Federal Register / Vol. 74, No. 182 / Tuesday, September 22, 2009 / Notices 48275 

WRRHC is a successful community 

health center that provides services to 

10 counties within Arkansas and has 

over 22 years of experience in managing 

State and federally funded programs, 

including three previous Rural Health 

Services Outreach grants. The 

comprehensive services that WRRHC 

provides and their ability to expand 

their service area will enable WRRHC to 

maintain the current scope of service 

and activities as originally awarded 

under the grant to Siloam Springs 

Memorial Hospital. This replacement 

award will help ensure the continued 

improvement of health care systems in 

the targeted service area. WRRHC has a 

demonstrated record of sound 

stewardship of Federal funds and can 

effectively serve as the network lead for 

the remainder period of support in a 

manner which minimizes any 

disruption of services provided by the 

network. Consequently, White River 

Rural Health Center has been designated 

the replacement award recipient. 

HRSA is unaware of any other entity 

that both meets the statutory eligibility 

requirements and has the ability to carry 

out these activities. 

FOR FURTHER INFORMATION CONTACT: Tom 

Morris, Associate Administrator, Office 

of Rural Health Policy, Health Resources 

and Services Administration, 5600 

Fishers Lane, Rockville, MD 20857; 

phone 301–443–0835; 

tmorris@hrsa.hhs.gov. 

Dated: September 16, 2009. 

Mary K. Wakefield, 

Administrator. 

[FR Doc. E9–22815 Filed 9–21–09; 8:45 am] 

BILLING CODE 4165–15–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

Office of Biotechnology Activities; 

Recombinant DNA Research: Actions 

Under the NIH Guidelines for Research 

Involving Recombinant DNA Molecules 

(NIH Guidelines) 

AGENCY: National Institutes of Health 

(NIH), Department of Health and Human 

Services (HHS). 

ACTION: Notice of changes to the NIH 

Guidelines. 

SUMMARY: Concerns about the 

emergence of a pandemic influenza 

virus have spurred research on 

influenza viruses that have either 

caused pandemics or are believed to 

have the potential to cause a pandemic. 

These viruses include human H2N2 

virus, which circulated from 1957–1968, 

the 1918–1919 H1N1, which caused the 

deadliest pandemic in the past century, 

and the Highly Pathogenic Avian 

Influenza (HPAI) H5N1 virus that is 

thought to have pandemic potential. 

The public health benefits of this 

research include developing a better 

understanding of the pathogenicity of 

pandemic influenza viruses, their 

virulence mechanisms, mechanisms of 

host adaptation, and ultimately the 

development of vaccines and antiviral 

drugs. These benefits are balanced 

against the potential risks that might 

include the inadvertent release of a 

highly transmissible and potentially 

virulent influenza virus. Consequently, 

explicit and uniform biosafety 

containment practices are critical to the 

safe conduct of research with these 

agents. The NIH Guidelines provide a 

framework for assessing the risks of 

such research. However, after extensive 

consultation with the NIH Recombinant 

DNA Advisory Committee (RAC), 

experts in biosafety and influenza, the 

Centers for Disease Control and 

Prevention (CDC), and the U.S. 

Department of Agriculture (USDA), the 

NIH Office of Biotechnology Activities 

(OBA) concluded that more specific 

guidance in the NIH Guidelines is 

warranted to promote uniform biosafety 

practices for recombinant research with 

these viruses. 

The resulting amendments are ‘‘Minor 

Actions’’ under Section IV–C–1–(b)–2 of 

the NIH Guidelines and, therefore, will 

be implemented immediately upon 

publication in the Federal Register. 

While a Minor Action only requires 

consultation with the RAC chair and 

one or more RAC members, as 

necessary, as noted above, these changes 

were developed after extensive 

consultation with the full RAC and 

other experts and were discussed at 

three public RAC meetings. The RAC 

voted on March 4, 2009 to recommend 

these changes. They are being published 

to inform the scientific and biosafety 

communities, as well as to solicit 

continued scientific input should 

further revisions be needed. 

The NIH Guidelines are being 

changed to provide the following 

biosafety guidance for research with 

potentially pandemic influenza viruses: 

• Designation of human H2N2 viruses 

that circulated from 1957–1968 (human 

H2N2 (1957–1968)), the fully 

reconstructed 1918–1919 H1N1 

influenza virus (1918 H1N1), and 

Highly Pathogenic Avian Influenza 

(HPAI) H5N1 within the Goose/ 

Guangdong/96-like H5 lineage (HPAI 

H5N1) as Risk Group 3 agents. Risk 

Group 3 agents have the potential to 

cause serious or lethal disease in 

humans for which preventative and 

therapeutic measures may be available. 

Up until this revision, all influenza 

viruses (Orthomyxoviruses) were Risk 

Group 2 agents, which are agents that 

are associated with human disease that 

is rarely serious and for which 

preventative and therapeutic agents are 

often available. 

• Requirement for enhanced biosafety 

practices, including the use of powered 

air purifying respirators (PAPRs) and 

other personal protective equipment to 

prevent laboratory worker exposure and 

minimize the risk of spread outside of 

the laboratory. 

• Guidance on the containment for 

research with influenza viruses 

generated by recombinant methods (e.g., 

generation by reverse genetics of 

chimeric viruses with reassorted 

segments, introduction of specific 

mutations) containing one or more 

genes and/or segments from human 

H2N2 (1957–1968), 1918 H1N1 or HPAI 

H5N1. For 1918 H1N1, the NIH 

Guidelines will require Biosafety Level 

3 enhanced containment for all 

influenza viruses that contain one of 

more genes and/or segments from 1918 

H1N1 because of the uncertainty about 

the virulence factors for this agent. 

• Guidance on occupational health 

practices, including policies regarding 

the use of prophylactic antiviral agents 

and isolation of laboratory workers who 

are exposed to one of these viruses. 

DATES: The public is encouraged to 

submit written comments on this action. 

Comments may be submitted to OBA in 

paper or electronic form at the OBA 

mailing, fax, and e-mail addresses 

shown below under the heading FOR

FURTHER INFORMATION CONTACT. All 

comments should be submitted by 

September 22, 2010. All written 

comments received in response to this 

notice will be available for public 

inspection in the NIH OBA office, 6705 

Rockledge Drive, Suite 750, MSC 7985, 

Bethesda, MD 20892–7985, weekdays 

between the hours of 8:30 a.m. and 5 

p.m. and may be posted to OBA’s Web 

site. 

FOR FURTHER INFORMATION: If you have 

questions, or require additional 

information about these changes, please 

contact OBA by e-mail at 

oba@od.nih.gov, or telephone at 301– 

496–9838. Comments may be submitted 

to the same e-mail address or by fax at 

301–496–9839 or by mail to the Office 

of Biotechnology Activities, National 

Institutes of Health, 6705 Rockledge 

Drive, Suite 750, MSC 7985, Bethesda, 

Maryland 20892–7985. Background 

information may be obtained by 


sroberts on DSKD5P82C1PROD with NOTICES
48276 Federal Register / Vol. 74, No. 182 / Tuesday, September 22, 2009 / Notices 

contacting NIH OBA by e-mail at 

oba@od.nih.gov. 

SUPPLEMENTARY INFORMATION: 

Background 

Recently, NIH support for research 

with influenza viruses involving 

recombinant DNA technology has 

significantly increased. The 

development of new laboratory 

methods, such as reverse genetics, has 

allowed for easier and more rapid 

generation of infectious influenza 

viruses from DNA plasmids, e.g. 

reassortant viruses. An increasing 

proportion of such research has focused 

on pandemic or potentially pandemic 

viruses. These include previously 

pandemic viruses that are not currently 

circulating in the human population, 

such as the human H2N2 virus that 

caused a pandemic resulting in 

approximately 66,000 excess deaths in 

the U.S. in 1957 and the 1918 H1N1 

virus, which caused 20–40 million 

excess deaths worldwide. Another focus 

of research is currently circulating 

highly pathogenic avian influenza 

viruses (HPAI) that may have potential 

to cause a human pandemic if efficient 

human-to-human transmission were to 

develop. Over 400 cases worldwide of 

human infection with the HPAI H5N1 

virus have been reported to date with 

approximately 60% mortality rate; 

however, evidence of human-to-human 

transmission has been limited to small, 

familial clusters. 

The public health benefits of research 

on potentially pandemic influenza 

viruses include identification of viral 

proteins that contribute to host 

adaptation and virulence to increase 

understanding of the pathogenicity of 

influenza viruses during pandemics, 

development of vaccine candidates, and 

identification of targets for antiviral 

drugs. While research into influenza 

viral virulence mechanisms and the 

development of vaccines and antiviral 

drugs are public health priorities, it is 

equally important that the research be 

performed under appropriate 

biocontainment to protect the health of 

laboratory researchers and the public. 

There are currently other biosafety 

requirements for certain types of 

research with these viruses. The CDC/ 

NIH Biosafety in Microbiological and 

Biomedical Laboratories (5th edition) 

(BMBL) recommends Biosafety Level 3 

with additional personal protection 

equipment designed to minimize the 

risk of laboratory acquired infection for 

research with the reconstructed 

replication competent forms of 1918 

H1N1 (i.e. Biosafety Level 3 enhanced). 

Reconstructed replication competent 

forms of 1918 pandemic influenza virus 

H1N1 were designated HHS/CDC Select 

Agents in 2005 (70 FR 61047). The 

BMBL also recommends Biosafety Level 

3 containment level for research with 

the full human H2N2 virus (1957–1968) 

with enhancements designed to prevent 

laboratory acquired respiratory 

infection. 

HPAI H5N1 influenza viruses are 

USDA Select Agents (9 CFR 121.3(b)). 

The USDA’s Animal and Plant Health 

Inspection Service (APHIS) regulates as 

a Select Agent avian influenza viruses 

(and constructs thereof pursuant to 9 

CFR 121.3(c)(3)) that demonstrate a high 

pathogenicity index in chickens, 

contain a specific poly-basic amino acid 

motif at the hemagglutinin (HA) gene 

cleavage site (or have an amino acid 

sequence at the cleavage site of the HA 

gene that is compatible with other 

highly pathogenic avian influenza 

viruses) and show growth 

characteristics of influenza virus in the 

presence and absence of trypsin. Avian 

influenza viruses that demonstrate 

evidence of attenuation in poultry can 

be excluded pursuant to 9 CFR 121.3(e). 

The biosafety containment level 

recommended for most Select Agent 

research with these viruses is a 

minimum of Biosafety Level 3 enhanced 

or Animal Biosafety Level 3 (ABSL3) 

enhanced. Influenza viruses containing 

genes from highly pathogenic avian 

influenza virus that are not classified as 

Select Agents by USDA are still 

regulated by that agency through 

‘‘permitting’’ regulations (9 CFR 122), 

which govern imports and interstate 

movements of the viruses. 

The current (April 2002) NIH 

Guidelines classify influenza viruses A, 

B, and C as Risk Group 2 agents in 

Appendix B. No distinction is made 

between potentially pandemic strains of 

influenza and other lower risk influenza 

viruses. According to the NIH 

Guidelines, an initial risk assessment is 

based on the Risk Group (RG) of the 

parent agent; however, appropriate 

containment is set following 

consideration of the specific agent and 

how it is to be manipulated. The NIH 

Guidelines emphasize that containment 

levels for recombinant research may be 

raised or lowered relative to the RG 

classification of the parent agent after a 

comprehensive risk assessment. 

Up until today, the NIH Guidelines 

had not been amended to address 

specifically recombinant influenza 

viruses that contain genes and/or 

segments from human H2N2 (1957– 

1968), 1918 H1N1 and HPAI H5N1 

viruses. Therefore, to clarify and 

augment the current biosafety guidance 

in the NIH Guidelines for research with 

potentially pandemic influenza viruses, 

and to harmonize with the BMBL and 

other regulatory policies, NIH/OBA in 

consultation with the RAC and outside 

experts, including the CDC and USDA, 

reviewed and revised the Risk Group 

designations for potentially pandemic 

influenza viruses human H2N2 (1957– 

1968), 1918 H1N1, and HPAI H5N1 and 

developed additional containment and 

occupational health guidance for 

research involving recombinant 

influenza viruses containing genes from 

these influenza viruses. 

In determining the Risk Group (RG) 

classification for human H2N2 (1957– 

1968), 1918 H1N1 and HPAI H5N1, the 

RAC considered the definition of risk 

groups in Appendix B. Risk Group 3 

agents are those ‘‘that are associated 

with serious or lethal disease for which 

preventative or therapeutic 

interventions may be available (high 

individual risk but low community 

risk).’’ Each strain was considered to be 

a risk for serious or lethal disease, 

although it was recognized that the case 

fatality rate for HPAI H5N1 is very high, 

over 50 percent, whereas the case 

fatality rate for 1918 H1N1 is 

considerably lower in the range of 1–2 

percent. Human H2N2 caused a much 

milder pandemic compared to 1918 

H1N1, but because it has not circulated 

for over forty years, a large population 

will likely not have immunity to the 

virus and therefore is at risk of serious 

disease. ‘‘Preventative or therapeutic 

interventions may be available’’ for 

infection with each of these viruses as 

there is evidence that the antiviral 

agents used against seasonal influenza 

are effective for prophylactic and 

therapeutic use for each virus and 

antibiotics are available for secondary 

bacterial pneumonias should they 

develop. Virus specific vaccines are not 

currently available to prevent infection. 

However, they are being developed and 

stockpiled for HPAI H5N1, and sources 

exist for the possible development of 

1918 H1N1 or human H2N2 (1957– 

1968) vaccines for laboratory workers 

who might be exposed or in the unlikely 

event of a release of the virus into the 

general population. In the case of 

human H2N2 (1957–1968), some preexisting immunity is likely in the 

population that was exposed to human 

H2N2 while these viruses circulated 

from 1957–1968 or from cross-reactivity 

with N2 in the currently circulating 

H3N2 strain. For 1918 H1N1, partial 

immunoprotection may exist from 

previous exposure or vaccination with 

recently circulating H1N1 strains, but 

definitive data are lacking. An 

important additional consideration for 


sroberts on DSKD5P82C1PROD with NOTICES
Federal Register / Vol. 74, No. 182 / Tuesday, September 22, 2009 / Notices 48277 

HPAI H5N1 RG classification was that, 

while the individual risk of serious or 

lethal disease is quite high, the 

community risk is currently considered 

low, as there is only limited evidence 

for human-to-human transmission. 

Based on these considerations, 

influenza viruses 1918 H1N1, human 

H2N2 (1957–1968), and highly 

pathogenic avian influenza H5N1 

viruses within the Goose/Guangdong/ 

96-like H5 lineage will be classified as 

Risk Group 3 agents in Appendix B–III– 

D. All viruses within HPAI H5N1 

lineages that have been associated with 

human disease, whether it is mild or 

severe and fatal, will be classified as 

RG3 agents. Thus BL3 enhanced 

containment will apply to a virus 

evolving from the current lineages that 

causes milder disease in humans, which 

could indicate adaptation to the human 

host. 

Because the generation of influenza 

viruses by reassorting RNA segments by 

recombinant techniques (i.e., reverse 

genetics) does not take place in a single 

host-vector system, OBA has received 

questions about which sections of the 

NIH Guidelines apply to such research 

with influenza viruses. Sections III–D– 

1 or III–D–2 (research that falls under 

Section III–D requires Institutional 

Biosafety Committee approval before 

initiation) refer to specific host-vector 

systems and, therefore, do not 

specifically address this research. To 

clarify this, an additional section has 

been added: Section III–D–7– 

Experiments Involving Influenza 

Viruses. This section will apply to 

recombinant research with influenza 

viruses (e.g., chimeric viruses with 

reassorted segments generated by 

reverse genetics, viruses in which 

specific mutations are introduced). 

Additional biosafety guidance for 

research with 1918 H1N1, HPAI H5N1 

within the Goose/Guangdong/96-like H5 

lineage and human H2N2 (1957–1968) 

has been included in Appendix G–II–C– 

5. Biosafety Level 3 Enhanced for 

Research Involving Risk Group 3 

Influenza Viruses. In addition to the 

standard BL3 containment and 

practices, the RAC recommended 

specific enhancements for research with 

these viruses including personal 

protective equipment (e.g., powered airpurifying respirators, protective suits), 

practices and procedures (e.g., clothing 

changes, showers when appropriate). In 

addition, the RAC made specific 

recommendations on training for these 

enhanced practices. Guidance is also 

provided for avoidance of inadvertent 

cross-contamination during research. To 

address the potential public health risks 

of a laboratory exposure, this section 

also includes recommendations for 

development of a detailed occupational 

health plan for research with each virus, 

including how to respond to known 

laboratory exposures or development of 

an influenza-like illness in laboratory 

workers. The community risk from an 

inadvertent laboratory release of a virus 

with human H2N2 (1957–1968) or 1918 

H1N1 is expected to be higher than for 

HPAI H5N1. Consequently, the 

occupational health recommendations 

for the response to a known laboratory 

exposure differ depending on whether 

the exposure was to HPAI H5N1, a virus 

that currently does not efficiently 

transmit human-to-human, or to either 

human H2N2 (1957–1968) or 1918 

H1N1, both of which have previously 

caused pandemics, therefore 

demonstrating efficient human-tohuman transmission. These 

recommendations regarding 

occupational health are also included in 

Appendix G–II–C–5. 

During development of the 

occupational health recommendations, 

the RAC discussed the use of preexposure prophylaxis with antiviral 

agents (e.g., oseltamivir) for research 

with 1918 H1N1. Initially, the RAC had 

proposed recommending a practice that 

is in place at the CDC (the first lab to 

work with 1918 H1N1), namely that 

researchers working with 1918 H1N1 

take pre-exposure prophylaxis with the 

antiviral oseltamivir for their protection, 

and to further limit the risk to the 

public. In addition, the 

Intragovernmental Select Agents and 

Toxins Technical Advisory Committee 

(ISATTAC), an advisory body to the 

USDA and CDC Select Agent Programs, 

recommended that the CDC Select 

Agent Program require pre-exposure 

prophylaxis for research with 1918 

H1N1 at BL3 enhanced but not at BL4 

containment. This recommendation was 

adopted by the CDC Select Agent 

Program. However, as research on 1918 

H1N1 progressed and more was learned 

about the virus, other influenza 

researchers expressed concerns that the 

risks of long-term use of antiviral drugs 

would not be balanced by potential 

benefit to the investigator or the public. 

To address this issue, the RAC and 

ISATTAC convened a Safety 

Symposium on Public Health and 

Biosafety Practices for Research with 

1918 H1N1 Influenza Virus on 

December 2, 2008 (a Webcast of the 

meeting is available at http:// 

oba.od.nih.gov/rdna_rac/ 

rac_past_meetings_2000.html). The 

discussion at the safety symposium 

focused on the scientific data regarding 

the efficacy of prophylactic 

administration and use of oseltamivir 

for extended periods of time, as well as 

public health and ethical issues. The 

RAC concluded that while prophylaxis 

can reduce the likelihood of an 

individual laboratory worker developing 

symptoms or complications should they 

become infected, it will not eliminate 

the risk of transmission to the 

community. Further, although the 

medications are generally safe, there are 

risks, and data on long-term use (beyond 

6 weeks) are limited. Therefore, the RAC 

concluded that the data do not support 

mandating pre-exposure prophylaxis. 

Instead, the RAC recommended that the 

use of antiviral agents as pre-exposure 

prophylaxis be discussed with 

laboratory workers and used on a caseby-case basis, after a risk assessment 

and appropriate counseling of the 

laboratory worker about the risks and 

potential benefits. Antiviral agents are 

recommended for post-exposure 

prophylaxis after medical evaluation. 

While most research with these 

viruses will be conducted at BL3 with 

specific enhanced practices, the RAC 

also considered whether certain 

research could be safely conducted at 

lower containment. After consulting 

with experts in influenza virology, the 

RAC concluded that due to the 

multigenic determinants of virulence 

observed in influenza viruses, it is 

difficult to predict the phenotype of 

recombinant influenza viruses created 

by reassorting segments from multiple 

strains of influenza viruses. As the 

current data are insufficient to generate 

a predictive framework upon which to 

base the risk assessment, a case-by-case 

evaluation is more appropriate. 

Section III–D–7 will specify when an 

IBC may determine containment for 

certain research (e.g., research with H2 

HA in cold-adapted, live attenuated 

vaccine strains, or research with 

chimeric influenza viruses containing a 

minority of genes and/or segments from 

HPAI H5N1) and when requests to 

lower containment must be considered 

by the NIH (e.g., research with 

recombinant viruses containing any 

gene and/or segment from 1918 H1N1). 

Because the revisions outlined herein 

are considered Minor Actions as defined 

in Section IV–C–1–b–(2) of the NIH 

Guidelines, public and Federal Agency 

comment is not required and the 

changes are to be implemented 

immediately. However, in order to 

promote transparency and to gather 

ongoing input from scientific 

community, OBA is publishing these 

changes in the Federal Register with 

opportunity for public comment. The 

NIH Guidelines are intended to be an 

evolving document that may be 

modified to address new developments 


sroberts on DSKD5P82C1PROD with NOTICES
48278 Federal Register / Vol. 74, No. 182 / Tuesday, September 22, 2009 / Notices 

in research. As the influenza virology 

field advances, new data will emerge to 

inform risk assessments for research 

with these viruses. The public is 

encouraged to submit written 

comments, in particular on the 

following question regarding 

containment for 1918 H1N1: 

• What data can be used to 

confidently predict an influenza virus 

containing one or more genes from the 

1918 H1N1 virus can be worked with 

safely at biosafety containment level 

lower than Biosafety level 3 enhanced? 

Are there animal models of infection 

that are consistent and predictive of 

attenuation or loss of virulence in 

humans? What data should be used to 

assess attenuation in animal model(s)? 

What criteria should be used to evaluate 

a request for reduction of containment? 

When data are available to answer 

these questions, or new data emerges 

regarding other aspects of these changes, 

the framework will be reevaluated. 

Amendments to the NIH Guidelines 

In order to ensure that biosafety 

considerations for research with human 

H2N2 (1957–1968), 1918 H1N1 and 

HPAI H5N1 are addressed 

appropriately, the NIH/OBA has made 

the following changes to the NIH 

Guidelines: 

Section III–D–7. Experiments Involving 

Influenza Viruses 

This section will apply to 

recombinant experiments with 

influenza viruses that contain genes 

and/or segments from human H2N2 

(1957–1968), HPAI H5N1, and 1918 

H1N1 (e.g., chimeric viruses with 

reassorted segments generated by 

reverse genetics, viruses in which 

specific mutations are introduced). 

Because the generation of viruses by 

reassortment of RNA segments does not 

involve a single host-vector system, 

such experiments do not fit neatly into 

Sections III–D–1 or III–D–2. The new 

Section III–D–7 states: ‘‘Experiments 

with influenza viruses generated by 

recombinant methods (e.g., generation 

by reverse genetics of chimeric viruses 

with reassorted segments, introduction 

of specific mutations) shall be 

conducted at the biosafety level 

containment corresponding to the risk 

group of the virus that was the source 

of the majority of segments in the 

recombinant virus (e.g., experiments 

with viruses containing a majority of 

segments from a RG3 virus shall be 

conducted at BL3). Experiments with 

influenza viruses containing genes or 

segments from 1918–1919 H1N1 (1918 

H1N1), human H2N2 (1957–1968) and 

highly pathogenic avian influenza H5N1 

strains within the Goose/Guangdong/96- 

like H5 lineage (HPAI H5N1) shall be 

conducted at BL3 enhanced 

containment (see Appendix G–II–C–5, 

Biosafety Level 3 Enhanced for Research 

Involving Risk Group 3 Influenza 

Viruses) unless indicated below.’’ 

Section III–D–7–a. Human H2N2 

(1957–1968). Experiments with 

influenza viruses containing the H2 

hemagglutinin (HA) segment shall be 

conducted at BL3 enhanced (see 

Appendix G–II–C–5, Biosafety Level 3 

Enhanced for Research Involving Risk 

Group 3 Influenza Viruses). 

Experiments with the H2 HA gene in 

cold-adapted, live attenuated vaccine 

strains (e.g., A/Ann Arbor/6/60 H2N2) 

may be conducted at BL2 containment 

provided segments with mutations 

conferring temperature sensitivity and 

attenuation are not altered in the 

recombinant virus. Experiments with 

Risk Group 2 influenza viruses 

containing genes from human H2N2 

(1957–1968) other than the HA gene can 

be worked on at BL2. 

Section III–D–7–b. Highly Pathogenic 

Avian Influenza H5N1 strains within the 

Goose/Guangdong/96-like H5 lineage 

(HPAI H5N1). Experiments involving 

influenza viruses containing a majority 

of genes and/or segments from a HPAI 

H5N1 influenza virus shall be 

conducted at BL3 enhanced 

containment, (see Appendix G–II–C–5, 

Biosafety Level 3 Enhanced for Research 

Involving Risk Group 3 Influenza 

Viruses). Experiments involving 

influenza viruses containing a minority 

of genes and/or segments from a HPAI 

H5N1 influenza virus shall be 

conducted at BL3 enhanced unless a 

risk assessment performed by the IBC 

determines that they can be conducted 

safely at biosafety level 2 and after they 

have been excluded pursuant to 9 CFR 

121.3(e). OBA is available to IBCs to 

provide consultation with the RAC and 

influenza virus experts when risk 

assessments are being made to 

determine the appropriate 

biocontainment for experiments with 

influenza viruses containing a minority 

of gene/segments from HPAI H5N1. 

Such experiments may be performed at 

BL3 enhanced containment or 

containment may be lowered to 

biosafety level 2, the level of 

containment for most research with 

other influenza viruses. (USDA/APHIS 

regulations and decisions on lowering 

containment also apply.) In deciding to 

lower containment, the IBC should 

consider whether, in at least two animal 

models (e.g., ferret, mouse, Syrian 

golden hamster, cotton rat, non-human 

primates), there is evidence that the 

resulting influenza virus shows reduced 

replication and virulence compared to 

the parental RG3 virus at relevant doses. 

This should be determined by 

measuring biological indices 

appropriate for the specific animal 

model (e.g., severe weight loss, elevated 

temperature, mortality or neurological 

symptoms). 

Section III–D–7–c. 1918 H1N1. 

Experiments involving influenza viruses 

containing any gene or segment from 

1918 H1N1 shall be conducted at BL3 

enhanced containment (see Appendix 

G–II–C–5, Biosafety Level 3 Enhanced 

for Research Involving Risk Group 3 

Influenza Viruses). 

Section III–D–7-d. Antiviral 

Susceptibility and Containment. The 

availability of antiviral drugs as 

preventive and therapeutic measures is 

an important safeguard for experiments 

with 1918 H1N1, HPAI H5N1, and 

human H2N2 (1957–1968). If an 

influenza virus containing genes from 

one of these viruses is resistant to both 

classes of current antiviral agents, 

adamantanes and neuraminidase 

inhibitors, higher containment may be 

required based on the risk assessment 

considering transmissibility to humans, 

virulence, pandemic potential, 

alternative antiviral agents if available, 

etc. Experiments with 1918 H1N1, 

human H2N2 (1957–1968) or HPAI 

H5N1 that are designed to create 

resistance to neuraminidase inhibitors 

or other effective antiviral agents 

(including investigational antiviral 

agents being developed for influenza) 

would be subject to Section III–A–1 

(Major Actions) and require RAC review 

and NIH Director approval. As per 

Section I–A–1 of the NIH Guidelines, if 

the agent is a Select Agent, the NIH will 

defer to the appropriate Federal agency 

(HHS or USDA Select Agent Divisions) 

on such experiments. 

Appendix B. Classification of Human 

Etiologic Agents on the Basis of Hazard 

Currently all influenza viruses types 

A, B, and C are classified as Risk Group 

2 agents. Appendix B–II–D currently 

states: 

Appendix B–II–D. Risk Group 2 

(RG2)—Viruses 

Orthomyxoviruses 

—Influenza viruses types A, B, and C. 

—Other, tick-borne orthomyxoviruses as 

listed in the reference source (see 

Section V–C, Footnotes and Reference 

of Sections I through IV). 

The revised Appendix B–II–D states: 


sroberts on DSKD5P82C1PROD with NOTICES
Federal Register / Vol. 74, No. 182 / Tuesday, September 22, 2009 / Notices 48279 

Orthomyxoviruses 

—Influenza viruses types A, B, and C 

(except those listed in Appendix B– 

III–D (RG3)). 

—Tick-borne orthomyxoviruses. 

The phrase ‘‘as listed in the reference 

source (see Section V–C, Footnotes and 

References of Sections I through IV)’’ 

will be deleted from the revised 

Appendix B–II–D due to the fact that 

tick-borne orthomyxoviruses are not 

listed in the current version of the 

reference source. 

The following is added to Appendix 

B–III–D. Risk Group 3 (RG3)—Viruses 

and Prions 

Orthomyxoviruses 

—Influenza viruses 1918–1919 H1N1 

(1918 H1N1), human H2N2 (1957– 

1968), and highly pathogenic avian 

influenza H5N1 strains within the 

Goose/Guangdong/96-like H5 lineage 

(HPAI H5N1). 

Appendix G–II–C–5. Biosafety Level 3 

Enhanced for Research Involving Risk 

Group 3 Influenza Viruses 

Appendix G–II–C–5 provides 

additional and specific biosafety 

guidance for research with 1918 H1N1, 

human H2N2 (1957–1968), and HPAI 

H5N1 viruses and is intended to 

supplement the guidance provided in 

Appendix G. Physical Containment and 

Appendix Q. Physical and Biological 

Containment for Recombinant DNA 

Research Involving Animals, which 

applies to large research animals. Any 

enhancements to standard BL3 facilities, 

practices, and procedures that are 

described in Appendix G–II–C–5–a shall 

be considered specific for research with 

the Risk Group 3 influenza viruses. Risk 

assessments for research with other 

agents may also determine that 

enhancements to standard containment 

are necessary, but such enhancements 

must be determined for the specific 

agents and experiments being proposed. 

Influenza viruses that contain the 

hemagglutinin gene from a HPAI avian 

influenza are Select Agents and research 

with such viruses is regulated by the 

USDA. The fully reconstructed 1918 

H1N1 virus is a Select Agent regulated 

by the HHS/CDC and certain 

experiments with genes and/or 

segments from 1918 may be regulated by 

HHS/CDC. Therefore, additional 

containment practices may apply and 

OBA will defer to the regulatory 

decisions of these agencies. Research 

with reassortant influenza viruses 

containing segments or genes from HPAI 

H5N1 will also require a permit from 

USDA/APHIS specifying containment 

and may require additional practices 

beyond those described in the NIH 

Guidelines. 

Appendix G–II–C–5–a. Containment, 

Practices, and Training for Research 

with Risk Group 3 Influenza Viruses 

(BL3 Enhanced) 

Appendix G–II–C–5–a–(1). In addition 

to standard BL3 practices, the following 

additional personal protective 

equipment and practices shall be used: 

(1) Powered Air-purifying Respirators 

(PAPR) are worn. 

(2) Street clothes are changed to 

protective suit (e.g., wrap-back 

disposable gown, olefin protective suit). 

(3) Double gloves are worn. 

(4) Appropriate shoe coverings are 

worn (e.g., double disposable shoe 

coverings, single disposable shoe 

coverings if worn with footwear 

dedicated to BL3 enhanced laboratory 

use, or impervious boots or shoes of 

rubber or other suitable material that 

can be decontaminated). 

(5) Showers prior to exiting the 

laboratory should be considered 

depending on risk assessment of 

research activities. 

Appendix G–II–C–5–a–(2). As proper 

training of laboratory workers is an 

essential component of biosafety, 

retraining and periodic reassessments 

(at least annually) in BL3 enhanced 

practices, especially the proper use of 

respiratory equipment, such as PAPRs, 

and clothing changes is required. 

Appendix G–II–C–5–a–(3). Reporting 

of all spills and accidents, even if 

relatively minor, is required as 

described in Appendix G–II–C–2–q. 

Appendix G–II–C–5–a–(4). To avoid 

inadvertent cross contamination of 1918 

H1N1, HPAI H5N1 or human H2N2 

(1957–1968): 

(1) Containment facilities and 

practices appropriate for highest risk 

group virus shall be used at all times 

with lower risk group viruses, when 

studied in the same laboratory room. 

(2) Tissue cultures with these viruses 

shall be conducted at separate times 

(temporal spacing) in the same room. 

(3) Separate reagents shall be used to 

minimize risk of cross contamination. 

(4) A laboratory worker shall not 

perform concurrent influenza virus 

experiments that carry the risk of 

unintended reassortment among 1918 

H1N1, human H2N2 (1957–1968), HPAI 

H5N1 and other human influenza 

viruses. 

(5) Two or more laboratory workers 

shall not perform within the same work 

area simultaneous influenza virus 

experiments that carry the risk of 

unintended segment reassortment 

between 1918 H1N1, or HPAI H5N1, or 

human H2N2 (1957–1968) and other 

human influenza viruses. 

(6) Between experiments good 

biosafety decontamination practices 

(e.g., surface and biosafety cabinet 

surface decontamination according to 

standard BL3 procedures) shall be used 

and there shall be a thirty minute wait 

period after decontamination before 

equipment is used for experiments with 

any other influenza A viruses. 

(7) Between experiments, in addition 

to decontamination of the work area, 

clothing changes and PAPR disinfection 

shall be performed prior to handling a 

different influenza virus in the same 

work area. (Shower-out capability may 

be required by USDA/APHIS for certain 

experiments with HPAI H5N1.) 

Appendix G–II–C–5–a–(5). Continued 

susceptibility of the reassortant 

influenza viruses containing genes and/ 

or segments from 1918 H1N1, HPAI 

H5N1, and human H2N2 (1957–1968) to 

antiviral agents shall be established by 

sequence analysis or suitable biological 

assays. After manipulation of genes that 

influence sensitivity to antiviral agents, 

susceptibility to these agents shall be 

reconfirmed. 

Appendix G–II–C–5–b. Containment for 

Animal Research 

Guidance provided in Appendix G– 

II–C and Appendix Q–II–C is applicable 

with the following emphasis on 

standard BL3 or BL3–N containment or 

additional enhancements. 

Appendix G–II–C–5–b–(1). Research 

with small animals shall be conducted 

in a class II biosafety cabinet. Small 

animals such as rodents (e.g. mice, 

hamsters, rats, guinea pigs) can be 

housed within a negative pressure BL3 

animal suite using high-density 

individually vented caging (IVC) 

systems that independently supply 

HEPA-filtered and directional air 

circulation. Other animals (e.g. rabbits, 

ferrets) that are of a size or have growth 

or caging requirements that preclude the 

use of high-density IVC systems are to 

be housed in negative pressure 

bioisolators. 

Appendix G–II–C–5–b–(2). Large 

animals such as non-human primates 

shall be housed in primary barrier 

environments according to BL3–N 

containment requirements (see Section 

Q–II–c). 

Appendix G–II–C–5–b–(3). Specialized 

training and proven competency in all 

assigned practices and procedures shall 

be required for laboratory staff, 

including staff involved in animal care. 

Appendix G–II–C–5–b–(4). For HPAI 

H5N1 research, the NIH Guidelines 

defer to USDA/APHIS recommendations 


sroberts on DSKD5P82C1PROD with NOTICES
48280 Federal Register / Vol. 74, No. 182 / Tuesday, September 22, 2009 / Notices 

for biocontainment practices for loose 

housed animals. 

Appendix G–II–C–5–c. Occupational 

Health 

A detailed occupational health plan 

shall be developed in advance of 

working with these agents in 

consultation, as needed, with 

individuals with the appropriate 

clinical expertise. In addition, the 

appropriate public health authority 

shall be consulted (e.g. local public 

health officials) on the plan and a mock 

drill of this plan shall be undertaken 

periodically. The plan should include 

an incident reporting system and 

laboratory workers shall report all 

incidents. 

Appendix G–II–C–5–c–(1). Laboratory 

workers shall be provided with medical 

cards which include, at a minimum, the 

following information: characterization 

of the influenza virus to which they 

have been potentially exposed, and 24- 

hour contact numbers for the principal 

investigator and institution’s 

occupational health care provider(s). 

Appendix G–II–C–5–c–(2). A detailed 

occupational health plan shall include: 

(1) Unless there is a medical 

contraindication to vaccination (e.g. 

severe egg allergy) annual seasonal 

influenza vaccination as prerequisite for 

research to reduce risk of influenza like 

illness requiring isolation and tests to 

rule out infection with experimental 

virus and possible co-infection with 

circulating influenza strains. 

(2) Virus specific vaccination, if 

available, should be offered; 

(3) Reporting of all respiratory 

symptoms and/or fever (i.e. influenza 

like illnesses); and 

(4) 24-hour access to a medical facility 

that is prepared to implement 

appropriate respiratory isolation to 

prevent transmission and is able to 

provide appropriate antiviral agents. 

Real-time reverse transcriptionpolymerase chain reaction (RT–PCR) 

procedures should be used to 

discriminate these viruses from 

currently circulating human influenza 

viruses. For exposures to viruses 

containing genes from 1918 H1N1 or the 

HA gene from human H2N2 (1957– 

1968), specimens shall be sent to the 

CDC for testing (RT–PCR and 

confirmatory sequencing). 

Appendix G–II–C–5–c–(3). In 

preparing to perform research with 1918 

H1N1, human H2N2 (1957–1968), or 

HPAI H5N1, principal investigators 

should develop a clear plan specifying 

who will be contacted in the event of a 

potential exposure (during and after 

work hours) to conduct a risk 

assessment and make decisions as to the 

required response, including the need 

for and extent of isolation of the 

exposed worker. After any kind of 

potential exposure, a rapid risk 

assessment shall be performed by the 

principal investigator, health and 

biosafety officials and subsequent 

actions should depend on the appraised 

level of risk of respiratory infection for 

the individual and potential for 

transmission to others. A laboratory 

worker performing research with either 

an influenza virus containing the HA 

gene from human H2N2 or an influenza 

virus containing genes and/or segments 

from 1918 H1N1, shall be informed in 

advance that, in the case of a known 

laboratory exposure with a high risk for 

infection, e.g., involving the upper or 

lower respiratory tract or mucous 

membranes, the laboratory worker will 

need to be isolated in a predetermined 

facility, rather than home isolation, 

until infection can be ruled out by 

testing (e.g., negative RT–PCR for 1918 

H1N1 or human H2N2 (1957–1968)) of 

appropriately timed specimens. 

Laboratory workers shall be informed in 

advance that in the case of a known 

laboratory exposure to highly 

pathogenic avian influenza H5N1 

strains within the Goose/Guangdong/96- 

like H5 lineage with high risk for 

infection, they should be prepared to 

self isolate (for example at home) until 

infection can be ruled out by testing 

(e.g., negative RT–PCR for HPAI H5N1) 

of appropriately timed specimens. The 

action taken for other types of exposures 

should be based on the risk assessment. 

In addition, based on the risk 

assessment: (1) Treatment with 

appropriate antiviral agents shall be 

initiated, and (2) the appropriate public 

health authorities shall be notified. 

Appendix G–II–C–5–c–(4). Influenzalike illness. If a laboratory worker, who 

had recent exposure (within ten days) to 

influenza viruses containing the human 

H2N2 HA gene or any gene from the 

1918 H1N1 or HPAI H5N1 viruses, or to 

animals exposed to such viruses, 

demonstrates symptoms and/or signs of 

influenza infection (e.g., fever/chills, 

cough, myalgias, headache), then the lab 

worker shall report by phone to the 

supervisor/principal investigator and 

other individuals identified in the 

occupational health plan. The 

laboratory worker shall be transported 

to a healthcare facility that can provide 

adequate respiratory isolation, 

appropriate medical therapy, and testing 

to determine whether the infection is 

due to a recombinant influenza virus. 

The appropriate public health 

authorities shall be informed whenever 

a suspected case is isolated. 

Appendix G–II–C–5–c–(5). For 1918 

H1N1 research, the use of antiviral 

agents (e.g., oseltamivir) for preexposure prophylaxis shall be discussed 

with laboratory workers in advance 

including a discussion of the data on the 

safety of long term exposure to these 

agents and their ability to reduce the 

risk of clinical disease and the limits of 

the data regarding protection of close 

contacts and the community. 

Appendix G–II–C–5–c–(6). Antiviral 

agents for post-exposure prophylaxis 

shall be provided only after medical 

evaluation. Home supplies shall not be 

provided in advance for research with 

1918 H1N1 or influenza viruses 

containing the HA gene from human 

H2N2. 

Dated: September 15, 2009. 

Jacqueline Corrigan-Curay, 

Acting Director, Office of Biotechnology 

Activities, National Institutes of Health. 

[FR Doc. E9–22693 Filed 9–21–09; 8:45 am] 

BILLING CODE 4140–01–P 

DEPARTMENT OF HOMELAND 

SECURITY 

U.S. Customs and Border Protection 

Agency Information Collection 

Activities: Application To Establish a 

Centralized Examination Station 

AGENCY: U.S. Customs and Border 

Protection (CBP), Department of 

Homeland Security. 

ACTION: 60-Day notice and request for 

comments; Extension of an existing 

collection of information: 1651–0061. 

SUMMARY: As part of its continuing effort 

to reduce paperwork and respondent 

burden, CBP invites the general public 

and other Federal agencies to comment 

on an information collection 

requirement concerning the Application 

to Establish a Centralized Examination 

Station (CES). This request for comment 

is being made pursuant to the 

Paperwork Reduction Act of 1995 (Pub. 

L. 104–13; 44 U.S.C. 3505(c)(2)). 

DATES: Written comments should be 

received on or before November 23, 

2009, to be assured of consideration. 

ADDRESSES: Direct all written comments 

to U.S. Customs and Border Protection, 

Attn: Tracey Denning, Office of 

Regulations and Rulings, 799 9th Street, 

NW., 7th Floor, Washington, DC 20229– 

1177. 

FOR FURTHER INFORMATION CONTACT: 

Requests for additional information 

should be directed to Tracey Denning, 

U.S. Customs and Border Protection, 

Office of Regulations and Rulings, 799 


sroberts on DSKD5P82C1PROD with NOTICES