Online Issues

ILAR Journal Vol 46(1)

Select Agent Regulations

Janet C. Gonder

Janet C. Gonder, D.V.M., Ph.D., is a Consultant and President of Garber Consulting LLC, Pinehurst, North Carolina.

Abstract

In recent years, there has been an increase in research with biological agents, particularly those that pose a potential for use by terrorists. In this environment, laws have been enacted and regulations developed to ensure the appropriate use of specified "select agents and toxins" for legitimate research. Within this regulatory environment, it has been necessary for institutions and investigators to adapt to an entirely new set of requirements to begin or continue to work with these pathogens. Registration and approval for use of select agents and toxins, security and safety requirements, and daunting record-keeping requirements are only some of the regulatory challenges that researchers face in working with these agents. A brief overview of recent regulations is presented, as well as where to obtain additional information on regulations, standards, and guidelines related to work with select agents and toxins.

Key Words: registration; regulations; safety; security; select agents; toxins

Introduction

The regulatory environment surrounding research with infectious agents began to evolve beyond basic safety and security measures with the Antiterrorism and Effective Death Penalty Act of 1996 (Public Law [PL¹] 104-132). This act required the Secretary of the Department of Health and Human Services (DHHS¹) to maintain a list of biological agents that have the potential to pose a severe threat to public health and safety, and to establish and enforce safety procedures for the transfer of listed biological agents, including proper training and skills to handle the agents and proper facilities to contain and dispose of the agents.

The enactment of the USA PATRIOT Act of 2001 (PL 107-56) and the Bioterrorism Preparedness Response Act of 2002 (PL 107-188) established the general regulatory framework for the handling of biological materials in the United States. The legislation and resulting regulations are designed to protect certain "select agents" from inadvertent use, while ensuring safe and appropriate use of these agents for legitimate research.

As a result of the USA PATRIOT Act, it is illegal in the United States for anyone to possess any biological agent for any inappropriate reason. This Act also prohibits the possession or transfer of a listed biological agent or toxin by certain individuals.

PL 107-188 provides for regulation of certain biological agents and toxins by the DHHS and the US Department of Agriculture (USDA¹), and provides for coordination between the two departments regarding agents that "overlap" the departments' areas of responsibility. For the DHHS, the Centers for Disease Control and Prevention (CDC¹) has been designated as the agency with primary responsibility for implementing the provisions of the Act; the Animal and Plant Inspection Service (APHIS¹) is the agency fulfilling the role for the USDA.

The long list of regulations and standards has had an impact, not only on the researchers, but also on the administrative and support infrastructure of institutions engaging in research with infectious agents (Jaax 2005). Focus in this area has been significant enough for the National Research Council to convene the Committee on Research Standards and Practices to Prevent the Destructive Application of Biotechnology. The report of this committee, Biotechnology Research in the Age of Terrorism (NRC 2004), contains a number of specific recommendations for ways to minimize threats from biological warfare and bioterrorism without hindering the progress of biotechnology. Following is a brief overview designed to assist in understanding and implementing regulations and guidelines applicable to work with select agents.

Key Regulations and Definitions

As noted above, two US government departments were required to draft and implement regulations pursuant to specific legislation enacted by Congress. Based on the resulting regulations, entities working with select agents considered a threat to human health must follow the regulations developed by DHHS in Title 42 Code of Federal Regulations Part 73 (CFR 2000a). Entities pursuing studies with plant or animal pathogens must follow regulations developed by APHIS in Title 7 Code of Federal Regulations Part 331 and Title 9 Code of Federal Regulations Part 121, respectively (CFR 2002b).

Select agents are dangerous pathogens, which include viruses, bacteria, rickettsiae, fungi, and toxins that are considered by the CDC to have the potential to pose substantial harm to human health (CFR 2002a). Also addressed in these regulations are "high consequence livestock pathogens and toxins" that the USDA considers to have the potential to pose a severe threat to animal or health or animal products, or those posing a threat to plant health or products (CFR 2002b). Agents that appear on both the CDC and USDA lists are referred to as "overlap agents."

An "entity" is any government agency (federal, state, or local), academic institution, corporation, company, partnership, society, association, firm, or other legal entity wishing to possess, use, receive, or transfer any select agent or toxin within or outside the United States.

A "restricted person," as defined by the USA PATRIOT Act, is "anyone who is under indictment for or has been convicted in any court of a crime punishable by imprisonment for a term exceeding one year; is a fugitive from justice; is an unlawful user of any controlled substance; is an alien illegally or unlawfully in the United States; has been adjudicated as a mental defective or has been committed to any mental institution; is an alien who is a national of a country which is currently designated by the Secretary of State as a supporter of terrorism; or has been dishonorably discharged from US armed forces."

The regulations are very specific, setting out requirements for the establishment and maintenance of certain program components and activities. These components (primarily as set forth in 42 CFR 73) are discussed below.

Registration Requirements

In accordance with 42 CFR 73, entities possessing biological agents that are listed as select agents must register with CDC or USDA, and must demonstrate compliance with safety and security standards for these agents. Registration entails submission of an application to the applicable agency (CDC or USDA) for each select agent or toxin it possesses, uses, or transfers. Institutions applying for registration must designate a responsible official (RO¹), who is responsible for ensuring compliance with the regulations, including

Developing and implementing safety, security, and emergency response plans;
Allowing only approved individuals to have access to select agents or toxins;
Providing appropriate training for safety, security, and emergency response;
Approval for transferring select agents or toxins;
Providing timely notice of any theft, loss, or release of a select agent or toxin;
Maintaining detailed records of information necessary to give a complete accounting of all activities related to select agents or toxins; and
Reporting the identification of a select agent or toxin as a result of diagnosis, verification, or proficiency testing.

Usually the RO is the biosafety officer or senior management official of the facility, or both. The CDC recommends that the RO not be an individual using, working with, or transferring or receiving the agents or toxins, to minimize potential conflicts of interest. Each institution (entity) must also designate an alternate RO who meets all the qualifications of the RO and can conduct all activities of the RO in his or her absence. From the list of responsibilities of the RO, it is clear that compliance also requires coordination of efforts of many facets of institutional research programs.

The registration process requires entities to provide a list of all select agents and toxins it intends to possess, use, or transfer, and the location within buildings of these activities. The names of individuals and the select agents to which they have access must be listed. Each single physical location (site) must be registered. Prior to granting registration, the laboratory may be inspected to assess compliance with all requirements of the regulations. Registration is valid for 2 to 3 yr.

Security Risk Assessment and Definitions

At all entities (except federal, state, or local government agencies), the RO, alternate RO, and all individuals with access to select agents or toxins must have an approved security risk assessment (SRA¹). In Section 73.8(b) of 42 CFR 73 (CFR 2002a), it is stated that an entity may not provide an individual access to a select agent or toxin unless the individual has been approved by either the DHHS Secretary or the USDA, based on a security risk assessment conducted by the Attorney General. Information on obtaining a security risk assessment is available online (<www.cdc.gov/od/sap/securisk.htm> or <www.fbi.gov/terrorinfo/bioterrorfd961.htm>). The purpose of the security risk assessment is to determine whether an individual is a restricted person based on the criteria of the USA PATRIOT Act. The security risk assessment is valid for 5 yr.

"Access" to select agents and toxins is considered to be the "freedom or ability to obtain and make use of" a select agent or toxin. Anyone, including visitors who fit this description, must be approved. As a practical matter, however, the regulations do reflect the recognition that access to select agents or toxins can be limited by security measures or by escorts. For example, "non-laboratory" functions such as routine cleaning, maintenance, and repairs may be accomplished by nonapproved individuals only if escorted and monitored by an individual who has been approved. The intent of these regulations is that the escort will have the means to prevent the nonapproved individual from obtaining or making use of select agents or toxins in the area. In this context, it is expected that facilities have written standard operating procedures (SOPs¹) that define all such procedures, including expected controls, documentation, and monitoring of compliance with the procedures.

Facilities are required to keep a current list of persons approved for access to select agents and toxins, a record of each individual who has actually gained access to a select agent or toxin, and a record of each individual who entered an area where select agents or toxins are used or stored. The records may be manual or electronic (or both), but must include certain specific information. For example, for an investigator working directly with a select agent, the record must show the name of the individual, name of the select agent, term of storage (short- or long-term), dates of removals and returns, and quantities removed and returned. In the case of a maintenance worker who enters an area (e.g., laboratory) in which a select agent or toxin is stored (even if locked), the record must show the name of the person who entered, the date and time entered and exited, and, if escorted, the name of the escort.

Safety

Each facility must implement a safety plan (42 CFR 73.10). The written plan should include applicable requirements of references such as the CDC publication Biosafety in Microbiological and Biomedical Laboratories (Richmond and McKinney 1999), the National Institutes of Health (NIH¹) Guidelines for Recombinant DNA (FR 1994), and other listed guidelines. The RO must conduct at least annual inspections of laboratories and storage areas to ensure compliance with all procedures and protocols of the safety plan. The inspection must be documented, and any deficiencies noted and corrected. Certain types of experiments, such as the deliberate transfer of a drug resistance trait to a select agent, may not be conducted unless approved by the DHHS Secretary.

Security Plan

Section 73.11 of 42 CFR 73 requires an entity to develop and implement a security plan, establishing policy and procedures that ensure the security of areas containing select agents and toxins. The plan must include

Inventory control procedures;
Minimum education and experience criteria for persons with access to select agents and toxins;
Provisions for routine cleaning, maintenance, and repair;
Provisions for training personnel in security procedures;
Provisions for securing the area (e.g., card access, key pads, locks);
Provisions for loss or compromise of keys, passwords, or other means of entry;
Inspection of all packages upon entry to or exit from the area; and
Protocol for intra-entity transfers.

Additional details on requirements of a security plan may be found in 42 CFR 73.11.

Emergency Response

An emergency response plan must be developed and implemented that meets the requirements of Occupational Safety and Health Administration (OSHA¹) hazardous waste operations and emergency response standards (CFR 1998). The plan must address events such as bomb threats, severe weather, earthquakes, power outages, and other natural disasters or emergencies. The emergency response plan must address the following:

The hazards associated with the select agents and toxins;
Hazards associated with the select agents or toxins that could lead to the spread of the agents;
Planning and coordination with outside parties;
Personnel roles, lines of authority, training, and communication;
Emergency recognition and prevention;
Safety distances and places of refuge;
Site security and control;
Evacuation routes and procedures;
Decontamination;
Emergency medical treatment and first aid;
Emergency alerting and response procedures;
Personal protective and emergency equipment; and
Special procedures needed to address the hazards of specific agents.

Record Keeping

The RO must maintain complete records relating to the activities (possession, use, transfer, disposition) involving select agents and toxins. A current list of all individuals approved for access to select agents and toxins must be maintained. An accurate, current inventory of each select agent and toxin held must be maintained. Inventory records must contain information such as name and characteristics; quantity, source, and date of acquisition; dates and quantity used or disposed of; and an explanation of any inventory discrepancies. A system must be created to ensure that all records are accurate and that the authenticity of all records can be verified. Records of inspections, safety, security and emergency response plans, training, and transfers must be kept. All such records must be kept for 3 yr.

Other Requirements

Entities working with select agents or toxins are required to provide training on safety and security for those individuals approved for access to areas where select agents or toxins are handled or stored. The facility must ensure that all individuals receive and understand the training provided. Records must be kept of the identity of individuals trained, the date of training, and the means used to verify that the individual understood the training.

A select agent or toxin may not be transferred to another entity within the United States, or received by an entity in the United States from an entity outside the United States, unless a number of requirements are met. Verification requirements, required forms, and required approvals are outlined in Section 73.14 of 42 CFR 73.

Select Information Sites

Several active web sites provide information on the select agent regulations, access to relevant documents, and links to a wide range of information on the subject. They include, but are not limited to, the following:

CDC Select Agent Program (http://www.cdc.gov/od/sap);
APHIS/USDA Veterinary Services (http://www.aphis.usda.gov/vs);
Federal Bureau of Investigation (including security risk assessment form 961) (http://www.fbi.gov/terrorinfo/terrorism.htm);
American Biological Safety Association (http://www.absa.org); and
NIH Recombinant DNA Guidelines (http://www4.od.nih.gov/oba/rac/guidelines/guidelines.html).

¹Abbreviations used in this article: APHIS, Animal and Plant Inspection Service; CDC, Centers for Disease Control and Prevention; DHHS, Department of Health and Human Services; NIH, National Institutes of Health; OSHA, Occupational Safety and Health Administration; PL, public law; RO, responsible official; SOP, standard operating procedure; SRA, security risk assessment; USDA, US Department of Agriculture.

References

CFR [Code of Federal Regulations]. 1998. Title 29, Part 1910.120. Inspection Procedures for the Hazardous Waste Operations and Emergency Response Standard. Washington DC: Office of the Federal Register. April 24, 1998.

CFR [Code of Federal Regulations]. 2002a. Title 42, Part 73. Possession, Use and Transfer of Select Agents and Toxins. Washington DC: Office of the Federal Register. December 13, 2002.

CFR [Code of Federal Regulations]. 2002b. Title 7, Part 331; and Title 9, Part 121. Agricultural Bioterrorism Protection Act of 2002: Possession, Use, and Transfer of Biological Agents and Toxins. Washington DC: Office of the Federal Register. December 13, 2002.

FR [Federal Register] 59 FR 34496. 1994. Guidelines for Research Involving Recombinant DNA Molecules. Washington DC: Office of the Federal Register. July 5, 1994, and subsequent amendments.

Jaax J. 2005. Administrative issues related to infectious disease research in the age of bioterrorism. ILAR J 46:8-14.

NRC [National Research Council]. 2004. Biotechnology Research in an Age of Terrorism. Washington DC: National Academy Press.

PL [Public Law] 104-132. 1996. Antiterrorism and Effective Death Penalty Act of 1996. Washington DC: GPO. April 24, 1996.

PL [Public Law] 107-56. 2001. The Uniting and Strengthening America by Providing Appropriate Tools Required to Intercept and Obstruct Terrorism (USA PATRIOT) Act of 2001. Washington DC: GPO. October 26, 2001.

PL [Public Law] 107-188. 2002. Public Health Security and Bioterrorism Preparedness and Response Act of 2002. Washington DC: GPO. June 12, 2002.

Richmond JY, McKinney RW, eds. 1999. Biosafety in Microbiological and Biomedical Laboratories. 4th ed. Washington DC: US DHHS.