Daily Rules, Proposed Rules, and Notices of the Federal Government
In a companion document published in this issue of the
The Final Rule timelines are based on the timelines that worked effectively for the Federal Select Agent Program Interim Final Rules that were published in December 2002. If the regulated community has concerns about the established timeline, they can contact Federal Select Agent Program for technical assistance.
The Preamble to this final rule is organized as follows:
We published an Advance Notice of Proposed Rulemaking (ANPRM) (75 FR 42363) on July 21, 2010 and a Notice of Proposed Rulemaking (NPRM) (76 FR 61206) on October 3, 2011. The NPRM solicited comments regarding (1) the appropriateness of the current HHS list of select agents and toxins; (2) whether there are other biological agents or toxins that should be added to the HHS list; (3) whether biological agents or toxins currently on the HHS list should be deleted from the list; (4) whether the HHS select agents and toxins list should be tiered based on the relative bioterrorism risk of each biological agent or toxin; and (5) whether the security requirements for select agents or toxins in the highest tier should be further stratified based on type of use or other factors. In addition, Executive Order 13546 “Optimizing the Security of Biological Select Agents and Toxins in the United States” directed the HHS Secretary to (1) designate a subset of the select agents and toxins list (Tier 1) that presents the greatest risk of deliberate misuse with the most significant potential for mass casualties or devastating effects to the economy, critical infrastructure; or public confidence; (2) explore options for graded protection for these Tier 1 agents and toxins to permit tailored risk management practices based upon relevant contextual factors; and (3) consider reducing the overall number of agents and toxins on the select agents and toxins list.
We provided a 60-day comment period for written comments that ended December 2, 2011. We extended the comment period for an additional 30-day period that ended January 17, 2012.
The changes to the current regulations include:
1. Modification of the select agent and toxin list:
a. The following viruses are added to the HHS select agent list based on scientific data related to their significant public health risk: SARS-CoV, Lujo and Chapare viruses.
b. The following agents would no longer be considered HHS select agents or toxins, or would be excluded from compliance with part 73: Cercopithecine Herpesvirus 1 (Herpes B virus),
c. The following agent would no longer be considered an overlap select agent: Venezuelan Equine Encephalitis Virus (subtypes ID and IE).
2. Tiering of the select agent and toxin list:
a. Tier I agents:
3. Establishing physical security standards for entities possessing Tier I select agents and toxins, including the requirement to conduct pre-access assessments and on-going monitoring of personnel with access to Tier 1 agents and toxins;
4. Miscellaneous revisions to the regulations to clarify regulatory language concerning security, training, biosafety, and incident response.
The final rules will further reduce or minimize the risk of misuse of select agents and toxins that have the potential to pose a severe threat to human, animal or plant health, or to animal or plant products. The USDA/Animal and Plant Health Inspection Service (APHIS) and HHS/CDC recognize that several of the required measures of the regulations may impose certain operational costs upon affected entities, particularly entities that have the newly designated Tier 1 select agents and toxins. In many cases, however, the affected entities already employ some or all of the required measures. Compliance costs actually incurred will therefore vary from one entity to the next.
While information on the specific changes that would need to occur at individual sites and the associated costs was not readily available during proposed rulemaking, some general observations regarding the potential costs were presented. These general cost observations can be found in table 2 in the Regulatory Impact Analysis located at:
The table below describes the changes to the current regulation.
The changes to the list of HHS select agents and toxins are based on comments received in response to the NPRM, recommendations from the Federal Experts Security Advisory Panel (FESAP) and HHS/CDC's Intragovernmental Select Agents and Toxins Technical Advisory Committee (ISATTAC), and our review of current scientific literature.
Executive Order 13546 established the FESAP to advise the HHS Secretary on the designation of Tier 1 agents and toxins, the reduction in the number of agents on the select agent list, the establishment of appropriate practices to ensure reliability of personnel with access to Tier 1 agents, and the establishment of the appropriate practices for physical security and cyber security for facilities that possess Tier 1 agents.
The ISATTAC was established by the CDC Director and is comprised of Federal government employees from the CDC, the National Institutes of Health (NIH), the Food and Drug Administration (FDA), the Biomedical Advanced Research and Development Authority (BARDA) within the HHS Office of the Assistant Secretary for Preparedness and Response (HHS/ASPR), the USDA/APHIS, USDA/Agricultural Research Service (ARS), USDA/CVB (Center for Veterinary Biologics), the Department of Homeland Security (DHS), and the Department of Defense (DOD). The purpose of the ISATTAC is to assist CDC's Division of Select Agents and Toxins in performing its regulatory functions under the select agent regulations, including conducting a review of the select agents and toxins list.
We received 113 comments that addressed the composition of the select agents and toxins list.
As discussed below, the final rule removes or excludes 13 select agents and toxins, added 3 select agents, and designated 11 select agents and toxins as “Tier 1” agents.
On August 19, 2009, we proposed adding the haemorrhagic fever virus Chapare, to the list of select agents (74 FR 41829). Chapare virus is a recently described New World arenavirus that is associated with fatal hemorrhagic fever syndrome and is most closely related to Sabia virus, an HHS select agent (Ref 1).
On October 3, 2011, we proposed adding the haemorrhagic fever virus Lujo to the list of select agents (76 FR 61206). According to available reports, Lujo virus (1) caused a fatal outbreak of hemorrhagic fever, (2) has a case fatality rate of 80 percent, (3) has been phylogenetically identified as an arenavirus, and (4) is related to those members of the Old World arenaviridae family (Junin, Machupo, Sabia, Guanarito, and Lassa) listed as HHS select agents that cause hemorrhagic fever and pose a significant risk to public health and safety (Ref 2).
Some commenters argued that there does not appear to be valid evidence that these viruses could be effectively utilized as terrorism agents. Another commenter recommended that all hemorrhagic arenaviruses be included in the select agent list.
We made no changes to the HHS list of select agents and toxins based on these comments. Although the literature on these newly described viruses is small and recent, both viruses have thus far produced high morbidity and mortality rates. Both Lujo and Chapare virus share other characteristics with regulated hemorrhagic fever viruses (Junin, Machupo, Sabia, Guanarito, and Lassa). As a taxonomic group, the hemorrhagic arenaviruses exhibit distinct differences in morbidity, mortality, transmissibility, and degree of pathogenicity. Therefore our consideration of whether to add a particular arenavirus to the list is made on a taxon-by-taxon basis. As more information becomes known about the public health risks of these two new hemorrhagic fever viruses, their status as select agents can be reassessed.
Individuals and entities that currently possess Chapare or Lujo virus, if they are not already registered entities, will have to either transfer the organism or genomic material to a registered entity, destroy their stocks and report the destruction to HHS/CDC, or if they choose to retain their stocks, register with HHS/CDC and comply with all applicable regulations as provided in this final rule. We also recognize that those entities that choose to become registered will need time to come into full compliance with the requirements of the regulations. This final rule will become effective on December 4, 2012. On and after that date, any individual or entity possessing, using, or transferring any listed select agent or toxin must be in compliance with the provisions of each part. However, to minimize the disruption of critical research or educational projects involving Chapare or Lujo virus that are underway as of the effective date of these regulations, we are providing that any individual or entity possessing Chapare or Lujo virus as of the effective date (current possessors) will be afforded additional time to reach full compliance with the regulations in each part. Accordingly, by December 4, 2012, all entities that possess Chapare and/or Lujo virus must provide notice to HHS/CDC regarding their possession of Chapare and/or Lujo virus, and by April 3, 2013, all previously unregistered entities must meet all of the requirements of this part.
SARS-CoV is associated with one of the most significant pandemics of the 21st century. According to the World Health Organization, the 2002-2003 SARS pandemic involved 29 countries, produced over 8000 cases of disease, and resulted in 774 deaths (Ref 3). Since the end of the pandemic the majority of reported SARS-CoV infections have occurred in laboratorians, or individuals who had close contact with infected laboratorians (Ref 4-6). At least 13 (6 primary cases and 7 contacts)
On July 13, 2009, we proposed the addition of SARS-CoV to the list of select agents and toxins (74 FR 33401). We received ten comments from representatives of universities, public health laboratories, commercial, and government facilities, all arguing that SARS-CoV should not be added to the select agent list. Commenters believed that further deliberation of the biosafety and biosecurity issues involved with this agent should be considered due to the implications for research and public health activities. The commenters further reasoned that adding SARS-CoV as a select agent would decrease public safety and security by preventing expert researchers from pursuing important work due to what they described as the additional costs and onerous burdens inherent with the select agent registration and compliance process.
During the public comment period for this rulemaking we received three comments from representatives from universities and a public health laboratory that recommended the addition of SARS-CoV to the list of select agents and toxins because (1) it exhibited high transmissibility and high lethality; (2) caused epidemics on four continents with significant mortality; (3) had a major economic impact; and (4) had a major psychological impact. Commenters further argued that the virus has demonstrated its ability to cause a contagious disease, has caused several laboratory infections (including one incident that led to cases in non-laboratory contacts) and is a virus which no longer circulates in nature.
We agree with the commenters who supported the addition of SARS-CoV to the list of select agents and toxins because of the significant impact of SARS-CoV on the public health system, the high degree of pathogenicity, and the lack of vaccines or proven therapeutics currently available to prevent or treat SARS-CoV infections. Additionally, we note that the virus no longer appears to be naturally circulating in humans, raising the concern that the general population does not possess a significant level of immunity.
The genome of SARS-CoV will be regulated as an HHS select agent. As a member of the
Based on information received from the HHS/CDC's Etiologic Agent Import Permit Program and the HHS/CDC's Office of Infectious Diseases, there are 119 entities that currently possess SARS-CoV. Of those 119 entities, 77 entities are registered with the Federal Select Agent Program; 42 entities are not registered. Of the 42 non-registered entities, only 38 may possess SARS-CoV or SARS-CoV genomic material (RNA). The 38 non-registered entities that may possess SARS-CoV or SARS-CoV genomic material (RNA) include 10 academic, 22 commercial, 5 State government, and 1 Federal government institutions.
Entities and individuals that currently possess SARS-CoV or SARS-CoV genomic material (RNA) will have to either (1) transfer the organism or genomic material to a registered entity; (2) destroy their stocks and report the destruction to CDC; or (3) register with HHS/CDC or USDA/APHIS to possess SARS-CoV and comply with all applicable regulations as provided in this final rule. We also recognize that those entities that choose to become registered with the Federal Select Agent Program will need time to come into full compliance with the requirements of the regulations. Since this final rule will become effective on December 4, 2012 and any individual or entity possessing, using, or transferring any listed agent or toxin must be in compliance with the provisions of each part on or after that date, we are providing that any individual or entity possessing SARS-CoV as of the effective date (current possessors) will be afforded additional time to reach full compliance with the regulations in each part. Accordingly, by December 4, 2012, all entities that possess SARS-CoV must provide notice to HHS/CDC regarding their possession of SARS-CoV, and by April 3, 2013, all previously unregistered entities must meet all of the requirements of this part. We are extending the effective date for these currently non-registered entities to minimize the disruption of critical research or educational projects involving SARS-CoV that are underway as of the effective date of these regulations.
We are removing Cercopithecine herpesvirus 1 (Herpes B virus) from the HHS list of select agents and toxins. We proposed the removal of Cercopithecine herpesvirus 1 (Herpes B virus) from the HHS list of select agents and toxins because the virus is not easily transmitted to humans, the person-to-person transmission risk is small, the numbers of recorded human infections are low, and multiple licensed antiviral treatments for Herpes B infections are available. The only comments that we received on this proposal were supportive for the removal.
The proposed rule retained
Although many of the concerns raised by the commenters are addressed by the exemption and exclusion provisions in the regulations (42 CFR 73.3 and 73.5), we agree with commenters and have determined that
The term “conotoxin” is used broadly to comprise a very large number of polypeptides isolated from the venom of
• Commenters noted that most components isolated from cone snail venom are harmless to humans; in fact, one of them (MVIIA = Ziconotide = Prialt
• Commenters pointed to the fact that the term “conotoxin” can be applied to several hundred thousand compounds found in
Other comments included the following:
• Conotoxins have never been weaponized.
• Conotoxins must be delivered parenterally.
• Conotoxins are difficult to manufacture.
• Conotoxins are not self‐replicating.
We agree, in part, with the commenters. Based upon available experimental evidence, most known conotoxins (
The short, paralytic alpha conotoxins containing the following amino acid sequence X
We are removing
We are removing Flexal virus from the HHS list of select agents and toxins. We proposed the removal of Flexal virus based on the lack of severity of disease and the lack of significant outbreaks of disease associated with this virus in humans. The only comments that we received on this issue were supportive of the removal of Flexal virus from the HHS list of select agents and toxins.
We are excluding the West African clade of Monkeypox from regulation under this part, while retaining the Congo Basin clade of Monkeypox. We proposed the retention of Monkeypox on the list of select agents and toxins, but invited comments on removing the West African clade of Monkeypox virus from the list. Monkeypox is closely related to smallpox virus and produces a clinical syndrome similar to that seen with smallpox. Mortality rates associated with Monkeypox infections have been reported to be as high as 17 percent (Ref 15-16). Monkeypox can be separated into two genetically distinct variants called the West African and Congo Basin clades. Clinical and laboratory studies indicate that the Congo Basin clade is significantly more pathogenic to humans and animals than the West African clade (Ref 17-18). The 37 confirmed cases of human Monkeypox associated with the 2003 importation of a West African strain from Ghana into the United States were associated with no case-fatalities and no observed chain of human-to-human transmission. Clinically severe human disease associated with West African strains is rare and this virus clade has not been associated with human mortality (Ref 19). Based on this information, we are excluding the West African clade from regulation under this part, while retaining the Congo Basin clade.
One commenter disagreed with the proposed retention of Monkeypox virus, regardless of clade, as a select agent. We agreed in part with the commenter. As indicated above, we recognize that significant differences in pathogenicity exist between the West African and Congo Basin clades and have determined that viruses of only the Congo Basin clade merit regulation as HHS select agents. We also note that there are published diagnostic tests that differentiate Congo Basin from West African clades (Ref 19).
While the listing found in section 3 (HHS select agents and toxins) will continue to read “Monkeypox”, a new subparagraph (d)(5) in that same section, excludes from regulation any West African clade of the Monkeypox virus provided that an individual or entity can verify that the Monkeypox virus is the West African clade.
We proposed the removal of South America EEEV genotypes from the list of HHS select agents and toxins and the final rule is consistent with the proposed rule.
One commenter believed that all strains of EEEV should be removed from
• The commenter noted that EEEV is endemic in Florida, but does not cause human epidemics even with high prevalence in the ecosystem and evidence of natural transmission activity to sentinels.
• The commenter noted that person-to-person transmission does not occur; transmission is only through mosquito bite. An average of only 5 human cases are identified annually in the United States.
• The commenter noted that there is a vaccine available for horses that can prevent disease even if there is ongoing natural virus transmission.
• The commenter noted that states with high endemicity of EEEV often have a state public health laboratory proactive comprehensive arbovirus surveillance program to define risk of human infection. Serum-neutralization assays are an essential part of such a program and require live virus which is needed for test performance. This work is performed at BSL3 level and additional federal regulatory requirements do not add to the safety of handling or storing the virus.
• The commenter noted that genotype analysis to determine if an EEEV strain is a North American or South American genotype is not practical in a state public health laboratory, where the goal is surveillance, not research.
• The commenter noted that this agent is not stable in the environment outside of its natural host (mosquitoes, birds).
We made no changes to the list of HHS select agents and toxins based on this comment. North American EEEV (NA EEEV), genotype strains, which are the strains responsible for human and equine disease, are all genetically very similar to each other (less than 3 percent divergence at the nucleotide level) and can be easily distinguished from South American EEEV (SA EEEV) genotype strains by sequencing. NA EEEV genotype strains differ from SA EEEV by greater than 20 percent at the nucleotide level and approximately 10 percent at the amino acid level. We are aware that EEEV is endemic in Florida, that person-to-person transmission does not occur, that an equine vaccine is available, and that EEEV isn't stable outside of its natural host. Among the factors that we considered in retaining the NA EEEV genotype were that this genotype exhibits high morbidity, high mortality, and has the potential to be weaponized. We also appreciate that public health laboratories focus on surveillance and utilize assays that do not specifically determine which subtype of EEEV is present. However, we believe that the risks posed by the NA EEEV outweigh the practical issues associated with subtype determination. Because the NA EEEV genotype strains are distinctly different from SA EEEV in their genetics, epidemiology, and pathogenicity, we believe that the two genotypes can be distinguished from each other in the laboratory.
While the listing found in section 3 (HHS select agents and toxins) will continue to read “Eastern Equine Encephalitis virus,” a new subparagraph (d) (5) in that same section excludes from regulation, any South American genotypes of Eastern Equine Encephalitis virus provided that an individual or entity can verify that the Eastern Equine Encephalitis virus is one of the South American genotypes.
The proposed rule retained
Commenters argued that
• The same rationale used by HHS/CDC to propose removal of Herpes B virus from the HHS select agent list;
• Human infections due to these agents are capable of being treated with doxycycline, other tetracyclines, and chloramphenicol;
• The bacteria are fastidious obligate intracellular pathogens, thus propagation requires growth in cultured host cells; and
• The inclusion of these rickettsiae on the HHS select agent list will produce no significant improvements in safety for the American public.
After careful consideration of these comments, we agree with the commenters that
We proposed the retention of Shigatoxins and Shiga-like ribosome inactivating proteins on the HHS list of select agents and toxins. One commenter asked us to reconsider the retention of Shigatoxins and Shiga-like ribosome inactivating proteins as a select toxin based on the following criteria:
• Introduction of Shigatoxins by the aerosol route has not been reported;
• Shigatoxins are extremely difficult to synthesize in quantities that are toxic to humans;
• Expression of toxin in bacteria is self-limiting due to inhibitory effects on bacterial cells of over-expressed toxin; and
• There are limitations to purification and concentration of Shigatoxins that make them impractical and ill-suited to methods of dispersal that would require large quantities of toxin for delivery by food, water, or air.
We have considered all of the points raised by the commenter and, after additional consultations with subject matter experts, agree that compelling data exist to support the removal of Shigatoxin and Shiga-like ribosome inactivating proteins from the HHS list of select agents and toxins. Therefore, we have decided to remove Shigatoxin and Shiga-like ribosome inactivating proteins from the HHS list of select agents and toxins. Additional significant factors considered in our determination include the difficulty in producing or administering large quantities of toxin via the aerosol route, their poor environmental stability, the lack of significant toxicity seen with oral exposure (which is the route by which an individual becomes intoxicated by Shigatoxin), and the observation that the worst effects seen with intoxication are associated with other pathogenic factors from the Shigatoxin-producing strains of
We proposed the reduction of
We made no changes to the HHS list of select agents and toxins based on this comment. Current data based on emesis in non-human primates demonstrates that
We proposed the removal of TBEV Central European subtype from the HHS list of select agents and toxins because the TBEV Central European Tick-borne subtype has been shown to be less virulent in humans than the Far Eastern subtype (Ref 21). We also proposed to reorganize the listing of the TBEV to reflect the current nomenclature given by the International Committee on Taxonomy of Viruses. For TBEV proper, there are now just three recognized subtypes: Central European, Far Eastern, and Siberian. The Russian Spring and Summer Encephalitis designation is no longer recognized (Ref 22). Two other viruses on the HHS list of select agents and toxins, Kyasanur Forest Disease virus and Omsk Hemorrhagic Fever virus, are no longer classified as TBEV. In recognition of these taxonomic changes, we proposed to include these viruses on the HHS list of select agents and toxins as follows:
We proposed the retention of
• This organism is ubiquitous in the United States, and can be detected in greater than 90 percent of bulk milk tank samples. Despite this, significant human consequences to infection with this agent are rare.
• The organism is readily susceptible to available antibiotics.
While perhaps easily transmitted to humans, the disease caused by this organism is generally mild and self-limiting in humans and does not have a huge economic impact in animals. It therefore does not have the potential to be an effective terrorist weapon. We made no changes to the HHS list of select agents and toxins based on these comments. We recognize that there is a low level of mortality associated with this agent; that it is present in some bulk unpasteurized milk supplies; and that antibiotics are available to treat this disease. However, treatment of chronic Q fever caused by
We proposed the retention of Diacetoxyscirpenol, Saxitoxin, T-2 toxin, and Tetrodotoxin on the HHS list of select agents and toxins. One commenter recommended the removal of these toxins along with Shiga-like ribosome inactivating proteins, Shigatoxin, Conotoxins, and
Although Shigatoxin producing strains of
With respect to the comment expressing concerns about the regulation of
We proposed to retain
We proposed the removal of VEE subtypes ID and IE from the list of overlap select agents and toxins, with subtypes IAB and IC being retained on the list. Commenters recommended
We made no changes to the overlap list of select agents and toxins based on these comments. Straightforward diagnostic molecular techniques, such as sequencing with subtype/variety specific polymerase chain reaction (PCR) primer sets or serological testing with specific monoclonal antibodies, can distinguish between enzootic and epizootic VEE. We also note that based on available data, the emergence of epidemic subtype 1C from subtype 1D is a rare event. In addition, while an equine vaccine is available for VEE, human vaccines are limited in supply and availability.
While the listing found in section 4 (Overlap select agents and toxins) will read “Venezuelan equine encephalitis virus,” a new subparagraph (d)(3) in that same section excludes from regulation, any ID and IE serotypes of Venezuelan equine encephalitis virus provided that an individual or entity can verify that the Venezuelan equine encephalitis virus is either the ID or IE serotype.
We proposed to designate
Commenters argued that because Laboratory Response Network (LRN) laboratories maintain live cultures of non-pathogenic
Commenters stated that the
Another commenter claimed that the designation of
We only agree in part with the commenters that it does not meet the Tier 1 designation, but do not agree to removing it from the select agent list altogether.
While we agree that the Pasteur strain does not meet the criteria for inclusion as a Tier 1 select agent, we believe that retaining the Pasteur strain as a select agent will allow for continued oversight of laboratories in which the accidental (or intentional) combination of this strain with the Sterne strain could occur to produce the wild type phenotype
We proposed to retain
We proposed to retain
We proposed the designation of
• The criteria by which
• The outcome of 99.9 percent of infections with
We disagree with the commenters that
On July 2, 2010, President Obama signed Executive Order 13546 “Optimizing the Security of Biological Select Agents and Toxins in the United States” that directed the HHS Secretary to designate a subset of the select agents and toxins list (Tier 1) that presents the greatest risk of deliberate misuse with the most significant potential for mass casualties or devastating effects to the economy, critical infrastructure, or public confidence. In the development of the Tier 1 subset, care was used to balance risks identified in Executive Order 13546 with the Congressional mandate found in the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (42 U.S.C. 262a) to ensure the availability of select agents and toxins for research, education, and other legitimate purposes. Executive Order 13546 also established the FESAP to advise the HHS Secretary on the designation of Tier 1 agents and toxins, reduction in the number of agents on the select agent list, establishment of suitability standards for those having access to Tier 1 select agents and toxins, and the establishment of physical security and information security standards for Tier 1 select agents and toxins. Tiering of the select agents and toxins list will allow for the application of optimized security measures for those select agents or toxins which pose a higher risk to public health and safety. A two-part risk analysis was conducted by the FESAP on each select agent and toxin on the list. First, experts in the biology of these agents and toxins evaluated their “potential for mass casualt