Infectious agents and toxins considered by the Department of Health and Human Services (HHS) or the Department of Agriculture (USDA) as having the potential to pose a severe threat to human, animal, or plant health are regulated as select agents.
The Centers for Disease Control and Prevention (CDC) and USDA maintain the Select Agents and Toxins List (SATL) (see Appendix H) and restrict the possession of the listed agents. Research on select agents is heavily regulated, and those who are not authorized to possess, use, or transfer select agents but do so are subject to criminal and civil penalties.
The SATL originated in regulations introduced in the mid-1990s. Section 511 of the Antiterrorism and Effective Death Penalty Act of 1996 directed the secretary of HHS (and ultimately the CDC) “to promulgate regulations to establish and maintain a list of biological agents that have the potential to pose a severe threat to public health and safety. This list subsequently became known as the Select Agents and Toxins List.”55 Currently, there are 65 agents and toxins on the Select Agents and Toxins List: 34 are HHS BSATs (biological select agents and toxins), 10 are overlap BSATs,56 14 are USDA BSATs, and 7 are USDA Plant Protection and Quarantine BSATs.57 It is important to recognize that the SATL is an instrument of biosecurity, not biosafety. Biosecurity is “a set of institutional and personal security measures designed to prevent the loss, theft, misuse, diversion, or intentional release of biological materials that could
55See S. A. Morse, “Pathogen Security – Help or Hindrance?” Frontiers in Bioengineering and Biotechnology, vol. 2, no. 83, (2015): 2.
56The CDC and APHIS (Department of Agriculture Animal and Plant Health Inspection Service) share responsibility for these agents because they potentially threaten both humans and animals.
57The USDA’s “Plant Protection and Quarantine (PPQ) program safeguards U.S. agriculture and natural resources against the entry, establishment, and spread of economically and environmentally significant pests, and facilitates the safe trade of agricultural products.” See https://www.aphis.usda.gov/wps/portal/aphis/ourfocus/planthealth.
be used with intent to harm people, livestock, agriculture, or the environment,” 58 while biosafety is defined as “the containment principles, technologies, and practices that are implemented to prevent the unintentional exposure to pathogens and toxins, or their accidental release.” 59 Although biosecurity and biosafety are related in the sense that securing these agents also provides a measure of safety, the concepts are separate and distinct.
HHS rulemaking requires those shipping and receiving BSATs to register with the CDC and requires that “safety procedures for agent transfer be established and enforced; that those handling these agents be properly trained; and that there are proper laboratory facilities to contain and dispose of the agents.”60
Following 9/11 and the mailing of anthrax spores in 2001, the select agent regulations were greatly expanded. The 2001 USA Patriot Act61 altered the criteria for who could handle or possess BSATs. Section 175 of U.S.C. 18 states that “whoever knowingly possesses any biological agent, toxin, or delivery system of a type or quantity that, under the circumstances, is not reasonably justified by prophylactic, protective, bona fide research, or other peaceful purpose, shall be fined under this title, imprisoned not more than 10 years, or both.”62 Under this statute, the terms biological agent and toxin did not include those in their naturally occurring environment so long as the agent or toxin had not been cultivated, collected, or otherwise extracted from its natural source.63 The regulation of BSATs was also affected by the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, which directed the HHS secretary to, among other things, establish and maintain the Select Agents and Toxins List and provide safeguards and security requirements for possessing, using, and transferring the materials on the list. Select agent regulations further require that the theft, loss, or release of a BSAT be reported to the Federal Select Agent Program. In addition, select agent regulations institute background checks and personnel reliability programs to reduce insider threat.64
Over the past 15 years, the SATL has been modified several times. Agents have been added to and deleted from the list, and additional regulations have been implemented.
Unlike research on select agents and toxins, policies governing dual-use research of concern—“life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products,
58See Morse, p. 1.
60Ibid., p. 2. These regulations were incorporated into Interstate Shipment of Etiologic Agents 1, 42 CFR 72 (2007).
61Uniting and Strengthening America by Providing Appropriate Tools Required to Intercept and Obstruct Terrorism (USA PATRIOT ACT) Act of 2001. Pub. L. No. 107-56 (2001).
62Prohibitions with Respect to Biological Weapons, 18 USC § 175b (2002).
63Morse, p. 3.
or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security” 65—have not been enacted into law, but institutions follow government guidelines. Questions related to research of dual-use concern are handled at most universities by Institutional Biosafety Committees and by the editors of scientific journals.66 Research of dual-use concern may subsequently become the subject of tight regulatory control; however, as current regulations focus on select agents, the committee has elected to focus its attention on select agent regulations.
Nature of Concern
Select agent regulations have created a burdensome regulatory framework for individuals working with a very specific list of microbial agents and toxins. There is controversy over the agents listed, the fact that some items on the list are present in the environment (e.g., Bacillus anthracis), and concern that select agent regulations hinder research on agents that pose the most serious threats to human health.
Select agent regulations may not provide appropriate protection against biological threats. On the contrary, such regulations may impede the very research that could help protect against such threats. The limitations imposed by select agent regulations may negatively impact the number of collaborations, the size of research projects, and scientific research on microbial pathogens generally.67
The items currently on the Select Agents and Toxins List differ significantly in degree of pathogenicity and in their capacity for use as agents of bioterrorism. The risk posed to public, animal, and plant health and safety varies depending on the agent. However, the strict controls in place for all agents impede researchers’ abilities to conduct legitimate research on less pathogenic organisms.68
65See National Institutes of Health Office of Science Policy, “Biosecurity,” http://osp.od.nih.gov/office-biotechnology-activities/biosecurity/dual-use-research-concern.
66For a discussion of how publication of research of dual-use concern is handled at American Society of Microbiology (ASM) journals, see A. Casadevall et al., “Dual-use Research of Concern (DURC) Review at American Society for Microbiology Journals,” mBio, vol. 6, no. 4 (2015): 1–3.
67N. Wurtz, M. P. Brobush, and D. Raoult. “Negative Impact of Laws Regarding Biosecurity and Bioterrorism on Real Diseases.” Clinical Microbiology and Infection, vol. 20, no. 6 (2014): 507–515.
68National Science Advisory Board for Biosecurity. “Enhancing Personnel Reliability among Individuals with Access to Select Agents: Report of the National Science Adviso-
As a result of select agent regulations, the cost of research involving select agents and toxins has increased significantly. Dias and others conducted the most comprehensive study of the effects of these regulations on research and concluded that “the most striking effect was a loss of efficiency, with an approximate 2- to 5-fold increase in the cost of doing select agent research as measured by the number of research papers published per millions of U.S. research dollars awarded.”69
Select agent regulations have led to the destruction of microbial collections and a dearth of new isolates of highly pathogenic organisms. Casadevall and Imperiale have documented that numerous microbial collections were destroyed as a consequence of their owners’ concerns about compliance with the new select agent regulations.70 As a result, many irreplaceable samples were lost in the destruction of these collections.
New clinical isolates of microbes on the Select Agents and Toxins List are routinely destroyed by clinical microbiology laboratories that lack the resources to transfer such materials in compliance with select agent regulations. This has affected the growth of microbial collections and resulted in a dearth of recent isolates.71 Both of these conditions are significant given that microbes evolve over time in both virulence and antigenicity.
Although regulations that affect the acquisition and handling of specimens in a clinical setting are arguably outside the scope of federal research regulations, the collection of new specimens is an essential component of research into the biology of these agents. Hence, regulations that obstruct the availability of clinical specimens have an indirect effect on research productivity. Such obstructions are especially problematic for public health emergencies.
There are concerns that the regulations governing select agent research have become so costly and administratively burdensome that researchers and students are abandoning research on select agents.72 There is evidence that re-
ry Board for Biosecurity,” (May 2009), p. vi, available at: http://osp.od.nih.gov/sites/default/files/resources/NSABB%20Final%20Report%20on%20PR%205-29-09.pdf.
69M. B. Dias et al., “Effects of the USA PATRIOT Act and the 2002 Bioterrorism Preparedness Act on Select Agent Research in the United States,” Proceedings of the National Academy of Sciences, vol. 107, no. 21 (2010): 9556–9561.
70A. Casadevall and M. J. Imperiale. “Destruction of Microbial Collections in Response to Select Agent and Toxin List Regulations.” Biosecurity and Bioterrorism, vol. 8, no. 2 (2010): 151–154.
72In addition, dedicated funding for this type of work (biodefense) has been flat and thus declining in real value. See, e.g., T. K. Sell and M. Watson, “Federal Agency Biodefense Funding, FY2013–FY2014,” Biosecurity and Bioterrorism, vol. 11, no. 3 (2013): 196–216. In addition, it is notable that NIH funding for Regional Centers for Excellence for research on biodefense and emerging infectious diseases ended in the spring of 2014. See National Institute of Allergy and Infectious Diseases, “Regional Centers of Excel-
search involving pathogens on the Select Agents and Toxins List has slowed relative to those not on the list. While it is difficult to compare agents on the list to agents outside the list, an analysis of PubMed papers for two B. anthracis strains, one a select agent and the other not, showed significantly more publications for the strain that does not appear on the list.73
There are large institutional costs associated with the maintenance of facilities where select agent research is conducted. Select agent research must be carefully controlled by the research institution. Such research must be conducted in designated spaces, increased security measures must be implemented, records must be scrupulously maintained, and facilities are subject to numerous inspections by the CDC and others.74
Following several biosafety incidents at U.S. government laboratories in 2014 and recognizing the burdens placed on those engaged in select agent research, the White House issued a memorandum outlining a series of short- and long-term actions to enhance both laboratory biosafety and laboratory biosecurity practices.75 The National Science and Technology Council established a Fast Track Action Committee (FTAC) on the select agent regulations under the Subcommittee on Biological Defense Research and Development of its Committee on Homeland and National Security. In October 2015, the FTAC issued a report, Recommendations on the Select Agent Regulations Based on Broad Stakeholder Engagement, which offers suggestions for improving the regulatory process and addressing perceived gaps in the select agent regulations in the future.76 Regarding inventory requirements, the FTAC recommended “retaining requirements to maintain inventories of samples containing biological select agents and toxins, while ensuring that BSAT institutions are not requested to characterize biological agents quantitatively.”77 The FTAC also recommended the “development of
lence in Biodefense and Emerging Infectious Diseases,” available at: http://www.niaid.nih.gov/labsandresources/resources/rce/Pages/default.aspx.
73A. Casadevall and D. A. Relman. “Microbial Threat Lists: Obstacles in the Quest for Biosecurity?” Nature Reviews Microbiology, vol. 8, no. 2 (2010): 149–154.
74E.g., the USDA and the Department of Transportation.
75National Science and Technology Council. “Recommendations on the Select Agent Regulations Based on Broad Stakeholder Engagement” (October 2015): p. iii, available at: https://www.whitehouse.gov/sites/default/files/microsites/ostp/ftac-sar_report_20151029.pdf.
77Ibid. The report further states that the FTAC “believes that institutions possessing BSAT are obligated to know and document what is stored in their laboratories and where those agents and toxins are located. It is therefore appropriate to require institutions to maintain inventories of their select agent stocks and be able to show not only that all their samples are documented, but that all entries in an inventory database correspond to physical samples. Maintaining and validating select agents are essential elements of responsible conduct, even if they cannot be used to rule in or rule out a theft or diversion.
Correlation of database and physical stocks is…an indicator of quality management, and entities should practice accountability. The SAR do not require quantitative inventory controls for select biological agents, only for select toxins. The FTAC therefore recom-
an approach to improve the consistency of the inspection process across inspectors, inspecting agencies, and inspected sites” and that “members of the regulated community establish a mechanism for sharing best practices.”78
On January 19, 2016, HHS and USDA published notices of proposed rulemaking regarding select agents and toxins regulations.79 In the notices, HHS and USDA consider whether to amend the select agents list by removing six biological agents.80 HHS is also considering whether to amend the select agents list by removing Brucella melitensis.81 In addition, the agencies are proposing several amendments to the select agent regulations, including “the addition of provisions to address the inactivation of select agents, provisions addressing biocontainment and biosafety, and clarification of regulatory language concerning security, training, incident response, and records.”82 According to the agen-
mends that accountability in the SAR be maintained at the level of identifiable physical items, such as vials or plates, and not extended to quantitative measurements of size, volume, mass, or concentration of biological agents (other than needed to describe them quantitatively). Currently, record keeping and inventory validation do not require accounting for and verifying biological agent concentrations or volumes. The FSAP [Federal Select Agent Program] should ensure that inventory validation through quantitative sample characterization (such as by thawing a frozen sample to measure its volume) is not occurring during inspections, except with toxins as appropriate. Quantitative sample characterization could otherwise needlessly degrade or destroy samples.” See p. 12.
79For the proposed HHS rule, see “Possession, Use, and Transfer of Select Agents and Toxins; Biennial Review of the List of Select Agents and Toxins and Enhanced Biosafety Requirements,” Federal Register 81, no. 11 (January 19, 2016): 2805, https://www.federalregister.gov/articles/2016/01/19/2016-00758/possession-use-and-transfer-of-select-agents-and-toxins-biennial-review-of-the-list-of-select-agents. For the proposed USDA rule, see “Agricultural Bioterrorism Protection Act of 2002; Biennial Review and Republication of the Select Agent and Toxin List; Amendments to the Select Agent and Toxin Regulations,” Federal Register 81, no. 11 (January 19, 2016): 2762, https://www.federalregister.gov/articles/2016/01/19/2016-00681/agricultural-bioterrorism-protection-act-of-2002-biennial-review-and-republication-of-the-select. The new rulemaking is in accordance with the Agricultural Bioterrorism Protection Act of 2002, which “requires the biennial review and republication of the list of select agents and toxins and the revision of the list as necessary.” See https://www.federalregister.gov/articles/2016/01/19/2016-00681/agricultural-bioterrorism-protection-act-of-2002-biennial-review-and-republicationof-the-select.
80Coxiella burnetii; Rickettsia prowazekii; Bacillus anthracis Pasteur strain; Brucella abortus and B. suis; Peronosclerospora philippinensis (Peronosclerospora sacchari); Phoma glycinicola (formerly Pyrenochaeta glycines); and Sclerophthora rayssiae.
81This would mean that B. melitensis would be identified as a “USDA-only” select agent.
82See https://www.federalregister.gov/articles/2016/01/19/2016-00681/agricultural-bioterrorism-protection-act-of-2002-biennial-review-and-republication-of-the-select. The new requirements are summarized by the agencies as follows:
cies, the proposed changes “would increase the usability of the select agent regulations as well as provide for enhanced program oversight.”83 A reduction in the number of agents subject to select agent regulations will be seen as a welcome development by investigators working with infectious agents and toxins. Furthermore, the proposed removal of agents that have been on the Select Agents and Toxins List for more than 15 years suggests that additional agents might be candidates for removal.
- For a select agent to be considered “non-viable,” and therefore excluded from the requirements of the regulations, an entity will be required to use a validated inactivation method. As part of the inactivation procedure, an entity will be required to develop a site-specific kill curve to identify conditions of inactivation for each select agent or regulated nucleic acid. In addition, a validated sterility testing protocol to ensure that the inactivation method has rendered a select agent non-viable, or regulated nucleic acid non-infectious, will be required.
- A requirement for a reference laboratory, which would conduct testing to confirm the identification of a select agent or toxin, to inform the specimen provider of a confirmation so the specimen provider will be aware they are in possession of a select agent or toxin and are subject to the select agent regulations.
- A requirement that the biosafety and incident response plans be submitted for initial select agent registration, renewal of registration, or when requested by [the] Federal Select Agent Program (FSAP).
- New specific requirements in the biosafety section would include: a written risk assessment for each registered select agent or toxin; written safety procedures to protect entity personnel, the public, and the environment from exposure to the select agent or toxin; written decontamination procedures; and written waste management procedures.
- A requirement that a laboratory-specific biosafety manual must be accessible to individuals entering a laboratory registered for select agents or toxins.
- Amend existing requirements for the security plan so that the security plan’s description of how the entity authorizes the means of entry into areas where select agents or toxins are stored or used would include description of centralized access control management systems (e.g., keycards) and/or key management (mechanical keys).
- Require that required drills or exercises be documented to include how the drill or exercise tested and evaluated a plan, any problems identified and corrective actions that were taken, and the names of the individuals who participated in a drill or exercise.
- The rulemaking would codify existing policy that all individuals who have received FSAP approval to have access to select agents and toxins will be required to have training that addresses the particular needs of the individual and the risks posed by the select agent or toxin, regardless of whether they routinely access select agents or toxins.
83Ibid. The comment period on the SATL NPRM closed March 21, 2016. The committee urges that revised select agent regulations be issued as soon as possible. However, any new regulations should be viewed as only an initial step in the reform of SATL regulations and should not preclude action on the other recommendations in this chapter.
Select agent regulations incorporated an approach to inventory control adopted in the management of radioactive materials. This approach focused on a tight control of physical material. Hence, within select agent regulations, there is a tremendous focus on the tracking of individual vials. Select agents, however, are often living, self-replicating microbes that can be removed from a vial without obviously affecting the volume of material in a vial. Thus, there is an inherent dissonance when accounting for biological materials by conventional (i.e., physical and chemical) inventory practices. Because they are microscopic, minute amounts of materials can be removed from stocks unnoticed and then propagated. Accounting for vials will not prevent the removal of material for nefarious purposes, and inventory control systems that require researchers to account for every individual vial will not ultimately offer protection against the removal of materials. In addition, as life sciences data is increasingly digitized and amalgamated into ever larger datasets, the framework for preventing the misuse of such data may need to be reconsidered.
Select agent regulations were intended to prevent non-cleared individuals from obtaining dangerous materials and make it harder to obtain such materials from research laboratories. Those working with select agents must be cleared to do so.84 The clearance process is lengthy85 and may adversely affect the number of researchers conducting such research and may limit student participation in select agent research.
There is a lack of consensus as to whether all agents on the Select Agents and Toxins List are so dangerous as to warrant their place on the list. In addition, there is a lack of transparency in how agents are added to the select agents list. For example, the criteria used to include or exclude agents from the list have never been made public, and certain decisions about the content of the list are viewed as arbitrary by some in the research community.86
One measure that would immediately aid select agent research would be to exclude from the list a number of strains with a lower virulence. Current regulations group all microbial strains by species without accounting for the virulence of specific strains. An increase in the availability of low-virulence strains could allow investigators to carry out critical work outside the select agent regulations. This has already been done in limited instances. For example, the Sterne strain of Bacillus anthracis is not considered a select agent.
84Individuals seeking access to work with BSATs undergo health screenings and federal background investigations.
85The federal background screening alone may take anywhere from 3 to 24 months. See Shurtleff et al., “The Impact of Regulations, Safety Considerations and Physical Limitations on Research Progress at Maximum Biocontainment,” Viruses, vol. 4, no. 12 (2012): 3936.
86See, e.g., A. Casadevall and D. A. Relman. “Microbial Threat Lists: Obstacles in the Quest for Biosecurity?” Nature Reviews Microbiology, vol. 8, no. 2 (2010): 149–154.
The classification system used by the select agents list is species based. However, there are problematic aspects of microbial species differentiation. The boundaries between microbial species can be indistinct. There is, for example, a Bacillus cereus strain that carries anthrax toxins and causes the same disease as B. anthracis. The B. cereus strain is not on the select agents list. B. anthracis is.
Institutions engaged in research on select agents and toxins may be subject to multiple inspections by multiple agencies. The time, effort, and cost of reconciling inconsistent inspection results and complying with different standards and interpretations of select agent regulations are a source of significant burden. Furthermore, violations identified during the course of an inspection receive equal treatment, regardless of the level of severity. Harmonizing of select agent regulations across agencies and entrusting a single agency with the responsibility for all select agents would increase efficiency and reduce administrative burden. The management of select agents presents unique challenges, and investing control within multiple agencies creates unnecessary tensions.
11.1. The committee recommends that the President assign the responsibility for regulating all microbes and toxins on the Select Agents and Toxins List to a single agency.87
11.2. The committee recommends that the Federal Select Agent Program develop and promulgate a reasonable inventory management system for biological select agents and toxins that takes account of the living, self-replicating nature of biological agents.
11.3. The committee recommends that the regulations88 governing select agents and toxins be amended to:
- Allow researchers to more readily access relevant select agents in times of public health emergencies;
- Increase the number of lower-virulence strains of select biological agents available to researchers;
- Make more transparent the process by which materials are added to and removed from the Select Agents and Toxins List.
87The proposed Research Policy Board could take a leadership role in discussions about which agency should have responsibility for the regulation of the microbes and toxins on the Select Agents and Toxins List.
88See Possession, Use and Transfer of Select Agents and Toxins, 7 CFR 331 (2005); Possession, Use and Transfer of Select Agents and Toxins, 9 CFR 121 (2005); and Select Agents and Toxins, 42 CFR 73 (2005).
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