voluntary consultation process. This guidance would help stakeholders better understand the food safety issues considered in the voluntary consultation process and thereby lead to higher quality submissions from program participants. This guidance may also provide business process improvements that enable FDA to respond to consultation submissions in a timelier way.

USDA will streamline its permitting process and update its user guides. Under USDA’s revised regulations, modified plants that do not meet the criteria for regulatory exemption and that have not successfully completed the RSR process require a permit for import, interstate movement, and environmental release. To improve consistency in oversight, the revised regulations adopted a single method to authorize regulatory activities using a permitting process. Separately, USDA adopted a new Web-based permitting system for a variety of different products, including but not limited to biotechnology products. According to the Plan, collectively, these actions added administrative steps related to biotechnology permit issuances for external and internal users, increasing processing times and impacting the predictability of the permitting process. To address these issues, beginning in the first quarter of FY 2024, USDA will take the following actions:

• In consultation with EPA and FDA, USDA will explore eliminating interstate movement permits for certain plants or establishing alternative import and interstate movement permit categories for certain plants with streamlined processes and permit conditions, while retaining inspection and recordkeeping requirements;
• USDA will streamline permit application reviews to remove identified redundancies within its permitting process, revise its confidential business information (CBI) review process, and conduct risk-based reviews of standard operating procedures (SOP) for which USDA has established standard supplemental permit conditions, including all interstate movement and importation permits for plants and for environmental releases for familiar crops (e.g., corn, soybean, cotton, potato, tomato, canola, and alfalfa) and traits. USDA will also consider issuing multi-year permits for all interstate movement and importation permits for plants and for environmental releases for familiar crops (e.g., corn, soybean, cotton, potato, tomato, and alfalfa) and traits;
• USDA will streamline Supplemental Permit Conditions to ensure it assigns permit conditions that meet USDA protection goals, are consistent among developers, and provide concise, plain-language requirements. According to the Plan, USDA is reviewing and revising current standard supplemental permit conditions for all movement types (importation, interstate movement, and environmental release). USDA will communicate key changes to stakeholders and complete its review and revisions during FY 2024;
• USDA will post updated and new user-friendly permitting guidance documents for product developers in FY 2024, including:
  • An update to the Permit User Guide to align with USDA’s revised regulations and Animal and Plant Health Inspection Service’s (APHIS) eFile permitting system; and
  • A final Guide to Submitting Data for Reports and Notices that will provide information and instructions for permit holders on submitting reports and notices to maintain compliance with USDA regulations during regulated activities.

EPA and USDA will clarify and streamline PIP regulation. As reported in our June 2, 2023, memorandum, EPA issued a final rule on May 31, 2023, that exempts a class of PIPs created using genetic engineering from registration requirements under FIFRA and from the food or feed residue tolerance requirements under the Federal Food, Drug, and Cosmetic Act (FFDCA). The Plan states that EPA plans to update existing guidance on small-scale field testing of PIPs to incorporate USDA’s containment measures and modify, as necessary, the list of containment measures intended to reduce the probability for PIP residues to enter the food and feed supply from small-scale field tests. To minimize duplicative regulation of products that are subject to EPA pesticide regulations, in FY 2024, USDA will clarify its exemption from permitting requirements for modified plants containing PIPs that are registered by EPA as pesticides and, in consultation with EPA, will explore additional mechanisms for minimizing duplicative regulation of such products. The Plan notes that in response to requests from developers, EPA intends to address the scope of plant regulator PIPs.

EPA, FDA, and USDA intend to clarify their regulatory approaches to genome-edited plants and ensure their regulatory approaches are risk proportionate. As reported in our February 29, 2024, blog item, FDA recently issued “Guidance for Industry: Foods Derived from Plants Produced Using Genome Editing” that clarifies FDA’s current thinking on the safety and regulatory status of foods derived from genome-edited plant varieties in accordance with its 1992 policy on foods from new plant varieties. According to the Plan, USDA and EPA will solicit feedback on additional modifications in plants that can be exempt from their respective regulations. USDA will consider comments on a November 15, 2023, notice on additional modifications that plants, including polyploid plants, can contain and be exempt from its regulations, based on publicly available scientific information describing advances in conventional breeding techniques. More information on the notice is available in our November 16, 2023, blog item. The Plan states that EPA will similarly issue a notice to solicit feedback to identify new categories of PIPs that could meet the FIFRA and FFDCA statute requirements for exemption that could be added to the list of exempt genetically engineered PIPs in future rulemakings.

USDA will streamline the process to update the List of Bioengineered Foods maintained in accordance with the National Bioengineered Food Disclosure Standard. USDA’s Agricultural Marketing Service (AMS) works with APHIS, FDA, and EPA to identify foods that meet the definition of a bioengineered food. This list helps identify foods or ingredients that may be required to be labeled as bioengineered. USDA will publish an RFI rather than an advance notice of proposed rulemaking to start each cycle of list updates to accelerate the rulemaking process, while continuing to allow for critical stakeholder input and feedback. As reported in our April 4, 2024, blog item, AMS published an RFI on March 28, 2024.

According to the Plan, FDA and USDA intend to collaborate to consider mechanisms for stewardship of food crops engineered to produce substances that could cause food safety concerns, or other food crops where stewardship may be important, if they inadvertently enter the food supply. The Plan states that USDA and FDA have noted an increased interest in using genetic engineering to produce, in food crops, ingredients intended for specific food uses that may pose food safety issues if they enter the general food supply (e.g., allergenic ingredients not previously produced by those crops), as well as other food crops where stewardship may be important. The Coordinated Framework did not explicitly address this subset of genetically engineered food crops. FDA and USDA intend to consider mechanisms for stewardship of such crops to ensure they are directed toward their intended uses and to minimize, where relevant, the possibility that material from the crops inadvertently enters the general food supply. Such mechanisms may be led by developers or third parties with advice from USDA and FDA, as appropriate, and could be applicable to other situations in the future if relevant.

Modified Animals

The Plan states that commenters stressed the importance of providing clarity about the regulatory process for modified agricultural animals falling under the Coordinated Framework, noted the ongoing discussions between FDA and USDA, and encouraged the agencies to bring closure to discussions, noting the importance of streamlining rather than complicating the regulatory process, although commenters differed in their preferred outcome. Commenters also requested that FDA and USDA provide information on principles and process for implementing regulatory oversight of cultured animal cell foods per their March 2019 Formal Agreement. The regulatory process for modified insects and other invertebrates also remains unclear and duplicative in some circumstances.

The Plan states that FDA and USDA recently signed a Memorandum of Understanding (MOU) on information sharing and regulatory cooperation on heritable intentional genomic alterations in animals that are also subject to USDA oversight. The MOU establishes policies and procedures to enhance the exchange of information between the agencies; describes the regulatory roles of the agencies; and promotes coordination of regulatory responsibilities. It does not change or add regulatory requirements for developers.

FDA recently issued two companion guidance documents on heritable intentional genomic alterations (IGA) in animals:

• Guidance for Industry (GFI) #187A, “Heritable Intentional Genomic Alterations in Animals: Risk-Based Approach,” is a final guidance document describing FDA’s general approach to the oversight of heritable IGAs in animals. Under this approach, FDA may exercise enforcement discretion and not expect people or companies developing certain types of IGAs in animals to submit an application or get approval before marketing their products; and
• GFI #187B, “Heritable Intentional Genomic Alterations in Animals: The Approval Process,” is a draft revised guidance document that describes how the FDA approval process applies to heritable IGAs in animals. According to the Plan, FDA is issuing GFI #187B as a draft guidance document to solicit comments that will enable the agency to update, and make as efficient as possible, the approval process for IGAs in animals.

The Plan states that FDA and USDA intend to clarify and provide guidance on the regulation of cultured animal cell foods. According to the Plan, FDA and USDA staff are in routine contact to ensure that oversight is implemented consistently with the roles and responsibilities described in the March 2019 Formal Agreement Between FDA and USDA Regarding Oversight of Human Food Produced Using Animal Cell Technology Derived from Cell Lines of USDA-amenable Species. FDA intends to issue draft guidance that would help manufacturers and other industry stakeholders understand the types of food safety issues they should consider when producing cultured animal cell foods and how to assemble and organize information that can support a firm’s conclusion about the safety of their food. The Plan notes that in 2024, USDA will propose new regulations pertaining to the labeling of meat and poultry products composed of or containing cultured cells derived from animals subject to the Federal Meat Inspection Act or the Poultry Products Inspection Act. USDA will also issue labeling guidance for establishments producing these cell-cultured meat and poultry products.

EPA, FDA, and USDA intend to provide updated information on the regulation of modified insect and invertebrate pests and work together to streamline and coordinate the regulation of modified insects. According to the Plan, EPA will provide efficacy guidance on genetic modifications in pest animals intended for use as a pesticide. EPA requires scientific evidence that registered products sold to control pests known to impact public health (such as those that carry West Nile virus, Zika virus, and dengue) are effective against the target pest. The Plan states that given the unique parameters involved with field testing of modified mosquito products, EPA will develop efficacy guidance for modified mosquito products for population control.

Modified Microorganisms

According to the Plan, stakeholders commented that agency roles and responsibilities remain unclear for various microbial products (e.g., microbial inoculants/biostimulants used for plant growth promotion, plant pests, microbial biocontrol organisms, and microbial biomass used for human and animal feed). Stakeholders requested an integrated approach to improving regulatory clarity and harmonization, limiting duplicative oversight, and ensuring risk-proportionate regulation of engineered microbes. The Plan notes that greater agency coordination will minimize the potential for stakeholder confusion or conflicting regulatory requirements among the agencies.

EPA and USDA will clarify, and as possible harmonize, regulatory roles, processes, and information, data, and authorization requirements for environmental release of modified microbes. The agencies will undertake this effort to reduce regulatory duplication where possible, harmonize risk-based processes and requirements, and increase interagency communication, particularly regarding small-scale field trials.

USDA will clarify the modified microorganisms that are subject to regulation under its authority. Under USDA’s revised regulations, modified plant pests, microorganisms modified with DNA from a plant pest where the DNA can produce an infectious agent or compound that causes plant disease, and modified microorganisms that are used to control plant pests and could pose a plant pest risk require a permit for import, interstate movement, and environmental release. USDA will develop, publish, and maintain a list of plant pests. In the legacy biotechnology regulations, USDA maintained a regulatory listing of taxa to describe “organisms that are or contain plant pests” to aid developers in determining whether a modified organism required a USDA permit. When USDA updated its regulations in 2020, it removed this listing from the regulations because it had become out of date and agreed to post a list of taxa on its website that could be regularly reviewed and updated. The Plan states that USDA plans to begin developing the plant pest list in FY 2024 and will provide an opportunity for public comment on the list.

According to the Plan, USDA will explore mechanisms to exempt certain modified microorganisms from its regulation. USDA will explore potential regulatory changes that would exempt from USDA regulations, in whole or in part, modified biological control organisms that are not plant pests and that are registered with EPA as microbial pesticides or that are not EPA registered pesticides but are being transferred, sold, or distributed in accordance with EPA’s regulations at 40 C.F.R. Section 152.30.

The Plan states that USDA will explore potential pathways to commercialization, including mechanisms for risk-based deregulation, for non-plant organisms that could be proposed in future rulemaking, including by considering comments from stakeholders on the RFI issued in November 2022, further engaging impacted developers and other stakeholders, and consulting with EPA and FDA. According to the Plan, USDA will further streamline permit application and review processes to enable efficient movement of modified microbes between APHIS-approved containment facilities for contained research activities. USDA will streamline Supplemental Permit Conditions for microbe release permits to ensure it assigns permit conditions that meet its protection goals, are consistent among developers, and provide concise, plain-language requirements. USDA will further revise its draft microorganism permit guide. As reported in our October 20, 2023, blog item, in October 2023, USDA published a revised draft guide for submitting permit applications for modified microorganisms and a response to public comments on the initial draft guide issued in March 2023. As part of its ongoing commitment to clarify the guide further, after intra- and interagency consultation, USDA will publish a revised draft guide for public comment. The revised draft guide will provide information on USDA processes, criteria, and any associated data requirements for determining regulatory jurisdiction for microorganisms based on whether an organism is a plant pest or biocontrol organism that could pose a plant pest risk. It will harmonize, where possible, information and data requirements for modified and non-modified microbes subject to USDA regulation under the Plant Protection Act.

The Plan notes that biopesticides often have lower toxicity profiles, reduced worker re-entry intervals, and reduced pre-harvest intervals. They can also support climate change mitigation (e.g., by providing alternatives to ozone-depleting pesticides or reducing on-field applications and use of fossil fuels) and help advance environmental justice. The Plan states that considering these benefits, EPA will prioritize review of biopesticide applications, provide technical assistance to biopesticide developers, and seek to collaborate with state lead pesticide agencies to reduce the time to bring new and effective biopesticide tools to farmers, as resources allow and in alignment with the Pesticide Registration Improvement Act (PRIA 5).

Human Drugs, Biologics, and Medical Devices

According to the Plan, stakeholders commented that FDA should update or issue new guidance documents or regulations in areas related to human drugs and biologics, such as aseptic processing of sterile drug products, validation and testing procedures, quality metrics reporting, the manufacture of multiple products in a single facility, lot release and product characterization requirements, cross-referencing of drug master files, sterility assurance and contamination control, and certain animal testing requirements. A commenter requested that FDA rather than EPA oversee products with anti-biofilm claims. Another commenter recommended that the United States should foster the domestic manufacture of active pharmaceutical ingredients.

The Plan states that FDA intends to issue a proposed rule to revise regulations related to post-approval chemistry, manufacturing, and controls (CMC) changes for both drugs and biological products, and intends to issue draft guidance to provide greater clarity on its oversight of post-approval CMC changes for certain biotechnology products. FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) are developing a proposed rule to revise regulations related to post-approval CMC changes (21 C.F.R. Sections 314.70, 314.81, and 601.12) to facilitate further application of risk-based approaches, including the use of tools described in the internationally harmonized guidance International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. In July 2023, CBER issued the draft guidance document Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products (CGT products) to provide more guidance on post-approval changes in these products. CDER and CBER are also developing draft guidance on post-approval manufacturing changes to biosimilar and interchangeable biosimilar products to provide clarity on how to make post-approval changes for biosimilar products.

The Plan states that FDA is developing guidance on its oversight of certain genome-editing products, including use of a platform approach to such therapeutics. In January 2024, CBER issued a final draft of the guidance document Human Gene Therapy Products Incorporating Human Genome Editing. This guidance addresses development of human genome-editing products for clinical studies and licensure. The Plan notes that while the potential of such products for the treatment of human disease is clear, the potential risks are not as well understood. To assist in the translation of these products from the bench to clinical trials, the guidance includes recommendations for how to assess the safety and quality of these products and address the potential risks of these products. According to the Plan, as the field evolves, product design advances, and FDA gains information on the safety of human genome-edited products, FDA may revise its recommendations to consider such changes.

CDER and CBER plan to issue draft guidance to implement Section 2503 of the 2023 Consolidated Appropriations Act. According to the Plan, to implement this provision, FDA intends to establish a platform technology designation program. The guidance would describe the program and how interested persons can submit a request for a platform technology to be designated. If a platform technology designation request is granted, FDA may accept a request for expedited development for any subsequent application submitted under Sections 505(b) of FFDCA or 351(a) of the Public Health Service (PHS) Act that uses the platform technology. Expedited development for a subsequent application may include engaging in early interactions with sponsors to discuss the use of a platform technology and providing timely advice to and having additional engagement with the sponsor during the development program.

In January 2024, CBER issued a final draft of the guidance Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products. The guidance provides CAR T cell-specific recommendations regarding CMC, pharmacology and toxicology, and design of clinical studies for cancer indications. This guidance also provides recommendations for analytical comparability studies for CAR T cell products.

In December 2023, CBER updated the guidance Potency Assurance for Cellular and Gene Therapy Products. The revised draft guidance document updates FDA’s recommendations for potency assays for CGT products and further recommends a comprehensive approach to ensuring potency that is grounded in quality risk management.

According to the Plan, FDA will continue to partner, along with the National Institutes of Health and multiple public and private organizations, in the Accelerating Medicines Partnership Bespoke Gene Therapy Consortium public-private partnership. The Partnership aims to develop platforms and standards that will speed the development and delivery of customized or “bespoke” gene therapies that could treat the millions of people affected by rare diseases.

Cross-Cutting Issues

The Plan states that commenters had many requests and suggestions for greater clarity on and assistance with the regulation of biotechnology products that fall under the Coordinated Framework. In addition to requests for increased clarity in specific product areas, commenters asked the agencies to provide simple, plain language information that clarifies agency responsibilities for different products, data requirements and regulatory processes, and the bases for decision-making. According to the Plan, commenters suggested using the Unified Website for Biotechnology Regulation to provide plain language summaries of regulations, as well as guidance and documents such as case studies, and as a one-stop shop for stakeholder questions and updates. Commenters asked the agencies to provide dedicated staff who would be directly available to provide regulatory assistance to developers. In addition to actions described above to increase regulatory clarity and assistance, EPA, FDA, and USDA will:

• Work together to provide plain language information on regulatory roles, responsibilities, and processes for products of biotechnology; and
• Develop and implement a mechanism for developers to submit information to, and request a meeting with, all three regulatory agencies, early in the product development process.

The Plan notes that commenters stressed the need for greater policy and process alignment across EPA, FDA, and USDA regarding regulation of biotechnology products to reduce uncertainties for developers and avoid unnecessary redundancies. Commenters urged the agencies to align definitions, regulatory exemptions, data and other information requirements, and timelines for reviews; to coordinate reviews and recognize their sister agencies’ expertise; and to establish a single point of entry into the regulatory system. Further, they asked for coordination across all federal agencies that touch products of biotechnology, from regulatory and trade agencies to administrative and security agencies, and made various recommendations for establishing a formal interagency coordinating body. The Plan states that EPA, FDA, and USDA intend to:

• Update and renew their information sharing MOU; and
• Work together to update the Coordinated Framework for the Regulation of Biotechnology by December 2024.

Commentary

The Plan is good news by any standard. The words “update,” “streamline,” and “clarify” are music to the ears of any innovator, registrant, or other stakeholder in this complicated and fast-evolving area of law, policy, and science. We noted the tremendous challenges stakeholders face with the lack of clarity among EPA, FDA, and USDA in our 2015 publication “The DNA of the U.S. Regulatory System: Are We Getting It Right for Synthetic Biology?,” published in the Woodrow Wilson International Center for Scholars Synthetic Biology Project Report. The report highlights just how porous the jurisdictional divide is among these agencies and the lack of clarity and direction for innovators in this space in terms of how to obtain approvals for products as a predicate to commercialization. We applaud the Plan and wholeheartedly support its goals. The hard part is executing on the plan and making the updating, streamlining, and clarifying part a reality, and soon!