ASM Responds to White House Office of Science and Technology Policy on P3CO and DURC
Office of Science and Technology Policy
Executive Office of the President
Attn: Stacy Murphy, Deputy Chief Operations Officer
1650 Pennsylvania Avenue
Washington, D.C. 20504
Re: Request for Information: Potential Changes to Policies for Oversight of Dual Use Research of Concern (DURC) and the Potential Pandemic Pathogen Care and Oversight (P3CO) Policy Framework. 88 Fed Reg 60513 (September 1, 2023) Docket ID: EOP-2023-0001
Dear Dr. Murphy:
°®¶¹´«Ã½ (ASM), one of the oldest and largest life science societies with well over 36,000 members in the U.S. and around the world, appreciates the opportunity to respond to this request for information (RFI) on potential changes to policies governing research on certain types of pathogens. We thank you for your commitment to reviewing and revising policies governing Enhanced Potential Pandemic Pathogen (ePPP) research and Dual-use Research of Concern (DURC). ASM recognizes the importance of cutting-edge research on human, animal and plant microbes, as well as our responsibility as scientists to minimize the risks associated with our experiments and ensure the safety of the facilities in which they take place, as well as ensuring the confidence of the public in the scientific community.
ASM supports efforts to improve current policies and strengthen oversight for research that could pose risks to the public or to national security. At the same time, 3 areas that raise particular concern among our community are: 1) the broad scope of the proposed policies; 2) the availability of resources required to support the training, laboratory infrastructure and access to expertise that will be required; and 3) the feasibility of enforcing these policies to ensure their effective implementation. Below we offer a few general comments followed by specific responses to the questions posed in the RFI.
A key challenge is ensuring that new policies flag proposals that warrant additional oversight. Otherwise, we risk squandering valuable human and financial resources reviewing projects that do not pose safety threats to public health. Overly broad and vague definitions and duplicative regulations will have the unwanted outcome of slowing progress against infectious disease threats and in turn have their own costs to society. We believe that revised, streamlined regulations can be effective at both keeping the world safe and allowing for flexibility, because each experiment has unique considerations, such as the pathogen, biocontainment facilities, purpose for the work, expected outcomes and the research design required for the project.
Scientists conducting work with ePPP and doing DURC have a responsibility to ensure that there is negligible risk from the work in which they are engaged. This is true at all times, whether or not there is an imminent threat. Revised standards should allow for adapting the risk benefit calculus to allow researchers to pursue understanding of novel and imminent threats, while continuing to minimize risk. Overly rigid standards that do not allow us to anticipate the next threat will slow our ability to respond and develop countermeasures.
Resources, including training, are essential to making appropriate oversight work and ensuring that life-saving research is not unduly impeded. There should be consideration given to the impact of proposed policies on research institutions, biotechnology companies and other stakeholders. This would not only assist the federal government in proposing budgets that reflect the needs, but also inform Congressional funding decisions.
Publishers and publishing entities like ASM also have the responsibility to ensure we are not inadvertently jeopardizing global health security. As a publisher of 15 scientific journals, and one of the largest microbiology publishers in the world, ASM places high value on responsible communication of research findings and has a rigorous process for addressing concerns associated with publication of findings that could pose a biosecurity risk. Such policies should be applied across the publishing ecosystem, and we stand ready to offer our processes as a model for other organizations and publications. Research involving high levels of biosafety and biosecurity risks should be flagged for additional oversight and review well before the time of publication, as ASM is already doing. However, the consolidation of ePPP and DURC policies, coupled with efforts to increase global standards, could have the unintended consequence of blocking publication of key findings with potentially global consequences.
ASM supports merging ePPP and DURC policies into a single set of guidelines that governs both types of research.
The benefits of applying the revised policy to the scope of entities outlined in the RFI include:
(b) What are the benefits and challenges of investigators and institutions having primary responsibility for identification of both DURC and ePPP research?
Investigators and their institutions have always been the first line of defense when it comes to biosafety and biosecurity. Risk assessment begins when an individual investigator comes up with an idea, and labs and institutions have robust review processes in place. No one wants to move forward with a project that poses unnecessary risk to the scientists conducting the work, their students and colleagues or the public.
There are opportunities for greater engagement from institutions and subject matter experts. To be most effective, agencies must provide clear guidance to these entities about policies to ensure a common understanding of the requirements and consistency of approach.
The benefit of a “bottom up” approach is that risk assessment begins at the level closest to the research being conducted. Beyond the principal investigator, the institutional biosafety committee (IBC) is an irreplaceable component in risk assessment. IBCs can and should have broader expertise beyond virology or bacteriology. This is the best way to ensure research proposals that are not properly designed, do not have the appropriate biosafety measures in place or are otherwise considered “risky” never get started. This IBC review needs to occur regardless of whether the project has been submitted to a funding entity. Early engagement by the IBC also ensures that unexpected findings can be properly managed and communicated to the funding agency.
Support for training will be key to ensuring a system like this works well, so federal funders need to consider resources available to assist with these activities, especially in under-resourced institutions or those without necessary expertise.
There are challenges associated with this approach, especially if the scope is broadened and more institutions (e.g. Tier 2) are affected. Oversight that pulls in additional institutions underscores the need for top-down guidance and resources for training. Otherwise, the result may be that valuable research is discouraged from taking place at these institutions and this raises both public health and equity concerns. There may also be additional financial costs for the institution to consider.
If an institution does not have an IBC with sufficient expertise to evaluate the proposal, there may be a need to support creation of “contract” IBCs that offer, timely, comprehensive and consistent review, similar to human use protocols and contract IRBs. There will need to be incentives for review committee members given the time this work involves. We recommend ensuring that service on such a committee can count toward academic credit similar to service on peer review study sections.
A minority of institutions do this work regularly and very well, but there is not a coordinated mechanism in place to allow sharing of practices. The U.S. should fund infrastructure that enables other institutions to benefit from best practices practiced by experienced institutions. Lastly, the international angle will continue to be challenging. Providing a high level of training can help with international funding considerations, and there is precedent for U.S. institutions training foreign researchers in biorisk management practices. Policies need to take into account what work can be done safely in the U.S. versus what is feasible with international collaborators.
(c) What types of resources or tools would be useful for researchers and institutions to determine if their research falls into a revised policy scope that is risk-based rather than list-based, and adequately conduct risk assessments to identify DURC and ePPP research?
ASM supports a risk-based approach to one that is list-based. Lists are static and do not account for emerging and evolving pathogens. Also, a list-based approach can lend itself to “box-checking” rather than consideration of the “why” and the “how” the research is being proposed (versus the “what”).
There are resources and tools available to help researchers and institutions with this transition, but new resources will be required. The National (NBL) and Regional Biocontainment laboratories (RBL) have models that could be scaled to a national level. For example, the process used by the Galveston National Laboratory requires the investigator to complete a questionnaire upon developing the proposal that begins a comprehensive assessment before the project is started. For those institutions needing additional guidance, the NBL/RBL network also could be the source of review for those institutions that lack an IBC altogether or an IBC with requisite expertise to conduct a review.
The importance of training cannot be overstated. There are certified experts in the field who could be tapped to assist with those institutions which do not have the expertise. Mentoring programs specific to biosafety and biocontainment could also be beneficial for researchers working with infectious agents.
2. (a) Considering the diversity of federally-funded research settings and portfolios, how would adoption of NSABB’s Recommendation 10.1 affect policy implementation and research programs at the institutional level?
(b) Rather than including any pathogen within the scope of DURC review, one possible modification of 10.1 would be to include DURC experiments that utilize the BSAT list, Pathogen Risk Group classification of 3 or 4 or any pathogen where the conduct of work under DURC would require BSL 3 or 4 containment. Would such a modification be useful?
Benefits/challenges/gaps anticipated by revised scope?
This approach still uses a list. ASM supports a risk-based approach to one that is list-based. Lists are static and do not consider emerging and evolving pathogens. Also, this approach can lend itself to “box-checking” rather than consideration of the “why” and the “how” the research is being proposed (versus the “what”).
(d) Given the possible revised scope of research requiring review for potential DURC, what modifications, if any, to the current DURC policy list of 7 experimental effects should be considered for a revised policy that captures appropriate research without hampering research progress?
Exclusions should include the development of medical countermeasures.
3. (a) How would the change in definition of ePPP affect the overall scope of a revised policy and its subsequent implementation?
Virulence and transmissibility are not just properties of the agent itself, but also relate to how the agent behaves in a given host or population in addition to other context dependent factors. This is where the reasons and justification for the project and the procedures and biorisk mitigation plan become important.
Focusing on transmissibility presents a path to further hone the dividing line between projects that need an additional layer of oversight and those for which institutional-level oversight is sufficient. Transmissibility is the quality that most determines the threat to public health should there be a laboratory escape, intentional or by accident.
Lack of therapeutic options or countermeasures such as vaccines is another aspect that could be considered a point of demarcation when a project should receive additional oversight. For example, modifying an infectious agent so that it no longer responds to therapeutic options (e.g. resistant Streptococcus, or Candida auris) or modifying an infectious agent that is not highly transmissible and making it more transmissible in a host when there is no natural immunity or countermeasures would be a project that should fall under these definitions.
We do not recommend expanding the definition to include “moderately” virulent because it could cut off important areas of research that pose little threat to public health outside the laboratory such as work on the common cold and endemic viruses such as herpesvirus, papilloma viruses and adenoviruses. The vast majority of individual exposures in the laboratory can be mitigated through sound, comprehensive procedures to protect staff. Returning to the context of the research, there is a big difference between risk at the host level versus a risk at a population level. Finally, oftentimes it is not known how a virus will respond and require scaled experiments under appropriate biosafety conditions, reinforcing that virulence is not the best measure for what requires additional oversight.
Without the ability to adapt definitions to the context of the work, we run the risk of inconsistent application of the new standards and unnecessarily flagging certain projects for additional high-level oversight. This would lead to missed scientific opportunities and risks public health without making us safer. We also need to ensure revised policies recognize and support the role and expertise of the IBCs, which will be the main line of defense against improperly designed projects. Revised policies also need to allow for access to expertise when the IBC does not have what is needed.
Terms like “moderately” or “highly” transmissible or virulent are subjective and need to be adaptable to the context of the work being proposed. Effective implementation requires clear guidance from the federal government and having specific examples to illustrate the intent of the new definitions would be helpful. Otherwise, changes run the risk of being too subjective and open to varying interpretations by IBCs and other oversight bodies. It is also critical to consider the stated purpose and scientific goal of the proposed project.
(b) One possible modification to the NSABB PPP definition is to specify a respiratory route of transmission. Would that be a more appropriate scope to mitigate risks and enhance effective implementation?
As noted above, ASM agrees that focusing on transmissibility makes the most sense. While focusing on respiratory routes narrows the scope in a way that could be potentially helpful, we are concerned that exclusively focusing on this area could miss other areas where transmissibility is a concern but is not the phenotype being manipulated (e.g. drug resistant infectious agents).
Conversely, focusing exclusively on respiratory routes could have the effect of “overcorrecting” and capturing projects focused on common cold and tuberculosis, as two examples, that may not need extra review.
(c) Do you have additional suggestions to modify the PPP definition to mitigate the most significant risks not currently addressed and enhance effective implementation, while limiting negative or unintended consequences and burden on researchers, institutions, and the Federal government?
In addition to focusing on transmissibility in the population as noted above, an additional approach is to consider a higher level of scrutiny on those pathogens for which there is resistance or for which there are no countermeasures. These projects should receive additional consideration and could require that the work be done at BSL-3 or above. Most pathogens for which there are many unknowns are already studied at this level but standardizing this practice may be warranted.
For example, modifying enteric pathogens to be more transmissible and resistant to all therapies should receive a higher level of review. Any type of research that enhances transmission should receive additional scrutiny and taken to a higher level of biosafety. This keeps the focus on where the greatest risk is to population-based spread and elevates the question of how the research is done.
(d) Are there characteristics related to human pathology, pathogen characteristics or other features that would be helpful to clarify the intent of “moderately virulent?” Are there characteristics related to human pathology that would be helpful to clarify the intent of “moderately transmissible?”
As noted above, virulence can be a challenging parameter to use because virulence is a quality that is difficult to measure in a laboratory environment except in animal models, which do not always reflect how a pathogen behaves in a human. This is because virulence is a property of the interaction between agent and a given host. In the case of vaccine development against novel viruses, scientists often need to make the virus more virulent in an animal model (e.g. a mouse) in order to develop a vaccine. This does not necessarily mean the virus at that stage is dangerous to humans or at a population level. We do not support expanding the term to include “moderately virulent” because it is not by itself a good indicator of risk. Focusing on transmission and considering high virulence in the context of transmissibility is more appropriate.
4. Does the definition of “reasonably anticipated” provide additional clarity to ensure greater consistency in identifying research that falls within the scope of the revised policy? What modifications to this definition would be most helpful?
A more appropriate term to use in science would be “expected outcome.” Including “reasonably” is not useful because it implies a level of subjectivity when considering intent versus outcome. With enhanced pathogens, unexpected results could happen given the nature of the pathogen. However, understanding this in advance and ensuring the appropriate biorisk mitigations steps are in place is critical.
The term “reasonably anticipated” lacks clarity and specificity and structure. While scientists making the determination can evaluate the scientific merit of the research proposal, consideration must also be given to how the work is perceived and how it could impact those not directly involved. We recommend looking at the International Animal Care & Use Committee (IACUC) as a potential model, as well as Institutional Biosafety Committees (IBCs) that do this particularly well. These structures includes appropriate stakeholders to identify research that may need additional review.
5. NSABB recommends the removal of certain blanket exclusions for research activities associated with surveillance and vaccine development or production for research with ePPPs.
(a) Should exemptions for certain activities be included in a revised policy?
ASM supports the continued exemptions for research activities associated with surveillance and vaccine development. Exemptions also should be considered when there are national and international public health emergencies.
The proposed revised policies for laboratory research are not an appropriate framework for fieldwork, an essential tool in understanding the pathogens and variants that are circulating in the environment and animal reservoirs and what could be a threat (i.e. the human-animal-environment interface).
Zoonotic spillover has long been understood to be a common source of human infectious diseases. Sampling in certain animal populations such as bats, rodents and shrews known to harbor viruses that infect humans is necessary for ecological studies that map animal viromes and understand what pathogens exist and are likely to jump species, thus posing a threat to humans. Taking a One Health approach, research to understand the drivers of spillover events is important to minimize risk of human infection by zoonotic pathogens, including interventions such as vaccines. Members of the World Health Organization (WHO) One Health High-Level Expert Panel wrote recently about the importance of fieldwork to spillover prevention and proposed a proactive versus reactive approach to addressing spillover at the source. 1
Exempting surveillance activities should not be confused with the need for clear guidelines and standardized biorisk management processes. These should be developed and shared to ensure that fieldwork and surveillance is conducted safely.
Exclusions should remain for vaccine development given the importance of these countermeasures to population health and safety, especially during a public health emergency when there is a novel threat. Vaccine escape studies are especially important work that would be affected by removal of these exclusions because ePPP research animal models are essential to this work.
If the processes described above (e.g. risk assessment conducted at the outset; strong IBC engagement) are in place, this work can be done safely and effectively.
Other activities for which there should be exclusions include sequencing and characterization studies and antimicrobial development studies.
(b) What are the benefits and drawbacks of including exemptions for domestic and international pandemic preparedness, biosafety, biosecurity, and global health security?
Global health security depends on the U.S., with other international partners, leading the way by doing vaccine development research. As noted above, exemptions for vaccine work are essential to domestic and international pandemic preparedness. We need look no further than the COVID-19 pandemic to understand the importance of flexibility and speed to developing vaccines for a threat for which there was no natural immunity or existing countermeasures. It is only matter of time before we will face another novel infectious disease threat.
(c) If exemptions are included, how could they be bounded to maximize safety and security and minimize negative impact on domestic and global public health, including outbreak and pandemic preparedness and response? (e.g. Vaccine R&D could be unjustifiably impeded?)
Exempted work does not mean unsafe work. Projects still employ biorisk mitigation processes as they do for all work of this nature. Experiments are conducted at the appropriate biosafety level (e.g. BSL-3) given the unknowns.
6. (a) Is there a subset of such “in silico” research that should require risk assessment and review in a revised policy and if so, how should this research be defined so that the policy captures the appropriate research without hampering activities with limited biosecurity risk?
ASM agrees that it is important to look ahead and consider emerging technologies that are currently not captured under oversight policies but could pose a risk to public health. However, accomplishing this will be difficult and may be beyond the scope of the policies updates needed at this time to address ePPP and DURC oversight. In silico modeling has important applications to hypothesis generation, vaccine development, and any policies would need to avoid hindering this critical work. This work of “in silico for good” also provides an alternative to wet lab work which could potentially pose greater biosafety risks. At the present time, it is very difficult to take a sequence and construct a pathogen de novo. While the threat is there in theory, there is no evidence that this is a real threat at the moment.
The challenge is determining how artificial intelligence or in silico models could result in a transmissible pathogen. Recognizing that policies must always be forward-looking and anticipate gaps, we recommend considering a National Academies review of this technology to develop more evidence to support new policies in this space.
In closing, as you look to finalize these updated policies, we encourage you to build in periodic reviews and assessments of these policies to ensure they can adapt to the realities “on the ground” and also take into account new technologies. We will learn as these policies are implemented whether there are unforeseen negative consequences to research or oversight gaps that need additional consideration. It will be important to have a system that is flexible and adaptable so we can strike an appropriate balance.
Thank you for your attention to our views. If we can be of further assistance or if you have any questions, please contact Mary Lee Watts, ASM Director of Federal Affairs at mwatts@asmusa.org.
Sincerely,
Stefano Bertuzzi, PhD, MPH
ASM Chief Executive Officer
1 https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011504#
Executive Office of the President
Attn: Stacy Murphy, Deputy Chief Operations Officer
1650 Pennsylvania Avenue
Washington, D.C. 20504
Re: Request for Information: Potential Changes to Policies for Oversight of Dual Use Research of Concern (DURC) and the Potential Pandemic Pathogen Care and Oversight (P3CO) Policy Framework. 88 Fed Reg 60513 (September 1, 2023) Docket ID: EOP-2023-0001
Dear Dr. Murphy:
°®¶¹´«Ã½ (ASM), one of the oldest and largest life science societies with well over 36,000 members in the U.S. and around the world, appreciates the opportunity to respond to this request for information (RFI) on potential changes to policies governing research on certain types of pathogens. We thank you for your commitment to reviewing and revising policies governing Enhanced Potential Pandemic Pathogen (ePPP) research and Dual-use Research of Concern (DURC). ASM recognizes the importance of cutting-edge research on human, animal and plant microbes, as well as our responsibility as scientists to minimize the risks associated with our experiments and ensure the safety of the facilities in which they take place, as well as ensuring the confidence of the public in the scientific community.
ASM supports efforts to improve current policies and strengthen oversight for research that could pose risks to the public or to national security. At the same time, 3 areas that raise particular concern among our community are: 1) the broad scope of the proposed policies; 2) the availability of resources required to support the training, laboratory infrastructure and access to expertise that will be required; and 3) the feasibility of enforcing these policies to ensure their effective implementation. Below we offer a few general comments followed by specific responses to the questions posed in the RFI.
Minimizing Risk While Allowing for Scientific Progress
The vast majority of pathogen-focused research in the U.S. poses very little risk to the public; only a small number of projects (much less then 1%) warrant additional oversight. In addition, while there are always opportunities to make safety improvements, the U.S. stands as a global leader in biosafety and biosecurity.A key challenge is ensuring that new policies flag proposals that warrant additional oversight. Otherwise, we risk squandering valuable human and financial resources reviewing projects that do not pose safety threats to public health. Overly broad and vague definitions and duplicative regulations will have the unwanted outcome of slowing progress against infectious disease threats and in turn have their own costs to society. We believe that revised, streamlined regulations can be effective at both keeping the world safe and allowing for flexibility, because each experiment has unique considerations, such as the pathogen, biocontainment facilities, purpose for the work, expected outcomes and the research design required for the project.
Scientists conducting work with ePPP and doing DURC have a responsibility to ensure that there is negligible risk from the work in which they are engaged. This is true at all times, whether or not there is an imminent threat. Revised standards should allow for adapting the risk benefit calculus to allow researchers to pursue understanding of novel and imminent threats, while continuing to minimize risk. Overly rigid standards that do not allow us to anticipate the next threat will slow our ability to respond and develop countermeasures.
Engaging the Public and other Stakeholders
Beyond biosafety practices and appropriate oversight, scientists have a responsibility to engage and better communicate with the public and stakeholders outside the scientific community, including policymakers. Recent debates have focused on the risks of ePPP and DURC research, without a commensurate discussion about the benefits of this research. Scientists have a responsibility to acknowledge the inherent risks with some types of research, while also communicating the importance of the questions being explored and the procedures in place to conduct this work safely. The federal government can support these messages through greater transparency and clear guidance.Resources, including training, are essential to making appropriate oversight work and ensuring that life-saving research is not unduly impeded. There should be consideration given to the impact of proposed policies on research institutions, biotechnology companies and other stakeholders. This would not only assist the federal government in proposing budgets that reflect the needs, but also inform Congressional funding decisions.
Publishers and publishing entities like ASM also have the responsibility to ensure we are not inadvertently jeopardizing global health security. As a publisher of 15 scientific journals, and one of the largest microbiology publishers in the world, ASM places high value on responsible communication of research findings and has a rigorous process for addressing concerns associated with publication of findings that could pose a biosecurity risk. Such policies should be applied across the publishing ecosystem, and we stand ready to offer our processes as a model for other organizations and publications. Research involving high levels of biosafety and biosecurity risks should be flagged for additional oversight and review well before the time of publication, as ASM is already doing. However, the consolidation of ePPP and DURC policies, coupled with efforts to increase global standards, could have the unintended consequence of blocking publication of key findings with potentially global consequences.
Linking U.S. and Global Health Security
Finally, U.S. health security is inextricably linked to global health security, and we must use every tool at our disposal to work with our international partners to ensure research is both conducted at the appropriate biosafety levels and keeps the safety of the public top of mind. Otherwise, we risk incentivizing that this research move to other countries, including those that may not have the robust infrastructure and track record of safety we have in the U.S. There is a strong precedent for diplomacy in this space, which is essential to success. The U.S. should consider diplomatic levers that can be used to ensure that research around the world is held to the high standards enforced here in the U.S. and in other countries with strong biosafety and biosecurity infrastructure. International scientific partners need to learn from each other and seek harmonization of biorisk management protocols and practices in the U.S. and around the world. We think that nonprofit organizations, such as ASM, are well poised to work with the global scientific community and the public to hold the space for such conversations and engagements, perhaps in a more effective way than national governments can.Responses to Specific Questions
1. (a) What are the anticipated benefits and challenges of applying a Revised Policy, inclusive of both DURC and ePPP to the Scope of Entities Outlined Above?ASM supports merging ePPP and DURC policies into a single set of guidelines that governs both types of research.
The benefits of applying the revised policy to the scope of entities outlined in the RFI include:
- Increased consistency resulting from the rules being applied across stakeholders.
- Creation of a streamlined, simpler process given that the benefits and risks to the public are the same regardless of funding source or location.
- Inclusivity, as the approach takes into account that risk can be associated with plant and animal pathogens in addition to human pathogens. For example, the environmental and economic consequences of loss of animal life due to disease could be significant and we cannot overlook it. In addition, the potential economic impact of pathogens affecting plant or crop production represents a real security concern and needs to be addressed with equal importance.
- International considerations. By including international entities receiving U.S. funding, it ensures that we are addressing concerns about biosafety practices outside the U.S. that have global impact. We recommend also ensuring that revised policies in this space are harmonized with NIH guidance regarding international subawardees.
- Its applicability to agencies that do not have the requisite expertise or experience with implementing these policies,
- Oversight of international entities that operate under different laws and regulations.
- Need for resources required for federal agencies to enforce these guidelines and to develop the infrastructure and expertise required to support it.
- A system that ensures timely regulatory review or proposals, given the expansion of the types of projects that will be captured by these policies. This is especially important for research with a high public health impact or urgency. For example, a 30-day turnaround for this high-level review is recommended and, with the right resources, should be feasible. Otherwise, additional oversight will have the same restrictive effect as a ban on the research because the streamlined infrastructure and needed resources are not in place. Researchers could decide the process is too onerous and may not propose potentially lifesaving work if it takes months for a review, and this has opportunity costs.
(b) What are the benefits and challenges of investigators and institutions having primary responsibility for identification of both DURC and ePPP research?
Investigators and their institutions have always been the first line of defense when it comes to biosafety and biosecurity. Risk assessment begins when an individual investigator comes up with an idea, and labs and institutions have robust review processes in place. No one wants to move forward with a project that poses unnecessary risk to the scientists conducting the work, their students and colleagues or the public.
There are opportunities for greater engagement from institutions and subject matter experts. To be most effective, agencies must provide clear guidance to these entities about policies to ensure a common understanding of the requirements and consistency of approach.
The benefit of a “bottom up” approach is that risk assessment begins at the level closest to the research being conducted. Beyond the principal investigator, the institutional biosafety committee (IBC) is an irreplaceable component in risk assessment. IBCs can and should have broader expertise beyond virology or bacteriology. This is the best way to ensure research proposals that are not properly designed, do not have the appropriate biosafety measures in place or are otherwise considered “risky” never get started. This IBC review needs to occur regardless of whether the project has been submitted to a funding entity. Early engagement by the IBC also ensures that unexpected findings can be properly managed and communicated to the funding agency.
Support for training will be key to ensuring a system like this works well, so federal funders need to consider resources available to assist with these activities, especially in under-resourced institutions or those without necessary expertise.
There are challenges associated with this approach, especially if the scope is broadened and more institutions (e.g. Tier 2) are affected. Oversight that pulls in additional institutions underscores the need for top-down guidance and resources for training. Otherwise, the result may be that valuable research is discouraged from taking place at these institutions and this raises both public health and equity concerns. There may also be additional financial costs for the institution to consider.
If an institution does not have an IBC with sufficient expertise to evaluate the proposal, there may be a need to support creation of “contract” IBCs that offer, timely, comprehensive and consistent review, similar to human use protocols and contract IRBs. There will need to be incentives for review committee members given the time this work involves. We recommend ensuring that service on such a committee can count toward academic credit similar to service on peer review study sections.
A minority of institutions do this work regularly and very well, but there is not a coordinated mechanism in place to allow sharing of practices. The U.S. should fund infrastructure that enables other institutions to benefit from best practices practiced by experienced institutions. Lastly, the international angle will continue to be challenging. Providing a high level of training can help with international funding considerations, and there is precedent for U.S. institutions training foreign researchers in biorisk management practices. Policies need to take into account what work can be done safely in the U.S. versus what is feasible with international collaborators.
(c) What types of resources or tools would be useful for researchers and institutions to determine if their research falls into a revised policy scope that is risk-based rather than list-based, and adequately conduct risk assessments to identify DURC and ePPP research?
ASM supports a risk-based approach to one that is list-based. Lists are static and do not account for emerging and evolving pathogens. Also, a list-based approach can lend itself to “box-checking” rather than consideration of the “why” and the “how” the research is being proposed (versus the “what”).
There are resources and tools available to help researchers and institutions with this transition, but new resources will be required. The National (NBL) and Regional Biocontainment laboratories (RBL) have models that could be scaled to a national level. For example, the process used by the Galveston National Laboratory requires the investigator to complete a questionnaire upon developing the proposal that begins a comprehensive assessment before the project is started. For those institutions needing additional guidance, the NBL/RBL network also could be the source of review for those institutions that lack an IBC altogether or an IBC with requisite expertise to conduct a review.
The importance of training cannot be overstated. There are certified experts in the field who could be tapped to assist with those institutions which do not have the expertise. Mentoring programs specific to biosafety and biocontainment could also be beneficial for researchers working with infectious agents.
2. (a) Considering the diversity of federally-funded research settings and portfolios, how would adoption of NSABB’s Recommendation 10.1 affect policy implementation and research programs at the institutional level?
(b) Rather than including any pathogen within the scope of DURC review, one possible modification of 10.1 would be to include DURC experiments that utilize the BSAT list, Pathogen Risk Group classification of 3 or 4 or any pathogen where the conduct of work under DURC would require BSL 3 or 4 containment. Would such a modification be useful?
Benefits/challenges/gaps anticipated by revised scope?
This approach still uses a list. ASM supports a risk-based approach to one that is list-based. Lists are static and do not consider emerging and evolving pathogens. Also, this approach can lend itself to “box-checking” rather than consideration of the “why” and the “how” the research is being proposed (versus the “what”).
(d) Given the possible revised scope of research requiring review for potential DURC, what modifications, if any, to the current DURC policy list of 7 experimental effects should be considered for a revised policy that captures appropriate research without hampering research progress?
Exclusions should include the development of medical countermeasures.
3. (a) How would the change in definition of ePPP affect the overall scope of a revised policy and its subsequent implementation?
Virulence and transmissibility are not just properties of the agent itself, but also relate to how the agent behaves in a given host or population in addition to other context dependent factors. This is where the reasons and justification for the project and the procedures and biorisk mitigation plan become important.
Focusing on transmissibility presents a path to further hone the dividing line between projects that need an additional layer of oversight and those for which institutional-level oversight is sufficient. Transmissibility is the quality that most determines the threat to public health should there be a laboratory escape, intentional or by accident.
Lack of therapeutic options or countermeasures such as vaccines is another aspect that could be considered a point of demarcation when a project should receive additional oversight. For example, modifying an infectious agent so that it no longer responds to therapeutic options (e.g. resistant Streptococcus, or Candida auris) or modifying an infectious agent that is not highly transmissible and making it more transmissible in a host when there is no natural immunity or countermeasures would be a project that should fall under these definitions.
We do not recommend expanding the definition to include “moderately” virulent because it could cut off important areas of research that pose little threat to public health outside the laboratory such as work on the common cold and endemic viruses such as herpesvirus, papilloma viruses and adenoviruses. The vast majority of individual exposures in the laboratory can be mitigated through sound, comprehensive procedures to protect staff. Returning to the context of the research, there is a big difference between risk at the host level versus a risk at a population level. Finally, oftentimes it is not known how a virus will respond and require scaled experiments under appropriate biosafety conditions, reinforcing that virulence is not the best measure for what requires additional oversight.
Without the ability to adapt definitions to the context of the work, we run the risk of inconsistent application of the new standards and unnecessarily flagging certain projects for additional high-level oversight. This would lead to missed scientific opportunities and risks public health without making us safer. We also need to ensure revised policies recognize and support the role and expertise of the IBCs, which will be the main line of defense against improperly designed projects. Revised policies also need to allow for access to expertise when the IBC does not have what is needed.
Terms like “moderately” or “highly” transmissible or virulent are subjective and need to be adaptable to the context of the work being proposed. Effective implementation requires clear guidance from the federal government and having specific examples to illustrate the intent of the new definitions would be helpful. Otherwise, changes run the risk of being too subjective and open to varying interpretations by IBCs and other oversight bodies. It is also critical to consider the stated purpose and scientific goal of the proposed project.
(b) One possible modification to the NSABB PPP definition is to specify a respiratory route of transmission. Would that be a more appropriate scope to mitigate risks and enhance effective implementation?
As noted above, ASM agrees that focusing on transmissibility makes the most sense. While focusing on respiratory routes narrows the scope in a way that could be potentially helpful, we are concerned that exclusively focusing on this area could miss other areas where transmissibility is a concern but is not the phenotype being manipulated (e.g. drug resistant infectious agents).
Conversely, focusing exclusively on respiratory routes could have the effect of “overcorrecting” and capturing projects focused on common cold and tuberculosis, as two examples, that may not need extra review.
(c) Do you have additional suggestions to modify the PPP definition to mitigate the most significant risks not currently addressed and enhance effective implementation, while limiting negative or unintended consequences and burden on researchers, institutions, and the Federal government?
In addition to focusing on transmissibility in the population as noted above, an additional approach is to consider a higher level of scrutiny on those pathogens for which there is resistance or for which there are no countermeasures. These projects should receive additional consideration and could require that the work be done at BSL-3 or above. Most pathogens for which there are many unknowns are already studied at this level but standardizing this practice may be warranted.
For example, modifying enteric pathogens to be more transmissible and resistant to all therapies should receive a higher level of review. Any type of research that enhances transmission should receive additional scrutiny and taken to a higher level of biosafety. This keeps the focus on where the greatest risk is to population-based spread and elevates the question of how the research is done.
(d) Are there characteristics related to human pathology, pathogen characteristics or other features that would be helpful to clarify the intent of “moderately virulent?” Are there characteristics related to human pathology that would be helpful to clarify the intent of “moderately transmissible?”
As noted above, virulence can be a challenging parameter to use because virulence is a quality that is difficult to measure in a laboratory environment except in animal models, which do not always reflect how a pathogen behaves in a human. This is because virulence is a property of the interaction between agent and a given host. In the case of vaccine development against novel viruses, scientists often need to make the virus more virulent in an animal model (e.g. a mouse) in order to develop a vaccine. This does not necessarily mean the virus at that stage is dangerous to humans or at a population level. We do not support expanding the term to include “moderately virulent” because it is not by itself a good indicator of risk. Focusing on transmission and considering high virulence in the context of transmissibility is more appropriate.
4. Does the definition of “reasonably anticipated” provide additional clarity to ensure greater consistency in identifying research that falls within the scope of the revised policy? What modifications to this definition would be most helpful?
A more appropriate term to use in science would be “expected outcome.” Including “reasonably” is not useful because it implies a level of subjectivity when considering intent versus outcome. With enhanced pathogens, unexpected results could happen given the nature of the pathogen. However, understanding this in advance and ensuring the appropriate biorisk mitigations steps are in place is critical.
The term “reasonably anticipated” lacks clarity and specificity and structure. While scientists making the determination can evaluate the scientific merit of the research proposal, consideration must also be given to how the work is perceived and how it could impact those not directly involved. We recommend looking at the International Animal Care & Use Committee (IACUC) as a potential model, as well as Institutional Biosafety Committees (IBCs) that do this particularly well. These structures includes appropriate stakeholders to identify research that may need additional review.
5. NSABB recommends the removal of certain blanket exclusions for research activities associated with surveillance and vaccine development or production for research with ePPPs.
(a) Should exemptions for certain activities be included in a revised policy?
ASM supports the continued exemptions for research activities associated with surveillance and vaccine development. Exemptions also should be considered when there are national and international public health emergencies.
The proposed revised policies for laboratory research are not an appropriate framework for fieldwork, an essential tool in understanding the pathogens and variants that are circulating in the environment and animal reservoirs and what could be a threat (i.e. the human-animal-environment interface).
Zoonotic spillover has long been understood to be a common source of human infectious diseases. Sampling in certain animal populations such as bats, rodents and shrews known to harbor viruses that infect humans is necessary for ecological studies that map animal viromes and understand what pathogens exist and are likely to jump species, thus posing a threat to humans. Taking a One Health approach, research to understand the drivers of spillover events is important to minimize risk of human infection by zoonotic pathogens, including interventions such as vaccines. Members of the World Health Organization (WHO) One Health High-Level Expert Panel wrote recently about the importance of fieldwork to spillover prevention and proposed a proactive versus reactive approach to addressing spillover at the source. 1
Exempting surveillance activities should not be confused with the need for clear guidelines and standardized biorisk management processes. These should be developed and shared to ensure that fieldwork and surveillance is conducted safely.
Exclusions should remain for vaccine development given the importance of these countermeasures to population health and safety, especially during a public health emergency when there is a novel threat. Vaccine escape studies are especially important work that would be affected by removal of these exclusions because ePPP research animal models are essential to this work.
If the processes described above (e.g. risk assessment conducted at the outset; strong IBC engagement) are in place, this work can be done safely and effectively.
Other activities for which there should be exclusions include sequencing and characterization studies and antimicrobial development studies.
(b) What are the benefits and drawbacks of including exemptions for domestic and international pandemic preparedness, biosafety, biosecurity, and global health security?
Global health security depends on the U.S., with other international partners, leading the way by doing vaccine development research. As noted above, exemptions for vaccine work are essential to domestic and international pandemic preparedness. We need look no further than the COVID-19 pandemic to understand the importance of flexibility and speed to developing vaccines for a threat for which there was no natural immunity or existing countermeasures. It is only matter of time before we will face another novel infectious disease threat.
(c) If exemptions are included, how could they be bounded to maximize safety and security and minimize negative impact on domestic and global public health, including outbreak and pandemic preparedness and response? (e.g. Vaccine R&D could be unjustifiably impeded?)
Exempted work does not mean unsafe work. Projects still employ biorisk mitigation processes as they do for all work of this nature. Experiments are conducted at the appropriate biosafety level (e.g. BSL-3) given the unknowns.
6. (a) Is there a subset of such “in silico” research that should require risk assessment and review in a revised policy and if so, how should this research be defined so that the policy captures the appropriate research without hampering activities with limited biosecurity risk?
ASM agrees that it is important to look ahead and consider emerging technologies that are currently not captured under oversight policies but could pose a risk to public health. However, accomplishing this will be difficult and may be beyond the scope of the policies updates needed at this time to address ePPP and DURC oversight. In silico modeling has important applications to hypothesis generation, vaccine development, and any policies would need to avoid hindering this critical work. This work of “in silico for good” also provides an alternative to wet lab work which could potentially pose greater biosafety risks. At the present time, it is very difficult to take a sequence and construct a pathogen de novo. While the threat is there in theory, there is no evidence that this is a real threat at the moment.
The challenge is determining how artificial intelligence or in silico models could result in a transmissible pathogen. Recognizing that policies must always be forward-looking and anticipate gaps, we recommend considering a National Academies review of this technology to develop more evidence to support new policies in this space.
In closing, as you look to finalize these updated policies, we encourage you to build in periodic reviews and assessments of these policies to ensure they can adapt to the realities “on the ground” and also take into account new technologies. We will learn as these policies are implemented whether there are unforeseen negative consequences to research or oversight gaps that need additional consideration. It will be important to have a system that is flexible and adaptable so we can strike an appropriate balance.
Thank you for your attention to our views. If we can be of further assistance or if you have any questions, please contact Mary Lee Watts, ASM Director of Federal Affairs at mwatts@asmusa.org.
Sincerely,
Stefano Bertuzzi, PhD, MPH
ASM Chief Executive Officer
1 https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011504#
