2
The Current Regulatory Environment

INTRODUCTION

Fundamental International Commitments

The fundamental international commitments not to use disease as a weapon are embodied in the Geneva Protocol, which was signed in 1925 and entered into force in 1928, and the Biological and Toxin Weapons Convention (BWC), which was signed in 1972 and entered into force in 1975.1 The Geneva Protocol prohibits the first use of chemical and biological warfare but does not ban production, storage, or transfer. That gap was closed by the BWC and later by the Chemical Weapons Convention of 1993. Article I of the BWC states:

Each State Party to this Convention undertakes never in any circumstances to develop, produce, stockpile or otherwise acquire or retain:

  1. Microbial or other biological agents, or toxins whatever their origin or method of production, of types and in quantities that have no justification for prophylactic, protective or other peaceful purposes;

  2. Weapons, equipment or means of delivery designed to use such agents or toxins for hostile purposes or in armed conflict.

1

The Geneva Protocol’s formal title is the Protocol for the Prohibition of the Use in War of Asphyxiating, Poisonous or Other Gases, and of Bacteriological Methods of Warfare and the BWC treaty’s formal title is the Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction. The United States signed the Geneva Protocol in 1925 but did not ratify it until 1975, at the same time the Senate ratified the BWC.



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2 The Current Regulatory Environment INTRODUCTION Fundamental International Commitments The fundamental international commitments not to use disease as a weapon are embodied in the Geneva Protocol, which was signed in 1925 and entered into force in 1928, and the Biological and Toxin Weapons Convention (BWC), which was signed in 1972 and entered into force in 1975.1 The Geneva Proto- col prohibits the first use of chemical and biological warfare but does not ban production, storage, or transfer. That gap was closed by the BWC and later by the Chemical Weapons Convention of 1993. Article I of the BWC states: Each State Party to this Convention undertakes never in any circumstances to develop, produce, stockpile or otherwise acquire or retain: (1) Microbial or other biological agents, or toxins whatever their origin or method of production, of types and in quantities that have no justification for prophylactic, protective or other peaceful purposes; (2) Weapons, equipment or means of delivery designed to use such agents or toxins for hostile purposes or in armed conflict. 1 TheGeneva Protocol’s formal title is the Protocol for the Prohibition of the Use in War of Asphyxiating, Poisonous or Other Gases, and of Bacteriological Methods of Warfare and the BWC treaty’s formal title is the Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction. The United States signed the Geneva Protocol in 1925 but did not ratify it until 1975, at the same time the Senate ratified the BWC. 

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 RESPONSIBLE RESEARCH WITH BIOLOGICAL SELECT AGENTS AND TOXINS The BWC does not prohibit research on defenses against biological weapons, which a number of countries, including the United States and its major allies, have continued. Of more direct relevance to bioterrorism, United Nations (UN) Security Council Resolution (UNSCR) 1540, passed in 2004 with strong support from the United States, imposes a binding international commitment on all UN members not to provide “any form of support to non-State actors that attempt to develop, acquire, manufacture, possess, transport, transfer or use nuclear, chemical or biological weapons” (UN 2004). UN member states must under- take and enforce domestic measures against the proliferation of weapons of mass destruction (WMD), related materials, and the means to deliver them, including specific measures such as effective border controls and physical security. “If implemented successfully, each state’s actions will significantly strengthen the international standards relating to the export of sensitive items and support for proliferators (including financing) and ensure that non-state actors, including terrorist and black-market networks, do not gain access to chemical, nuclear or biological weapons, their means of delivery or related materials” (Department of State 2009a).2 Evolution of U.S. Policies and Procedures for Research with Biological Agents and Toxins Measures to Address Safety: Biosafety Guidelines Over time, scientists have developed best practices for research with po - tentially dangerous biological agents or toxins—including but not limited to biological select agents and toxins (BSAT). Such practices are designed to ensure this research does not cause harm to those working in laboratories or to the broader public and environment because of accidents or accidental releases. In the United States, the National Institutes of Health (NIH) published its first edition of Biosafety in Microbiological and Biomedical Laboratories (BMBL) in 1984; the fifth edition was published in 2007 (CDC/NIH 2007).3 The BMBL categorizes infectious agents and laboratory activities into four biosafety levels (BSL-1 through BSL-4) and establishes safety requirements for each level based on risk.4 2 UNSCR 1810, passed in 2008, extended the mandate of UNSCR 1540 for an additional three years and urges states to complete its implementation (UN 2008). 3 The World Health Organization (WHO) also produces a Laboratory Biosafety Manual. The first edition was published in 1983, and the third was released in 2004. 4 The risk groups defined by the NIH Guidelines for Research Inoling Recombinant DNA Molecules provide another classification of agents and toxins based on risk. See Box 5-1 for more information.

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 THE CURRENT REGULATORY ENVIRONMENT • BSL-1 laboratories are for working with agents and toxins that do not consistently cause disease in healthy human adults; • BSL-2 laboratories are for working with agents and toxins that can be spread through puncture, absorption through mucus membranes, or ingestion; • BSL-3 laboratories are for working with agents and toxins that are capable of aerosol transmission and that may cause serious or lethal infection; and • BSL-4 laboratories are for working with agents or toxins that pose a high risk of life threatening disease that may be aerosol transmitted and for which there is no available therapy or vaccine. BSL-3 and BSL-4 laboratories are considered “high” and “maximum contain - ment,” respectively. They require specialized expertise to design, construct, operate, and maintain. It should be noted that there are no inherent security requirements associated with the BSL levels; these are intended for safety. Se - curity considerations are tied to the agents being used; the specific type of agent or toxin drives the requirement for security. While some research and testing for the development of countermeasures for select agents can be conducted at BSL-2, work on the most dangerous agents requires BSL-3 and -4 conditions. High and maximum containment laboratories may also be necessary for some diagnostic and analytical services and for basic research on pathogenesis and other aspects of hazardous infec - tious agents. Table 2-1 contains a more detailed summary of the recommended practices, safety equipment, and facilities for each of the biosafety levels for infectious agents. The BMBL guidelines have become the accepted practice in U.S. labora- tories and have provided a model for similar practices in other countries. They are not codified in formal regulations, but are powerful performance-based standards for how laboratories are expected to operate. “According to federal grant policy and standard contract language, researchers and laboratory work - ers at institutions receiving federal funds are to be trained in the procedures described in the BMBL before they gain access to the laboratory” (Gottron and Shea 2009:6). For the first time, the fifth edition of the BMBL contains a discussion of “biosecurity,” whose objective is defined as preventing “loss, theft or misuse of microorganisms, biological materials, and research-related information” (CDC/ NIH 2007:105).5 The manual provides guidelines for a biosecurity program, including physical security and personnel management measures. 5 The latest edition of the WHO manual also includes information on “laboratory biosecurity,” which is defined as the “institutional and personal security measures designed to prevent the loss, theft, misuse, diversion or intentional release of pathogens and toxins” (WHO 2004:47).

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0 RESPONSIBLE RESEARCH WITH BIOLOGICAL SELECT AGENTS AND TOXINS TABLE 2-1 Recommended Practices, Safety Equipment, and Facilities for Biosafety Levels 1-4 Facilities Primary Barriers and (Secondary BSL Agents Practices Safety Equipment Barriers) 1 Not known to Standard None required Laboratory bench consistently cause microbiological and sink required diseases in healthy practices adults 2 Agents associated BSL-1 practices Primary barriers: Class I BSL-1 plus: with human disease plus: or II biosafety cabinets • Autoclave • Limited access (BSCs) or other available Routes of • Biohazard physical containment transmission warning signs devices used for all include • “Sharps” manipulations of agents percutaneous precautions that cause splashes or injury, ingestion, • Biosafety manual aerosols of infectious mucous membrane defining any materials exposure needed waste Personal protective decontamination equipment (PPEs): or medical Laboratory coats, surveillance gloves, face protection policies as needed 3 Indigenous or BSL-2 practices Primary barriers: Class BSL-2 plus: exotic agents with plus: I or II BSCs or other • Physical potential for aerosol • Controlled physical containment separation from transmission access devices used for open access corridors • Decontamination manipulation of agents • Self-closing, Disease may have of all waste double-door serious lethal PPEs: Protective • Decontamination access consequences laboratory clothing, of laboratory • Exhaust air not gloves, respiratory clothing before recirculated protection as needed laundering • Negative airflow • Baseline serum into laboratory 4 Dangerous/exotic BSL-3 practices Primary barriers: All BSL-3 plus: agents pose plus: procedures conducted • Separate high risk of life • Clothing change in Class III BSCs or building or threatening disease before entering Class I or II BSCs isolated zone • Shower on exit in combination with • Dedicated Aerosol-transmitted • All material full-body, air-supplied, supply and laboratory decontaminated positive pressure exhaust, infections have upon exit from personnel suit vacuum, and occurred; related facility decontamination agents with systems unknown risk of • Additional transmission requirements SOURCE: CDC/NIH 2007.

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 THE CURRENT REGULATORY ENVIRONMENT Measures to Address Security The BWC calls on its member states to enact legislation to support the implementation of the treaty. The United States passed the Biological Weapons Anti-Terrorism Act of 1989 (Public Law 101–298, May 22, 1990), which estab - lished penalties for violating the Convention’s prohibitions, unless “(1) such biological agent, toxin, or delivery system is for a prophylactic, protective, or other peaceful purpose; and (2) such biological agent, toxin, or delivery system, is of a type and quantity reasonable for that purpose.” In keeping with the treaty, the legislation focused on the purpose for which agents or toxins were possessed, rather than the agents themselves. The law authorizes the govern - ment to apply for a warrant to seize any biological agent, toxin, or delivery system that has no apparent justification for peaceful purposes, but prosecution under the law would require the government to prove that an individual did not have peaceful intentions (Atlas 1999). Since President Richard M. Nixon had already ended the U.S. offensive biological weapons program 20 years earlier, 6 the law attracted little attention when it was enacted. THE BEGINNINGS OF THE SELECT AGENT PROGRAM The first legislation that sought to limit the threat that biological agents or toxins from legitimate U.S. research laboratories would fall into the hands of terrorists was the Antiterrorism and Effective Death Penalty Act of 1996 (Public Law 104–132, April 24, 1996). The Act was passed amid rising concerns about terrorism, including with nuclear, chemical, or biological materials, in the wake of the 1993 World Trade Center and 1995 Oklahoma City bombings and the revelation of the Aum Shinrikyo’s efforts to create biological as well as chemical weapons after its release of sarin in the Tokyo subway system. The immediate cause of the legislation was the attempt by a U.S. scientist with ties to white supremacist organizations to obtain plague-causing bacteria for poten- tially nefarious purposes (Stern 2000; Carus 2001; Gronvall 2008). The Act contained several findings about the risks of bioterrorism: (1) certain biological agents have the potential to pose a severe threat to public health and safety; 6 On November 25, 1969, President Nixon issued National Security Decision Memorandum 35, which renounced the “use of lethal methods of bacteriological/biological warfare. The United States bacteriological/biological programs will be confined to research and development for de - fensive purposes (immunization, safety measures, et cetera)” (NSC 1969:2-3). The Memorandum stated, “This does not preclude research into those offensive aspects of bacteriological/biological agents necessary to determine what defensive measures are required” (NSC 1969:3). This order did not regulate possession of potentially dangerous pathogens, but instead focused on the purpose of the research. The BWC took a similar approach, as already noted.

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 RESPONSIBLE RESEARCH WITH BIOLOGICAL SELECT AGENTS AND TOXINS (2) such biological agents can be used as weapons by individuals or organiza- tions for the purpose of domestic or international terrorism or for other criminal purposes; (3) the transfer and possession of potentially hazardous biological agents should be regulated to protect public health and safety; and (4) efforts to protect the public from exposure to such agents should ensure that individuals and groups with legitimate objectives continue to have access to such agents for clinical and research purposes. (Public Law 104–132, April 24, 1996, Sec. 511) The Act required the Secretary of Health and Human Services (HHS) to issue regulations to govern the transport of biological agents with the potential to pose a severe threat to public health and safety through their use in bioter- rorism. In establishing the list of materials to regulate, the Secretary was to consider: “(I) the effect on human health of exposure to the agent; (II) the degree of contagiousness of the agent and the methods by which the agent is transferred to humans; (III) the availability and effectiveness of immunizations to prevent and treatments for any illness resulting from infection by the agent; and (IV) any other criteria that the Secretary considers appropriate” (Public Law 104–132, April 24, 1996, Sec. 511). The Secretary delegated the authority to regulate these “select agents” to the Centers for Disease Control and Preven- tion (CDC). To ensure that the transfer of these agents was carried out only by and between responsible parties, CDC required that laboratories transferring select agents be registered and report each transfer.7 The initial list of select agents, introduced in 1997, contained 42 agents and toxins. It included some agents that could affect both humans and animals (for example, Bacillus anthracis and Francisella tularensis), but did not include those affecting only animals and plants. In drawing up the list, groups of experts from inside and outside the government focused on the agents and toxins that had been weaponized in the United States. and other offensive biological weapons 7 “The purpose of registration was to control domestic transfers based upon a permitting system. A registered laboratory could legally transfer select agents only to another registered laboratory; some transfers were denied because of concerns about the adequacy of the facility proposed to receive the agent. Transfers to nonregistered laboratories were prohibited. Registration, however, was principally a matter of notification: a laboratory was obligated to notify relevant authorities of a transfer to another registered facility and that the transfer itself complied with applicable safety standards. Specific information about particular pathogens that the facility possessed did not have to be reported, not even if they were the subjects of extensive research, so long as they were not transferred. This was not intended to be a strict licensing system but merely a way of overseeing transfers and shipments of lethal pathogens” (NRC 2004a:75).

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 THE CURRENT REGULATORY ENVIRONMENT programs prior to the advent of the BWC or those that were considered to have the greatest potential for weaponization.8 In the wake of the terrorist attacks of September 11, 2001, and the Bacillus anthracis9 mailings in October of 2001, Congress passed legislation that sub - stantially expanded the scope of the Select Agent Program. The USA PATRIOT Act of 2001 (Public Law 107–56, October 26, 2001) made it an offense for a person to knowingly possess any biological agent, toxin, or delivery system of a type or in a quantity that, under the circumstances, is not reasonably justified by prophylactic, protective, bona fide research, or other peaceful purpose. The Act also established restrictions on the possession or transfer of select agents by “restricted persons,” which are individuals with one or more disqualifying factors in their background or behavior (see below). The provisions of the USA PATRIOT Act were subsequently augmented by the Public Health Security and Bioterrorism Preparedness and Response Act, known as the Bioterrorism Act of 2002 (Public Law 107–188, June 12, 2002). This Act added requirements for regulations governing possession of select agents, including approval for laboratory personnel by the Attorney General following a background check by the Federal Bureau of Investigation (FBI). It also gave the U.S. Department of Agriculture (USDA), through its Animal and Plant Health Inspection Service (APHIS), the authority to regulate the possession, use, and transfer of BSAT materials that relate to plant and animal health and products, complementing the authority granted to CDC for human pathogens. The regulation of select agents and toxins is thus a shared federal responsibility involving HHS/CDC, USDA/APHIS, and the Department of Justice (DOJ). The Bioterrorism Act has been implemented through a series of regulations; the final regulations—42 CFR 73 (human pathogens), 9 CFR 121 (animal pathogens), and 7 CFR 331 (plant pathogens)—became effective in the spring of 2005.10 THE CURRENT SELECT AGENT PROGRAM The current Select Agent Program has a number of components, which are described in the first part of this section. This is followed by a discussion of the operation of the program, such as inspections and inventory requirements. 8 The United States had also weaponized some anti-crop agents, but they were not included in the initial list. 9 Bacillus anthracis is the bacterium that causes anthrax. 10 Agents that can affect both human and animals, called “overlap agents,” are listed in both the CDC and USDA lists.

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 RESPONSIBLE RESEARCH WITH BIOLOGICAL SELECT AGENTS AND TOXINS The List of Select Agents and Toxins The addition of agents and toxins that could affect animals and plants almost doubled the size of the original select agent list (see Table 2-2 for the current list). In the years since the revised list was issued, the reconstructed 1918 influenza virus was added to the list in 2005; some of the discussion over the wisdom of reconstructing the virus focused on its potential as a biological weapon or bioterror agent. As mentioned in Chapter 1, at the time this report was written, two Federal Register notices were seeking comment on proposals TABLE 2-2 Current List of Select Agents and Toxins HHS SELECT AGENTS AND TOXINS Shigatoxin South American Haemorrhagic Fever viruses Abrin Flexal Botulinum neurotoxins Guanarito Botulinum neurotoxin producing species of Junin Clostridium Machupo Cercopithecine herpesvirus 1 (Herpes B virus) Sabia Clostridium perfringens epsilon toxin Staphylococcal enterotoxins Coccidioides posadasii/Coccidioides immitis T-2 toxin Conotoxins Tetrodotoxin Coxiella burnetii Tick-borne encephalitis complex (flavi) viruses Crimean-Congo haemorrhagic fever virus Central European Tick-borne encephalitis Diacetoxyscirpenol Far Eastern Tick-borne encephalitis Eastern Equine Encephalitis virus Kyasanur Forest disease Ebola virus Omsk Hemorrhagic Fever Francisella tularensis Russian Spring and Summer encephalitis Lassa fever virus Variola major virus (Smallpox virus) Marburg virus Variola minor virus (Alastrim) Monkeypox virus Yersinia pestis Reconstructed replication competent forms of the 1918 pandemic influenza virus OVERLAP SELECT AGENTS AND containing any portion of the coding regions TOXINS of all eight gene segments (Reconstructed 1918 Influenza virus) Bacillus anthracis Ricin Brucella abortus Rickettsia prowazekii Brucella melitensis Rickettsia rickettsii Brucella suis Saxitoxin Burkholderia mallei (formerly Pseudomonas Shiga-like ribosome inactivating proteins mallei)

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 THE CURRENT REGULATORY ENVIRONMENT to add the SARS-associated coronavirus and Chapare virus to the list (HHS 2009ab). The question of adding the SARS and Chapare viruses also illustrates a continuing argument/discussion of whether the list should include agents and toxins that are primarily serious public health threats rather than only those that are likely candidates for use in bioterrorism. The language of the USA PATRIOT Act and the Bioterrorism Preparedness Act speak of agents that pose threats to “public health,” but the acts are focused on the threats posed by bioterrorism rather than more general infectious diseases. Some of the pro - posals to stratify the list reflect an effort to focus the Select Agent Program on Burkholderia pseudomallei (formerly Mycoplasma mycoides subspecies mycoides Pseudomonas pseudomallei) small colony (MmmSC) (contagious bovine Hendra virus pleuropneumonia) Nipah virus Peste des petits ruminants virus Rift Valley fever virus Rinderpest virus Venezuelan Equine Encephalitis virus Sheep pox virus Swine vesicular disease virus USDA SELECT AGENTS AND TOXINS Vesicular stomatitis virus (exotic): Indiana subtypes VSV-IN2, VSV-IN3 African horse sickness virus Virulent Newcastle disease virusa African swine fever virus Akabane virus USDA PLANT PROTECTION AND Avian influenza virus (highly pathogenic) QUARANTINE (PPQ) SELECT AGENTS Bluetongue virus (exotic) AND TOXINS Bovine spongiform encephalopathy agent Camel pox virus Peronosclerospora philippinensis Classical swine fever virus (Peronosclerospora sacchari) Ehrlichia ruminantium (Heartwater) Phoma glycinicola (formerly Pyrenochaeta Foot-and-mouth disease virus glycines) Goat pox virus Ralstonia solanacearum race 3, biovar 2 Japanese encephalitis virus Rathayibacter toxicus Lumpy skin disease virus Sclerophthora rayssiae ar zeae Malignant catarrhal fever virus Synchytrium endobioticum (Alcelaphine herpesvirus type 1) Xanthomonas oryzae Menangle virus Xylella fastidiosa (citrus variegated chlorosis Mycoplasma capricolum subspecies strain) capripneumoniae (contagious caprine pleuropneumonia) aA virulent Newcastle disease virus (avian paramyxovirus serotype 1) has an intracerebral patho - genicity index in day-old chicks (Gallus gallus) of 0.7 or greater or has an amino acid sequence at the fusion (F) protein cleavage site that is consistent with virulent strains of Newcastle disease virus. A failure to detect a cleavage site that is consistent with virulent strains does not confirm the absence of a virulent virus. SOURCE: 7 CFR 331, 9 CFR 121, and 42 CFR 73; .

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6 RESPONSIBLE RESEARCH WITH BIOLOGICAL SELECT AGENTS AND TOXINS those agents and toxins that pose the greatest threats to security (e.g., NSABB 2009). We return to this issue in Chapters 3 and 5 but note it here as part of the context for the operation of the Select Agent Program. The Security Risk Assessment11 A Security Risk Assessment (SRA) is required for all individuals who have access to select agents or toxins, including principal investigators, laboratory staff, and some maintenance personnel. Certain designated officials—the Re - sponsible Official (RO) and the Alternate Responsible Official (ARO), who oversee the program at an individual entity,12 as well as any owners/controllers of nongovernment entities—must also undergo an SRA even if they will not have personal access to select agents. All registered entities (except for federal, state, or local governmental agencies or accredited public academic institutions) must also undergo an SRA.13 The SRA for individuals is carried out by the FBI’s Criminal Justice In - formation Services (CJIS) Division. An individual’s SRA is valid for five years unless terminated sooner by CDC, APHIS, or the employer. The SRA is tied to the entity for which the individual works; it cannot be transferred if she or he moves to another BSAT facility. A certificate of registration for an entity is valid for a maximum of three years. The entity, the RO, ARO, and individuals that own or control the entity must obtain security risk assessment approval each time the certificate of registration is renewed. The purpose of the SRA is to determine whether an applicant has any of the factors that would prohibit him or her from working with select agents, 11 Unless otherwise noted, this section is based on a briefing prepared for the committee by Robbin Weyant, Division of Select Agents and Toxins, Coordinating Office for Terrorism Prepared - ness and Emergency Response, Centers for Disease Control and Prevention, and Elizabeth Snyder, Criminal Justice Information Services, Federal Bureau of Investigation, and presented on June 29, 2009 (Weyant and Snyder 2009). 12 “An entity is defined as any government agency (federal, state, or local), academic institution, corporation, company, partnership, society, association, firm, sole proprietorship, or other legal entity. An entity is thus not limited to a single facility or to a single laboratory. An entity may possess one or multiple facilities, each facility containing one or multiple laboratories” (Gottron and Shea 2009:2). Clinical laboratories were granted a special exemption to permit them to legally isolate and identify (and thereby possess) select agents cultured from patients as part of the medical diagnostic process, even if they were not registered to possess select agents, and to handle those materials that were part of proficiency training. This was considered essential for medical diagnoses where there is no way to predict what disease a patient might have, thereby precluding the ability to register for specific select agents. The clinical laboratories, however, are mandated to destroy any select agents or transfer them to a registered laboratory that is permitted to possess them within speci - fied periods, and they must also notify public health authorities whenever a select agent has been isolated and identified (Deminn 2007:547). 13 The government facilities are presumed to have equivalent security procedures in place.

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 THE CURRENT REGULATORY ENVIRONMENT based upon the exclusions enumerated in relevant legislation. An individual is considered a “restricted person” under the USA PATRIOT Act if he or she: 14 • Is under indictment for a crime punishable by imprisonment for a term exceeding one year or has been convicted in any court of a crime punishable by imprisonment for a term exceeding one year. • Has received a dishonorable discharge from the U.S. military. This provision ensures that those who commit comparable crimes while in the military will also be denied access to BSAT materials. • Is a fugitive from justice. • Is an unlawful user of any controlled substance (as defined in section 102 of the Controlled Substances Act (21 USC 802)). • Has been adjudicated as a mental defective or has been committed to any mental institution. The prohibition is based on specific legal distinctions that make this a small category of individuals. 15 • Is an alien illegally or unlawfully in the United States. • Is an alien (other than an alien lawfully admitted for permanent resi- dence) who is a national of a country that has repeatedly provided support for acts of international terrorism. This is operationalized as nationals of countries formally designated as state sponsors of terror- ism. Currently there are four such countries: Cuba, Iran, Sudan, and Syria (Department of State 2009b).16 Unlike formal security clearances, foreign nationals are thus eligible for access to BSAT.17 Additionally, under the Bioterrorism Preparedness Act, an individual could 14 According to several accounts of the creation of the USA PATRIOT Act, including those at the public consultation for the Executive Order Working Group on Strengthening the Biosecurity of the United States, the list of disqualifying factors was based on those in the Brady Handgun Vio - lence Prevention Act (Public Law 103–159, November 30, 1993), on the principle that anyone who would not be allowed to own a handgun should not be permitted access to dangerous pathogens. 15 “Adjudicated as a mental defective. (a) A determination by a court, board, commission, or other lawful authority that a person, as a result of marked subnormal intelligence, or mental ill - ness, incompetency, condition, or disease: (1) Is a danger to himself or to others; or (2) Lacks the mental capacity to contract or manage his own affairs. (b) The term shall include (1) A finding of insanity by a court in a criminal case; and (2) Those persons found incompetent to stand trial or found not guilty by reason of lack of mental responsibility pursuant to articles 50a and 72b of the Uniform Code of Military Justice, 10 USC 850a, 876b” (27 CFR 478.11). See Chapter 4 for further discussion. 16 At the time the SRA was developed, there were seven countries on the list, the four current ones and Iraq, Libya, and North Korea. 17 Foreign nationals who possess unique skills or knowledge can obtain special security clearances that provide limited access for specific purposes.

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 RESPONSIBLE RESEARCH WITH BIOLOGICAL SELECT AGENTS AND TOXINS cludes presenting workshops, having a primary point of contact assigned to each entity, developing frequently asked questions that are posted on the program Web site, and making technical presentations at meetings and conferences. Inventory Entities that possess BSAT materials are required to keep specific kinds of records and other information about the materials in their possession. (Add- tional information about current policies is included in Chapter 5.) An accurate, current inventory is required for each agent in long-term storage, that is, main - tained in a condition that keeps them viable for future use. 31 Entities are also required to have protocols in place for transfer and accountability of inventories when the investigator responsible for the inventory leaves, including change in employment, retirement, death, sabbatical, or other reasons, and no longer has an active role in the entity. Reports of Theft, Loss, and Release All reports of theft, loss, or release of select agents are investigated to ensure that public health and safety are protected. From 2003 until the end of September 2009, there were 154 incidents reported to CDC and USDA through the Select Agent Program’s theft, loss, and release reporting system. Follow-up investigations conducted by HHS, USDA, and the FBI determined that there were no confirmed losses or theft of a select agent. There were three confirmed releases of a select agent, and these were all identified by illnesses in five labora- tory workers as a result of working with the agents (Besser 2007). OTHER FEDERAL REGULATIONS RELATED TO BSAT RESEARCH The Select Agent Program’s regulations apply to all federal agencies and departments. Most of the federal agencies conducting or supporting BSAT research—including DOD and the military services, NIH, CDC, DOE, and USDA—currently have additional security-related policies or regulations in place beyond these requirements. At least some of the agencies require that the entities conducting BSAT research they fund via contracts and grants also apply these practices. This section contains a brief summary of these additional polices and regulations, based largely on information provided by the Executive Order (EO) Working Group on Strengthening the Biosecurity of the United 31 A definition of “long-term storage” can be found at . See Box 5-2 for required elements in inventory records.

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 THE CURRENT REGULATORY ENVIRONMENT States. After a brief recap of personnel reliability and physical security, the sec - tion is organized by agency.32 Physical Security and Personnel Reliability Physical Security Physical security programs are intended to prevent unauthorized access to BSAT materials. They are largely but not exclusively addressed to combating the outsider threat. Three common elements of physical security programs are: (a) access controls, which include security for the perimeter, points of entry, and the interior of the facility; (b) information systems control, which includes information technology, protection of infrastructure and hardware, assuring reliability of information technology personnel or vendors, and inventory pro - tection; and (c) inventory controls, which includes managing and tracking both the BSAT materials and the data about them. Personnel Reliability A “personnel reliability program” (PRP) is the general term used to de - scribe policies intended to ensure that individuals who are given access to BSAT materials are worthy of that trust. There may be many qualities that define a “reliable” employee; the NSABB, for example, concluded that trustworthy, responsible employees would: • Be free of felony convictions; • Have no domestic or international terrorist ties; • Have no history of scientific or professional misconduct in the workplace; • Possess emotional stability and capacity for sound judgment; • Have a positive attitude toward safety and security measures, and standard operating procedures; and Be free of vulnerability to coercion (NSABB 2009).33 • 32 The section does not address issues related to transportation, which the committee has decided not to include in its report. 33 The report goes on to say that: “The NSABB considers these to be reasonable characteristics for individuals with access to select agents and toxins. It found, however, that some of the characteris - tics were exceedingly difficult to measure in any objective way and that it was unclear whether these characteristics were suitable surrogates (or predictors) for not posing an insider threat. Further- more, as it considered the potential utility of the various assessments commonly utilized in PRPs, it found little evidence to suggest that personnel reliability assessments going beyond the SRA and other institutional background checks that are already in place would correlate with, or effectively identify, an insider threat. In addition, as was the case with the optimal personnel characteristics, there were no objective criteria for translating the information gathered from a given assessment into a determination of reliability” (NSABB 2009:8).

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60 RESPONSIBLE RESEARCH WITH BIOLOGICAL SELECT AGENTS AND TOXINS A PRP may apply in the pre-employment screening phase as part of the hiring process or to measures that apply while an individual is working or both. At hiring, applicants may be screened for drug or alcohol (ab)use; undergo medical examinations, psychological evaluations, credit checks, and reviews of past employment or service records; be required to take psychological tests or polygraph exams; and undergo background investigations, possibly including a formal security clearance process. Drug and alcohol screening might continue during employment, along with a range of mechanisms for continuous moni - toring, including self-reporting and peer reporting and periodic updates of the checks and assessments done prior to hiring. A number of the personnel reli - ability programs carried out by federal agencies require various types of formal background investigations; these are described briefly in Box 2-2. The federal Office of Personnel Management (OPM) currently conducts 90 percent of the suitability and security clearance investigations for 100 fed - eral agencies, using approximately 9,000 investigators to conduct 2.2 million background investigations each year (Crowley 2009). Of these, approximately 750,000 are national security clearance investigations (GAO 2009b:1). The process for determining access to classified information rests on a series of executive orders dating back to the 1950s; the current process is based on EO 12968, issued in August 1995.34 Examples of Federal Agency Physical Security and Personnel Reliability Requirements This section is intended to provide a sampling, agency by agency, of some of the additional provisions that federal agencies have put in place to increase security for BSAT materials beyond the requirements of the Select Agent Pro - gram. Some of the measures simply reflect the agency’s practice for many of its employees—such as requiring security clearances—and are not limited to those working with BSAT materials. Others, such as the Army’s Biological Surety Program, are specifically directed at BSAT research. U.S. Department of Agriculture USDA’s PRP policy covers personnel who work with BSAT at the BSL-3 level, with the extent of the background investigation determined by the level of risk. Continuous evaluation by managers and required self-reporting are part 34 In June 2008, President George W. Bush issued EO 13467, which was intended to “ensure an efficient, practical, reciprocal, and aligned system for investigating and determining suitability for Government employment, contractor employee fitness, and eligibility for access to classified information” (White House 2008). This EO set in motion a number of reforms, but these are beyond the scope of this study.

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6 THE CURRENT REGULATORY ENVIRONMENT BOX 2-2 Types of Personnel Security Investigations National Agency Check. The National Agency Check (NAC) consists of searches of the Security/Sustainability Investigation Index and the Defense Clearance and Investigations Index, as well as the FBI Identification Division’s name and fin- gerprint files, and other files as necessary. These are conducted by the Office of Personnel Management. National Agency Check and Inquiries. The National Agency Check and In- quiries (NACI) is a basic investigation required for all new federal employees. It consists of the National Agency Check investigation, as well as written inquiries and record searches covering specific areas of a person’s background during the past five years. Inquiries are sent to employers, schools attended, references given, and local law enforcement authorities. NACI and Credit. The NACI and Credit (NACIC) consists of the NACI with the addition of a credit record check. Access NACI. The Access NACI (ANACI) consists of a required initial investiga- tion for federal employees who will need access to classified national security information at the Confidential and Secret levels. The ANACI includes the NACIC with additional law enforcement agency checks. NAC with Local Agency Check and Credit. The NAC with Local Agency Check and Credit (NACLC) is the initial investigation for government contractors at the Confidential and Secret national security access levels. The NACLC is also used to meet reinvestigation requirements for all individuals holding Confidential and Secret clearances. Single Scope Background Investigation. The Single Scope Background In- vestigation (SSBI) is a government-wide investigation required for all personnel needing access to Top Secret classified national security information. The SSBI covers the last seven years of the person’s activities and includes verification of citizenship and the date and place of birth. In addition, the SSBI conducts national agency records checks on the person’s spouse or cohabitant and interviews with selected references and former spouses. SSBI-Periodic Reinvestigation. The SSBI-Periodic Reinvestigation (SSBI-PR) is required every five years for personnel with Top Secret security clearances. Schedule. Investigations are nominally conducted on a five-year reinvestigation schedule. In some cases, a specific type of national security clearance may call for a reinvestigation on a faster schedule. Investigations for collateral Secret and lower clearances sometimes exceed five years due to budgeting or workload constraints. SOURCE: Appendix B in DSB 2009.

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6 RESPONSIBLE RESEARCH WITH BIOLOGICAL SELECT AGENTS AND TOXINS of the system. USDA employees have an employee assistance program in place to provide counseling services. Agricultural Research Serice (ARS) ARS policies regarding BSAT inventories are included in a USDA manual that sets out procedures for BSL-3 laboratories (USDA 2002). Three types of records are required for facilities to demonstrate proper accountability for BSAT materials. The first is the National Pathogen Inventory, a system that is intended to enable managers to determine quickly what pathogens are in use at their facility. The second requirement is for a de- tailed inventory of records, both current and historical, which must be retained for five years. Facilities are also expected to have a materials accountability program for experimental and working samples they maintain. Department of Defense DOD has a number of special instructions related to physical security, some across the military and others specific to individual services. The DOD person - nel reliability program includes one kind of security clearance and background investigation for military personnel and contractors, the National Agency Check with Local Agency Check and Credit Check (NACLC), to confirm information supplied by applicants, in most cases going back seven years. DOD also has another, comparable process for federal civilian employees, the Access National Agency Check and Inquiries (ANACI). Reinvestigations are done every five years if a clearance is to be continued. Unlike the nuclear and chemical PRP programs, foreign nationals are allowed access in the biological PRP. Peer and self-reporting of any potentially disqualifying information are required. As the Defense Science Board (DSB) report on the DOD biological safety and security program notes, DOD’s nuclear surety program has two catego - ries for personnel in its workforce and each category is subject to different background investigations. “A critical position is someone who possesses both technical knowledge and access to the nuclear weapon/system (e.g., launch officers, maintenance personnel, etc.) and non-critical is an individual who pos- sesses access but not technical knowledge (e.g., guard forces)” (DSB 2009:31; emphasis added). Department of the Army The Army applies additional physical security mea- sures to all of the BSAT laboratories and facilities it owns or controls. The same rules apply to the major Army commands, and to contractors who have received BSAT materials from DOD; the latter requirement caused some questions and concerns during the public consultations. Commenters suggested a formal vulnerability assessment for both outsider and insider threats, based on Army and DOD guidance. Rather than the site-specific plan required by the Select

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6 THE CURRENT REGULATORY ENVIRONMENT Agent Program, an extensive list of specific features, subject to annual review, is required for both the facility and the rooms and laboratories where BSAT work takes place under Army regulations. Two people are required to access refer- ence stocks, for example, but there is no current requirement for cameras. In the summer of 2008, the U.S. Army issued a new set of regulations governing personnel reliability: AR 50-1, the “Biological Surety” program (De - partment of the Army 2008). In addition to the security clearances required for those granted access to BSAT, AR 50-1 gives responsible officials substantial new discretion to deny or remove access. Some of the provisions, which de - scribe factors well beyond those in the current SRA that would disqualify an individual access to BSAT, are potentially exceedingly expansive. For example, one can be disqualified for an “inappropriate attitude, conduct, or behavior” (Department of the Army 2008:10). Department of Energy Of the five DOE national laboratories that work with BSAT materials, all require elements of a PRP beyond what is required by the Select Agent Pro - gram. Polygraph examinations are not required, in contrast to DOE’s nuclear activities where individuals with access to certain kinds of highly classified in - formation may be required to undergo polygraph testing. Different laboratories use one of two different programs, both of which include an annual medical exam and psychological evaluation, annual credit and criminal records checks, and various training components. As part of its Worker Safety and Health Program outlined in 10 CFR 851, DOE sets out requirements for its contractors to maintain an inventory and to submit an annual report on its status to the contractor’s Institutional Biosafety Committee, which is also provided to the relevant DOE field and area offices. Copies of reports of transfers of BSAT materials, including notification when the transfer is complete, are also sent to the relevant DOE field office. Department of Health and Human Services National Institutes of Health The NIH Biological Surety Program covers all personnel who work in BSL-4 facilities and anyone who works in certain other designated facilities. These individuals must undergo a Collective Foreign Threats Assessment, which searches most of the databases used in the SRA and several others. The level of additional background investigation conducted is based on the sensitivity of the job responsibilities. For those working in desig - nated facilities including BSL-4 laboratories, NIH may require a two-person rule or buddy system, although this is for occupational health and safety rather than security. On the job, continuous monitoring, self- and peer-reporting,

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6 RESPONSIBLE RESEARCH WITH BIOLOGICAL SELECT AGENTS AND TOXINS training, and medical and behavioral health exams are required, although again the primary motive is safety. Centers for Disease Control and Preention CDC is currently developing a personnel screening program and monitoring program for all employees who work with or have access to BSAT that is expected to include an ANACI se - curity clearance process, drug testing and occupational health screening, and self and peer-reporting. Smallpox was declared eradicated in 1980, and in 1983, two centers—CDC and one in Russia—were authorized by the World Health Assembly as the sole entities able to house or conduct research on smallpox. The original plan was to destroy all remaining stocks after 10 years, but this was changed to create a standing World Health Organization (WHO) Advisory Committee on Variola Virus Research that monitors the state of all research, grants permission to con - duct specific experiments, and reports to the World Health Assembly annually (IOM 2009:1-2; WHO 2008). Department of Homeland Security Although it does not have a formal PRP program, DHS already requires all employees to have a minimum of a Secret security clearance. The two DHS laboratories that work with BSAT materials—the Plum Island Animal Dis - ease Center and NBACC—require drug screening for all potential employees. NBACC also requires a reliability screening by a senior laboratory manager, which includes personnel and medical information. Employees are required to report potentially disqualifying information. REGULATIONS AND PRACTICES OUTSIDE THE UNITED STATES Life sciences research is an increasingly global enterprise, including that involving BSAT materials (NRC 2006). A number of regional and international organizations have developed standards and practices that are relevant to the conduct of BSAT research. In addition, a number of countries have regulations and guidance that either govern work with BSAT materials directly or have an impact on how such work is conducted. What happens outside the United States needs to be considered because it may provide useful ideas or models. Moreover, international collaboration benefits from harmonized standards and practices. The Geneva Protocol, the BWC, and UN Security Council Resolutions 1540 and 1810 were described earlier in this chapter. In addition, a number of formal and informal groups address parts of BSAT research.

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6 THE CURRENT REGULATORY ENVIRONMENT International and Regional Activities The Australia Group The Australia Group (AG) is an informal forum of 40 countries and the European Commission that “through the harmonisation of export controls, seeks to ensure that exports do not contribute to the development of chemical or biological weapons.”35 The AG was formed in 1985 in response to a pro- posal from Australia to improve consultation over export controls on chemical weapons precursors after the use of chemical weapons in the Iran-Iraq War. Biological materials and equipment were included in the AG’s concerns in the early 1990s. The AG maintains “common control lists” for dual use biological equipment and related technology and software, biological agents, and plant and animal pathogens to provide the basis for encouraging standard national export licensing regulations. European Committee for Standardization The European Committee for Standardization/Comité Européen de Normalisation (CEN) is a private, nonprofit organization that seeks to promote the development of standards in order to reduce trade barriers, promote safety, allow interoperability of products, systems and services, and promote common technical understanding. “All standards help build the ‘soft infrastructure’ of modern, innovative economies. They provide certainty, references, and bench - marks for designers, engineers and service providers. They give ‘an optimum degree of order.’”36 Much of CEN’s effort is carried out through workshops that reach consensus on voluntary standards (called CEN Workshop Agreements) that can be applied internationally and do not have the force of regulation. In 2008, CEN published its International Laboratory Biorisk Management Stan- dard (CEN 2008), whose goal “is to set requirements necessary to control risks associated with the handling or storage and disposal of biological agents and toxins in laboratories and facilities” (CEN 2008:8), with a “biorisk” defined as the “combination of the probability of occurrence of harm and the severity of that harm where the source of harm is a biological agent or toxin” (CEN 2008:9).37 35 Forfurther information see the AG website at . 36 For further information, see the CEN website at . 37 “The source of harm may be an unintentional exposure, accidental release or loss, theft, misuse, diversion, unauthorized access or intentional unauthorized release.”

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66 RESPONSIBLE RESEARCH WITH BIOLOGICAL SELECT AGENTS AND TOXINS World Health Organization As mentioned earlier, the WHO published its most recent Biosafety Manual in 2004, which for the first time, contains a discussion of “biosecurity” (WHO 2004). To complement the manual, WHO published Biorisk Management: Laboratory Biosecurity Guidance in 2006, which attempts to “strike a balance” between longstanding biosafety practices and newer concepts of biosecurity by recommending a “biorisk management approach” to provide guidance to its member states in developing their own national approaches (WHO 2006:1). The WHO defined “biorisk” as the “probability or chance that a particular adverse event (in the context of this document: accidental infection or unau - thorized access, loss, theft, misuse, diversion or intentional release), possibly leading to harm, will occur” (WHO 2006: iii). National Regulations and Practices38 At present very few countries other than the United States have regulations in place governing either facilities or personnel, and for those that do—the United Kingdom (UK), France, Japan, Australia and Canada—the regulations are of recent vintage (i.e., since 2001). The exception is Germany, which has had regulations in place since 1900. Rather than attempt to describe various national practices in any detail, we offer some summary comments on the trends in various regulatory practices. Personnel There is a wide variety among regulations addressing personnel reliability, ranging from strong local control to national registries. In the cases of local control, there is almost always a provision in the regulations that higher authorities should have access to personnel records upon request. Only the UK, Germany, and Australia appear to conduct personnel screening comparable to the SRA or security clearances. Canada has passed legislation creating the equivalent of security clearances for those working in BSL-4 laboratories, and Germany has the equivalent of security clearances for those working at the BSL-4 level already in place. Facilities Unlike personnel, facilities are generally regulated at the national level. Such regulation takes many forms and may include requirements govern - ing registration of specific activities. These types of regulations appear to be more common than those governing personnel, perhaps because of the preva - lence of concerns with biosafety or genetically modified organisms (GMOs). In 38 This section draws on the research undertaken by Dr. Robert Butera, a professor of Bio- engineering and Computer Engineering at the Georgia Institute of Technology while serving as a Jefferson Science Fellow with the Department of State in 2008-2009. The material was contributed by the EO Working Group.

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6 THE CURRENT REGULATORY ENVIRONMENT general, biosafety regulations are more common than those focused specifically on BSAT research. A number of countries have tiers of regulations, requiring various levels of notification, authorization, record keeping, and so forth. Some countries require permission or licensing of facilities at a particular biosafety level, inde - pendent of the agents the facility may work with and store. Some form of reg - istration or licensing of BSL-3 and -4 facilities is required in Germany, China, South Korea and Switzerland. There are also examples of stratification of the types of notifications and permissions required to work at various biosafety levels. In Switzerland, for example, the equivalent of BSL-2 research requires notifying the relevant authorities, while permission is required to work at the BSL-3 or -4 level. Japan has four tiers, ranging from internal record keeping at the lowest level to notification and then permission. Some activities are pro - hibited outright. European countries have strict rules governing work with GMOs, which in many cases are more stringent than their rules governing pathogens. These rules tend to be focused on regulating facilities and setting standards for accounting for inventories. Since much of potential pathogen research would involve the use of recombinant DNA methods, however, the GMO regulations effectively cover a large portion of pathogen research as well. Some countries regulate BSAT research via their regulations on biosafety risk levels. Germany, Canada, and Switzerland regulate personnel and/or facilities for all the agents designated as BSL-3 or BSL-4. Other countries regulate via lists of “select agents,” which vary in length and composition, and in what special requirements they impose upon listed agents. The lists range in size from Australia’s 22 to South Korea (32), France (37), Japan (51), and the UK (105). SUMMARY This chapter has provided background information on the origins and current operation of the Select Agent Program, additional requirements for personnel reliability and physical security that many federal agencies have ap - plied to their own and, in some cases, their grant and contract BSAT research, and how the regulation of BSAT research is handled outside the United States. The committee drew on this information, as well as its own knowledge and experience, to develop a set of principles to guide formulation of its recom - mendations. Those principles are presented in the next chapter.

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