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Notice2023-17178

National Institutes of Health (NIH) Office of Science Policy (OSP): Proposed Changes to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines)

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Published

August 10, 2023

Issuing agencies

Health and Human Services DepartmentNational Institutes of Health

Abstract

The National Institutes of Health (NIH) seeks input on a proposal to revise the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) to include specific considerations and requirements for conducting research involving gene drive modified organisms (GDMO) in contained research settings. NIH is proposing to update the NIH Guidelines to clarify minimum containment requirements, propose considerations for performing risk assessments, and define additional institutional responsibilities regarding Institutional Biosafety Committees (IBCs) and Biosafety Officers (BSOs). The proposed revisions are specific to GDMO research subject to the NIH Guidelines, conducted in contained settings and are consistent with the recommendations of the NIH Novel and Exceptional Technology Research Advisory Committee report, Gene Drives in Biomedical Research (NExTRAC Report). NIH does not currently support research involving potential field release of GDMOs and the NIH Guidelines pertain to contained research; accordingly, no changes regarding potential field release are being proposed in this Notice. NIH is also proposing revisions to the NIH Guidelines to harmonize with the Biosafety in Microbiological and Biomedical Laboratories (BMBL), 6th edition regarding the Risk Group (RG) categorization of West Nile Virus (WNV) and Saint Louis Encephalitis Virus (SLEV).

Full Text

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[Federal Register Volume 88, Number 153 (Thursday, August 10, 2023)]
[Notices]
[Pages 54332-54340]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2023-17178]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Institutes of Health (NIH) Office of Science Policy
(OSP): Proposed Changes to the NIH Guidelines for Research Involving
Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines)

AGENCY: National Institutes of Health, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The National Institutes of Health (NIH) seeks input on a
proposal to revise the NIH Guidelines for Research Involving
Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) to
include specific considerations and requirements for conducting
research involving gene drive modified organisms (GDMO) in contained
research settings. NIH is proposing to update the NIH Guidelines to
clarify minimum containment requirements, propose considerations for
performing risk assessments, and define additional institutional
responsibilities regarding Institutional Biosafety Committees (IBCs)
and Biosafety Officers (BSOs). The proposed revisions are specific to
GDMO research subject to the NIH Guidelines, conducted in contained
settings and are consistent with the recommendations of

[[Page 54333]]

the NIH Novel and Exceptional Technology Research Advisory Committee
report, Gene Drives in Biomedical Research (NExTRAC Report). NIH does
not currently support research involving potential field release of
GDMOs and the NIH Guidelines pertain to contained research;
accordingly, no changes regarding potential field release are being
proposed in this Notice. NIH is also proposing revisions to the NIH
Guidelines to harmonize with the Biosafety in Microbiological and
Biomedical Laboratories (BMBL), 6th edition regarding the Risk Group
(RG) categorization of West Nile Virus (WNV) and Saint Louis
Encephalitis Virus (SLEV).

DATES: To ensure consideration, comments must be submitted in writing
by October 10, 2023.

ADDRESSES: Comments may be submitted electronically to <a href="https://osp.od.nih.gov/proposed-amendments-to-the-nih-guidelines-for-research-involving-recombinant-or-synthetic-nucleic-acid-molecules-nih-guidelines/">https://osp.od.nih.gov/proposed-amendments-to-the-nih-guidelines-for-research-involving-recombinant-or-synthetic-nucleic-acid-molecules-nih-guidelines/</a>. Comments are voluntary and may be submitted anonymously.
You may also voluntarily include your name and contact information with
your response. Other than your name and contact information, please do
not include in the response any personally identifiable information or
any information that you do not wish to make public. Proprietary,
classified, confidential, or sensitive information should not be
included in your response. After the Office of Science Policy (OSP) has
finished reviewing the responses, the responses may be posted to the
OSP website without redaction.

FOR FURTHER INFORMATION CONTACT: Caroline Young, ScM, Acting Director
of the Division of Biosafety, Biosecurity, and Emerging Biotechnology
Policy, Office of Science Policy, at (301) 496-9838 or
<a href="/cdn-cgi/l/email-protection#96c5f5fff3f8f5f3c6f9fafff5efd6f9f2b8f8fffeb8f1f9e0"><span class="__cf_email__" data-cfemail="5605353f3338353306393a3f352f16393278383f3e78313920">[email&#160;protected]</span></a>.

SUPPLEMENTARY INFORMATION: The NIH currently supports basic gene drive
research in contained laboratory settings as the technology holds great
promise for advancing public health, particularly through the potential
to reduce transmission of vector-borne human diseases such as malaria,
dengue, or Zika. Under certain conditions, gene drive technology
enables researchers to promote the spread of certain genetic traits
that has the potential to mitigate disease by driving traits through a
specific species population at a faster rate with fewer reproductive
cycles.
Gene drive technology presents opportunities for many life sciences
applications with potential benefits to public health, agriculture, and
the environment but also raise biosafety, ethical, and social concerns.
To help consider issues associated with conducting research involving
GDMOs safely and responsibly, the NIH charged an advisory committee to
the NIH Director, the Novel and Exceptional Technology and Research
Advisory Committee (NExTRAC), to consider whether existing biosafety
guidance is adequate for contained laboratory research utilizing GDMOs.
The NExTRAC made multiple recommendations for strengthening NIH's
existing policies and guidance, which were shared for public input and
ultimately accepted by the NIH Director. These proposed changes only
address the NExTRAC's recommendations pertaining to contained research.
NIH does not currently support research involving potential field
release of GDMOs and the NIH Guidelines pertain to contained research;
as such, no changes are being proposed in this notice regarding field
release research of GDMOs.
NIH is seeking input on its proposal to amend the NIH Guidelines to
ensure the continued responsible research involving GDMOs in contained
research settings. Specifically, NIH proposes to:
(1) clarify minimum containment requirements for research involving
GDMOs;
(2) propose considerations for risk assessment;
(3) define additional institutional responsibilities for
Institutional Biosafety Committees (IBCs) and Biosafety Officers
(BSOs).
In addition to the amendments proposed related to contained
research involving GDMOs, the NIH is seeking input on its proposal to:
1. replace the term ``helper viruses'' with the broader term
``helper systems''; and
2. reclassify WNV and SLEV as risk group 2 agents for consistency
with containment guidance provided in the Biosafety in Microbiological
and Biomedical Laboratories (BMBL), 6th edition.

Current Language and Proposed Amendments to the NIH Guidelines

A definition for gene drive is proposed to be added to Section I-E,
specifically:

Section I-E. General Definitions

Section I-E-7. ``Gene drive'' is defined as a technology whereby a
particular heritable element biases inheritance in its favor, resulting
in the heritable element becoming more prevalent than predicted by
Mendelian laws of inheritance in a population over successive
generations.
Section II-A-3, which provides guidance for conducting a
comprehensive risk assessment, has been updated in the past to provide
additional guidance regarding issues that should be considered for
research involving emerging technologies (e.g., guidance for research
with organisms involving synthetic nucleic acids when the parent
organism is not obvious). Robust risk assessment for research with
GDMOs may present challenges due to different or increased risks
associated with the potential to persist and spread in the environment.
To address some of these challenges, Section II-A-3 is proposed to be
amended to include considerations for risk assessment.
Section II-A-3 currently states:

Section II-A-3. Comprehensive Risk Assessment

In deciding on the appropriate containment for an experiment, the
first step is to assess the risk of the agent itself. Appendix B,
Classification of Human Etiologic Agents on the Basis of Hazard,
classifies agents into Risk Groups based on an assessment of their
ability to cause disease in humans and the available treatments for
such disease. Once the Risk Group of the agent is identified, this
should be followed by a thorough consideration of how the agent is to
be manipulated. Factors to be considered in determining the level of
containment include agent factors such as: virulence, pathogenicity,
infectious dose, environmental stability, route of spread,
communicability, operations, quantity, availability of vaccine or
treatment, and gene product effects such as toxicity, physiological
activity, and allergenicity. Any strain that is known to be more
hazardous than the parent (wild-type) strain should be considered for
handling at a higher containment level. Certain attenuated strains or
strains that have been demonstrated to have irreversibly lost known
virulence factors may qualify for a reduction of the containment level
compared to the Risk Group assigned to the parent strain (see Section
V-B, Footnotes and References of Sections I-IV).
While the starting point for the risk assessment is based on the
identification of the Risk Group of the parent agent, as technology
moves forward, it may be possible to develop an organism containing
genetic sequences from multiple sources such that the parent agent may
not be obvious. In such cases, the risk assessment should include at
least two levels of analysis. The first involves a

[[Page 54334]]

consideration of the Risk Groups of the source(s) of the sequences and
the second involves an assessment of the functions that may be encoded
by these sequences (e.g., virulence or transmissibility). It may be
prudent to first consider the highest Risk Group classification of all
agents that are the source of sequences included in the construct.
Other factors to be considered include the percentage of the genome
contributed by each parent agent and the predicted function or intended
purpose of each contributing sequence. The initial assumption should be
that all sequences will function as they did in the original host
context.
The Principal Investigator and Institutional Biosafety Committee
must also be cognizant that the combination of certain sequences in a
new biological context may result in an organism whose risk profile
could be higher than that of the contributing organisms or sequences.
The synergistic function of these sequences may be one of the key
attributes to consider in deciding whether a higher containment level
is warranted, at least until further assessments can be carried out. A
new biosafety risk may occur with an organism formed through
combination of sequences from a number of organisms or due to the
synergistic effect of combining transgenes that results in a new
phenotype.
A final assessment of risk based on these considerations is then
used to set the appropriate containment conditions for the experiment
(see Section II-B, Containment). The appropriate containment level may
be equivalent to the Risk Group classification of the agent, or it may
be raised or lowered as a result of the above considerations. The
Institutional Biosafety Committee must approve the risk assessment and
the biosafety containment level for recombinant or synthetic nucleic
acid experiments described in Sections III-A, Experiments that Require
NIH Director Approval and Institutional Biosafety Committee Approval,
Before Initiation; III-B, Experiments that Require NIH OSP and
Institutional Biosafety Committee Approval Before Initiation; III-C,
Experiments Involving Human Gene Transfer that Require Institutional
Biosafety Committee Approval Prior to Initiation; III-D, Experiments
that Require Institutional Biosafety Committee Approval Before
Initiation.
Careful consideration should be given to the types of manipulation
planned for some higher Risk Group agents. For example, the RG2 dengue
viruses may be cultured under the Biosafety Level (BL) 2 containment
(see Section II-B); however, when such agents are used for animal
inoculation or transmission studies, a higher containment level is
recommended. Similarly, RG3 agents such as Venezuelan equine
encephalomyelitis and yellow fever viruses should be handled at a
higher containment level for animal inoculation and transmission
experiments.
Individuals working with human immunodeficiency virus (HIV),
hepatitis B virus (HBV) or other bloodborne pathogens should consult
the applicable Occupational Safety and Health Administration (OSHA)
(<a href="https://www.osha.gov/">https://www.osha.gov/</a>) (regulation, 29 CFR 1910.1030, and OSHA
publication 3127 (1996 revised). BL2 containment is recommended for
activities involving all blood-contaminated clinical specimens, body
fluids, and tissues from all humans, or from HIV- or HBV-infected or
inoculated laboratory animals. Activities such as the production of
research-laboratory scale quantities of HIV or other bloodborne
pathogens, manipulating concentrated virus preparations, or conducting
procedures that may produce droplets or aerosols, are performed in a
BL2 facility using the additional practices and containment equipment
recommended for BL3. Activities involving industrial scale volumes or
preparations of concentrated HIV are conducted in a BL3 facility, or
BL3 Large Scale if appropriate, using BL3 practices and containment
equipment.
Exotic plant pathogens and animal pathogens of domestic livestock
and poultry are restricted and may require special laboratory design,
operation and containment features not addressed in Biosafety in
Microbiological and Biomedical Laboratories (see Section V-C, Footnotes
and References of Sections I through IV). For information regarding the
importation, possession, or use of these agents see Sections V-G and V-
H, Footnotes and References of Sections I through IV.
Risk mitigation strategies employed in contained settings are not
likely to differ for GDMOs compared to other gene modified organisms in
the laboratory. However, given the relative newness of GDMO technology
and its use in biomedical research, any risk assessment is likely to
have greater uncertainty regarding potential risks. Section II-A-3 is
proposed to be amended to provide additional guidance for conducting
these assessments by insertion of new paragraphs five and six:
Section II-A-3 is proposed to be amended to:
In deciding on the appropriate containment for an experiment, the
first step is to assess the risk of the agent itself. Appendix B,
Classification of Human Etiologic Agents on the Basis of Hazard,
classifies agents into Risk Groups based on an assessment of their
ability to cause disease in humans and the available treatments for
such disease. Once the Risk Group of the agent is identified, this
should be followed by a thorough consideration of how the agent is to
be manipulated. Factors to be considered in determining the level of
containment include agent factors such as: virulence, pathogenicity,
infectious dose, environmental stability, route of spread,
communicability, operations, quantity, availability of vaccine or
treatment, and gene product effects such as toxicity, physiological
activity, and allergenicity. Any strain that is known to be more
hazardous than the parent (wild-type) strain should be considered for
handling at a higher containment level. Certain attenuated strains or
strains that have been demonstrated to have irreversibly lost known
virulence factors may qualify for a reduction of the containment level
compared to the Risk Group assigned to the parent strain (see Section
V-B, Footnotes and References of Sections I-IV).
While the starting point for the risk assessment is based on the
identification of the Risk Group of the parent agent, as technology
moves forward, it may be possible to develop an organism containing
genetic sequences from multiple sources such that the parent agent may
not be obvious. In such cases, the risk assessment should include at
least two levels of analysis. The first involves a consideration of the
Risk Groups of the source(s) of the sequences and the second involves
an assessment of the functions that may be encoded by these sequences
(e.g., virulence or transmissibility). It may be prudent to first
consider the highest Risk Group classification of all agents that are
the source of sequences included in the construct. Other factors to be
considered include the percentage of the genome contributed by each
parent agent and the predicted function or intended purpose of each
contributing sequence. The initial assumption should be that all
sequences will function as they did in the original host context.
The Principal Investigator and Institutional Biosafety Committee
must also be cognizant that the combination of certain sequences in a
new biological context may result in an organism whose risk profile
could be higher than that of the contributing organisms or sequences.
The synergistic function of these sequences may be one of the key

[[Page 54335]]

attributes to consider in deciding whether a higher containment level
is warranted, at least until further assessments can be carried out. A
new biosafety risk may occur with an organism formed through
combination of sequences from a number of organisms or due to the
synergistic effect of combining transgenes that results in a new
phenotype.
A final assessment of risk based on these considerations is then
used to set the appropriate containment conditions for the experiment
(see Section II-B, Containment). The appropriate containment level may
be equivalent to the Risk Group classification of the agent or it may
be raised or lowered as a result of the above considerations. The
Institutional Biosafety Committee must approve the risk assessment and
the biosafety containment level for recombinant or synthetic nucleic
acid experiments described in Sections III-A, Experiments that Require
NIH Director Approval and Institutional Biosafety Committee Approval,
Before Initiation; III-B, Experiments that Require NIH OSP and
Institutional Biosafety Committee Approval Before Initiation; III-C,
Experiments Involving Human Gene Transfer that Require Institutional
Biosafety Committee Approval Prior to Initiation; III-D, Experiments
that Require Institutional Biosafety Committee Approval Before
Initiation.
Research involving gene drive modified organisms may require risk
assessments that incorporate a broader scope of considerations because
of greater uncertainty of the technology and potential uncertainty of
the impact of the newly modified organism. Specific attention must be
paid to risks of an unintended release from the laboratory and the
potential impact on humans, other populations of organisms, and the
environment.
Considerations for conducting risk assessments for research
involving gene drive modified organisms might include:
1. The specific types of manipulations based on:
a. Function or intended function of the genetic/gene drive
construct (i.e., a designed or engineered assembly of sequences);
b. Source of the genetic material (e.g., sequences of transgenes)
in the construct;
c. The modifications to the construct;
d. Whether it is possible to predict the consequences of a
construct, including the recognition of an unintended gene drive (i.e.,
construct not specifically designed as a gene drive but nonetheless
having properties of a gene drive) and the possible consequences of
escape into the environment;
e. The potential ability of the gene drive to spread or persist in
local populations;
2. Options for approaches to risk mitigation for specific types of
risks in experiments or when dealing with a high degree of uncertainty
about risks;
3. Considerations for implementing more stringent containment
measures until biosafety data are accrued to support lowering
containment.
Careful consideration should be given to the types of manipulation
planned for some higher Risk Group agents. For example, the RG2 dengue
viruses may be cultured under the Biosafety Level (BL) 2 containment
(see Section II-B); however, when such agents are used for animal
inoculation or transmission studies, a higher containment level is
recommended. Similarly, RG3 agents such as Venezuelan equine
encephalomyelitis and yellow fever viruses should be handled at a
higher containment level for animal inoculation and transmission
experiments.
Individuals working with human immunodeficiency virus (HIV),
hepatitis B virus (HBV) or other bloodborne pathogens should consult
the applicable Occupational Safety and Health Administration (OSHA)
regulation, 29 CFR 1910.1030, and OSHA publication 3127 (1996 revised).
BL2 containment is recommended for activities involving all blood-
contaminated clinical specimens, body fluids, and tissues from all
humans, or from HIV- or HBV-infected or inoculated laboratory animals.
Activities such as the production of research-laboratory scale
quantities of HIV or other bloodborne pathogens, manipulating
concentrated virus preparations, or conducting procedures that may
produce droplets or aerosols, are performed in a BL2 facility using the
additional practices and containment equipment recommended for BL3.
Activities involving industrial scale volumes or preparations of
concentrated HIV are conducted in a BL3 facility, or BL3 Large Scale if
appropriate, using BL3 practices and containment equipment.
Exotic plant pathogens and animal pathogens of domestic livestock
and poultry are restricted and may require special laboratory design,
operation and containment features not addressed in Biosafety in
Microbiological and Biomedical Laboratories (see Section V-C, Footnotes
and References of Sections I through IV). For information regarding the
importation, possession, or use of these agents see Sections V-G and V-
H, Footnotes and References of Sections I through IV.
In 2012 when the NIH Guidelines were updated to expand the scope to
cover synthetic nucleic acid molecules, Section III-C and Section III-
F-1 were amended to exempt research with certain oligonucleotides based
on the lower risk posed by their transient nature. These sections also
outlined criteria for higher risk nucleic acids that would not be
exempt (e.g., nucleic acids that replicated, were transcribed,
translated, or integrated etc.). At that time, much research with
oligonucleotides was likely to involve a delivery method using a
recombinant nucleic acid molecule (e.g., viral vector or plasmid), and
thus would still be subject to the NIH Guidelines. Since then, gene
editing using CRISPR/Cas systems and non-recombinant delivery methods
(e.g., lipid nanoparticles) has come into more common use. Currently,
transgenic organisms with the same genetic modification may or may not
be subject to the NIH Guidelines depending on the method of generation
(e.g., recombinant viral vector delivery and expression of Cas9 and
guide RNAs vs. lipid nanoparticle delivery of protein Cas9 and guide
RNAs). Because of the higher risks associated with stable genetic
modifications to viruses, cells, or organisms, Sections III-C and III-
F-1 each have a criterion that precludes the exemption of nucleic acids
that integrate, the main method to introduce such changes in 2012. To
avoid exempting certain gene editing approaches or GDMOs, the language
in Sections III-C and III-F-1 is proposed to be amended to replace the
criterion involving integration with a broader criterion covering the
introduction of a stable genetic modification.
Section III-C-1 currently states in part:

Section III-C-1. Experiments Involving the Deliberate Transfer of
Recombinant or Synthetic Nucleic Acid Molecules, or DNA or RNA Derived
From Recombinant or Synthetic Nucleic Acid Molecules, Into One or More
Human Research Participants

[[Page 54336]]

b. Possess biological properties that enable integration into the
genome (e.g., cis elements involved in integration); or
c. Have the potential to replicate in a cell; or
d. Can be translated or transcribed.
This portion of Section III-C-1 1 is proposed to be amended to:

Human gene transfer is the deliberate transfer into human research
participants of either:
1. Recombinant nucleic acid molecules, or DNA or RNA derived from
recombinant nucleic acid molecules, or
2. Synthetic nucleic acid molecules, or DNA or RNA derived from
synthetic nucleic acid molecules, that meet any one of the following
criteria:
a. Contain more than 100 nucleotides; or
b. Possess biological properties that enable introduction of stable
genetic modifications into the genome (e.g., cis elements involved in
integration, gene editing); or
c. Have the potential to replicate in a cell; or
d. Can be translated or transcribed.
Section III-F-1 currently states:
Section III-F-1. Those synthetic nucleic acids that: (1) can
neither replicate nor generate nucleic acids that can replicate in any
living cell (e.g., oligonucleotides or other synthetic nucleic acids
that do not contain an origin of replication or contain elements known
to interact with either DNA or RNA polymerase), and (2) are not
designed to integrate into DNA, and (3) do not produce a toxin that is
lethal for vertebrates at an LD50 of less than 100 nanograms per
kilogram body weight. If a synthetic nucleic acid is deliberately
transferred into one or more human research participants and meets the
criteria of Section III-C, it is not exempt under this Section.
Section III-F-1 is proposed to be amended to:
Section III-F-1. Those synthetic nucleic acids that: (1) can
neither replicate nor generate nucleic acids that can replicate in any
living cell (e.g., oligonucleotides or other synthetic nucleic acids
that do not contain an origin of replication or contain elements known
to interact with either DNA or RNA polymerase), and (2) are not
designed to introduce a stable genetic modification, and (3) do not
produce a toxin that is lethal for vertebrates at an LD50 of less than
100 nanograms per kilogram body weight. If a synthetic nucleic acid is
deliberately transferred into one or more human research participants
and meets the criteria of Section III-C, it is not exempt under this
Section.
To provide guidance on physical containment for research involving
GDMOs, Section III-D is proposed to be amended in multiple subsections
to require that experiments involving GDMOs be conducted at a minimum
of BL2 containment to provide the appropriate laboratory practices,
containment equipment, and special laboratory design to protect
laboratory workers, the public, and local ecosystems. A section
specific to experiments involving GDMOs is proposed to be added as
Section III-D-8. Sections III-D-4, III-D-5, and III-E-3, which cover
experiments with whole animals, plants, and transgenic rodents, are
also proposed to be amended to reference Section III-D-8.
Section III-D-4, which is part of Section III-D, Experiments that
Require Institutional Biosafety Committee Approval Before Initiation,
currently states:

Section III-D-4. Experiments Involving Whole Animals

This section covers experiments involving whole animals in which
the animal's genome has been altered by stable introduction of
recombinant or synthetic nucleic acid molecules, or nucleic acids
derived therefrom, into the germ-line (transgenic animals) and
experiments involving viable recombinant or synthetic nucleic acid
molecule-modified microorganisms tested on whole animals. For the
latter, other than viruses which are only vertically transmitted, the
experiments may not be conducted at BL1-N containment. A minimum
containment of BL2 or BL2-N is required.
Caution--Special care should be used in the evaluation of
containment conditions for some experiments with transgenic animals.
For example, such experiments might lead to the creation of novel
mechanisms or increased transmission of a recombinant pathogen or
production of undesirable traits in the host animal. In such cases,
serious consideration should be given to increasing the containment
conditions.
Section III-D-4-a. Recombinant or synthetic nucleic acid molecules,
or DNA or RNA molecules derived therefrom, from any source except for
greater than two-thirds of eukaryotic viral genome may be transferred
to any non-human vertebrate or any invertebrate organism and propagated
under conditions of physical containment comparable to BL1 or BL1-N and
appropriate to the organism under study (see Section V-B, Footnotes and
References of Sections I-IV). Animals that contain sequences from viral
vectors, which do not lead to transmissible infection either directly
or indirectly as a result of complementation or recombination in
animals, may be propagated under conditions of physical containment
comparable to BL1 or BL1-N and appropriate to the organism under study.
Experiments involving the introduction of other sequences from
eukaryotic viral genomes into animals are covered under Section III-D-
4-b, Experiments Involving Whole Animals. For experiments involving
recombinant or synthetic nucleic acid molecule-modified Risk Groups 2,
3, 4, or restricted organisms, see Sections V-A, V-G, and V-L,
Footnotes and References of Sections I-IV. It is important that the
investigator demonstrate that the fraction of the viral genome being
utilized does not lead to productive infection. A U.S. Department of
Agriculture permit is required for work with plant or animal pathogens
(see Section V-G, Footnotes and References of Sections I-IV).
Section III-D-4-b. For experiments involving recombinant or
synthetic nucleic acid molecules, or DNA or RNA derived therefrom,
involving whole animals, including transgenic animals, and not covered
by Section III-D-1, Experiments Using Human or Animal Pathogens (Risk
Group 2, Risk Group 3, Risk Group 4, or Restricted Agents as Host-
Vector Systems), or Section III-D-4-a, the appropriate containment
shall be determined by the Institutional Biosafety Committee.
Section III-D-4-c. Exceptions under Section III-D-4, Experiments
Involving Whole Animals
Section III-D-4-c-(1). Experiments involving the generation of
transgenic rodents that require BL1 containment are described under
Section III-E-3, Experiments Involving Transgenic Rodents.
Section III-D-4-c-(2). The purchase or transfer of transgenic
rodents is exempt from the NIH Guidelines under Section III-F, Exempt
Experiments (see Appendix C-VII, The Purchase or Transfer of Transgenic
Rodents).
Section III-D-4 is proposed to be amended to state:

Section III-D-4. Experiments Involving Whole Animals

This section covers experiments involving deliberate transfer of
recombinant or synthetic nucleic acid

[[Page 54337]]

molecules, DNA or RNA derived from recombinant or synthetic nucleic
acid molecules, or recombinant or synthetic nucleic acid molecule-
modified microorganisms into whole animals and experiments involving
whole animals in which the animal's genome has been altered by
recombinant or synthetic nucleic acid molecules, or nucleic acids
derived therefrom, into the germ-line (transgenic animals). Experiments
involving gene drive modified animals or experiments involving viable
recombinant or synthetic nucleic acid molecule-modified microorganisms,
except for viruses that are only vertically transmitted, may not be
conducted at BL1-N containment. A minimum containment of BL2 or BL2-N
is required (see Section III-D-8).
Caution--Special care should be used in the evaluation of
containment conditions for some experiments with transgenic animals.
For example, such experiments might lead to the creation of novel
mechanisms (e.g., a gene drive; refer to Section III-D-8) or increased
transmission of a recombinant pathogen or production of undesirable
traits in the host animal. In such cases, serious consideration should
be given to increasing the containment conditions.
Section III-D-4-a. Recombinant or synthetic nucleic acid molecules,
or DNA or RNA molecules derived therefrom, from any source except for
greater than two-thirds of eukaryotic viral genome may be transferred
to any non-human vertebrate or any invertebrate organism and propagated
under conditions of physical containment comparable to BL1 or BL1-N and
appropriate to the organism under study (see Section V-B, Footnotes and
References of Sections I-IV). Animals that contain sequences from viral
vectors, which do not lead to transmissible infection either directly
or indirectly as a result of complementation or recombination in
animals, may be propagated under conditions of physical containment
comparable to BL1 or BL1-N and appropriate to the organism under study.
Experiments involving the introduction of other sequences from
eukaryotic viral genomes into animals are covered under Section III-D-
4-b, Experiments Involving Whole Animals. For experiments involving
recombinant or synthetic nucleic acid molecule-modified Risk Groups 2,
3, 4, or restricted organisms, see Sections V-A, V-G, and V-L,
Footnotes and References of Sections I-IV. It is important that the
investigator demonstrate that the fraction of the viral genome being
utilized does not lead to productive infection. A U.S. Department of
Agriculture permit is required for work with plant or animal pathogens
(see Section V-G, Footnotes and References of Sections I-IV).
Section III-D-4-b. For experiments involving recombinant or
synthetic nucleic acid molecules, or DNA or RNA derived therefrom,
involving whole animals, including transgenic animals, and not covered
by Section III-D-1, Experiments Using Human or Animal Pathogens (Risk
Group 2, Risk Group 3, Risk Group 4, or Restricted Agents as Host-
Vector Systems), or Section III-D-4-a, the appropriate containment
shall be determined by the Institutional Biosafety Committee.
Experiments involving gene drive modified animals generated by
recombinant or synthetic nucleic acid molecules shall be conducted at a
minimum of BL2 or BL2-N (see Section III-D-8).
Section III-D-4-c. Exceptions under Section III-D-4, Experiments
Involving Whole Animals
Section III-D-4-c-(1). Experiments involving the generation of
transgenic rodents that require BL1 containment are described under
Section III-E-3, Experiments Involving Transgenic Rodents.
Section III-D-4-c-(2). The purchase or transfer of BL1 transgenic
rodents is exempt from the NIH Guidelines under Section III-F, Exempt
Experiments (see Appendix C-VII, The Purchase or Transfer of Transgenic
Rodents).
Section III-D-4-c-(3). Experiments involving the generation or use
of gene drive modified animals require a minimum of BL2 containment and
are covered under III-D-8, Experiments Involving Gene Drive Modified
Organisms.
Section III-D-5 currently states in part:

Section III-D-5. Experiments Involving Whole Plants

Experiments to genetically engineer plants by recombinant or
synthetic nucleic acid molecule methods, to use such plants for other
experimental purposes (e.g., response to stress), to propagate such
plants, or to use plants together with microorganisms or insects
containing recombinant or synthetic nucleic acid molecules, may be
conducted under the containment conditions described in Sections III-D-
5-a through III-D-5-e. If experiments involving whole plants are not
described in Section III-D-5 and do not fall under Sections III-A, III-
B, III-D or III-F, they are included in Section III-E.
This portion of Section III-D-5 is proposed to be amended to:

Section III-D-5. Experiments Involving Whole Plants

Experiments to genetically engineer plants by recombinant or
synthetic nucleic acid molecule methods, to use such plants for other
experimental purposes (e.g., response to stress), to propagate such
plants, or to use plants together with microorganisms or insects
containing recombinant or synthetic nucleic acid molecules, may be
conducted under the containment conditions described in Sections III-D-
5-a through III-D-5-e. If experiments involving whole plants are not
described in Section III-D-5 and do not fall under Sections III-A, III-
B, III-D or III-F, they are included in Section III-E. Experiments
involving the generation or use of gene drive modified organisms
require a minimum of BL2 containment and are described under Section
III-D-8, Experiments Involving Gene Drive Modified Organisms.
Section III-D-8 is proposed to be added to state:

Section III-D-8. Experiments Involving Gene Drive Modified Organisms

Experiments involving gene drive modified organisms generated by
recombinant or synthetic nucleic acid molecules shall be conducted at a
minimum of Biosafety Level (BL) 2, BL2-N (Animals) or BL2-P (plant)
containment.
Only transgenic rodents that may be contained under BL1 are covered
under Section III-E-3. Section III-E-3 is proposed to be amended to
reference the new Section III-D-8 to reinforce that research with GDMOs
shall be conducted at a minimum of BL2. Section III-E-3, which is part
of Section III-E, Experiments that Require Institutional Biosafety
Committee Notice Simultaneous with Initiation, states in part:

Section III-E-3. Experiments Involving Transgenic Rodents

This section covers experiments involving the generation of rodents
in which the animal's genome has been altered by stable introduction of
recombinant or synthetic nucleic acid molecules, or nucleic acids
derived therefrom, into the germ-line (transgenic rodents). Only
experiments that require BL1 containment are covered under this
section; experiments that require BL2, BL3, or BL4 containment are
covered under Section III-D-4, Experiments Involving Whole Animals.

[[Page 54338]]

This portion of Section III-E-3 is proposed to be amended to:

Section III-E-3. Experiments Involving Transgenic Rodents

This section covers experiments involving the generation or use of
rodents in which the animal's genome has been altered by stable
introduction of recombinant or synthetic nucleic acid molecules, or
nucleic acids derived therefrom, into the germ-line (transgenic
rodents). Only experiments that require BL1 containment are covered
under this section; experiments that require BL2, BL3, or BL4
containment are covered under Section III-D-4, Experiments Involving
Whole Animals or Section III-D-8, Experiments Involving Gene Drive
Modified Organisms.
In the NExTRAC report, the committee recommended that NIH should
require appropriate expertise in the review of gene drive research by
IBC members and BSO. Portions of Section IV-B are proposed to be
amended regarding institutional responsibilities for the establishment
of IBCs and requirements for BSOs.
Section IV-B-1-c currently states:
Section IV-B-1-c. Appoint a Biological Safety Officer (who is also
a member of the Institutional Biosafety Committee) if the institution:
(i) conducts recombinant or synthetic nucleic acid molecule research at
Biosafety Level (BL) 3 or BL4, or (ii) engages in large-scale (greater
than 10 liters) research. The Biological Safety Officer carries out the
duties specified in Section IV-B-3.
Section IV-B-1-c is proposed to be amended to:
Section IV-B-1-c. Appoint a Biological Safety Officer (who is also
a member of the Institutional Biosafety Committee) if the institution:
(i) conducts recombinant or synthetic nucleic acid molecule research at
Biosafety Level (BL) 3 or BL4, (ii) engages in large-scale (greater
than 10 liters) research or (iii) conducts research involving gene
drive modified organisms. The Biological Safety Officer carries out the
duties specified in Section IV-B-3.
Section IV-B-2-a, Membership and Procedures of IBCs currently
states in part:
Section IV-B-2-a-(1). The Institutional Biosafety Committee must
comprise no fewer than five members so selected that they collectively
have experience and expertise in recombinant or synthetic nucleic acid
molecule technology and the capability to assess the safety of
recombinant or synthetic nucleic acid molecule research and to identify
any potential risk to public health or the environment. At least two
members shall not be affiliated with the institution (apart from their
membership on the Institutional Biosafety Committee) and who represent
the interest of the surrounding community with respect to health and
protection of the environment (e.g., officials of state or local public
health or environmental protection agencies, members of other local
governmental bodies, or persons active in medical, occupational health,
or environmental concerns in the community). The Institutional
Biosafety Committee shall include at least one individual with
expertise in plant, plant pathogen, or plant pest containment
principles when experiments utilizing Appendix L, Physical and
Biological Containment for Recombinant or Synthetic Nucleic Acid
Molecule Research Involving Plants, require prior approval by the
Institutional Biosafety Committee. The Institutional Biosafety
Committee shall include at least one scientist with expertise in animal
containment principles when experiments utilizing Appendix M, Physical
and Biological Containment for Recombinant or Synthetic Nucleic Acid
Molecule Research Involving Animals, require Institutional Biosafety
Committee prior approval. When the institution conducts recombinant or
synthetic nucleic acid molecule research at BL3, BL4, or Large Scale
(greater than 10 liters), a Biological Safety Officer is mandatory and
shall be a member of the Institutional Biosafety Committee (see Section
IV-B-3, Biological Safety Officer). When the institution participates
in or sponsors recombinant or synthetic nucleic acid molecule research
involving human research participants, the institution must ensure that
the Institutional Biosafety Committee has adequate expertise and
training (using ad hoc consultants as deemed necessary). Institutional
Biosafety Committee approval must be obtained from the clinical trial
site.
Section IV-B-2-a-(1) is proposed to be amended to read:
Section IV-B-2-a-(1). The Institutional Biosafety Committee must
comprise no fewer than five members so selected that they collectively
have experience and expertise in recombinant or synthetic nucleic acid
molecule technology and the capability to assess the safety of
recombinant or synthetic nucleic acid molecule research and to identify
any potential risk to public health or the environment. At least two
members shall not be affiliated with the institution (apart from their
membership on the Institutional Biosafety Committee) and who represent
the interest of the surrounding community with respect to health and
protection of the environment (e.g., officials of state or local public
health or environmental protection agencies, members of other local
governmental bodies, or persons active in medical, occupational health,
or environmental concerns in the community). The Institutional
Biosafety Committee shall include at least one individual with
expertise in plant, plant pathogen, or plant pest containment
principles when experiments utilizing Appendix L, Physical and
Biological Containment for Recombinant or Synthetic Nucleic Acid
Molecule Research Involving Plants, require prior approval by the
Institutional Biosafety Committee. The Institutional Biosafety
Committee shall include at least one scientist with expertise in animal
containment principles when experiments utilizing Appendix M, Physical
and Biological Containment for Recombinant or Synthetic Nucleic Acid
Molecule Research Involving Animals, require Institutional Biosafety
Committee prior approval. When the institution conducts research
involving gene drive modified organisms the institution must ensure
that the Institutional Biosafety Committee has adequate expertise
(e.g., specific species containment, ecological or environmental risk
assessment) using ad hoc consultants if necessary. When the institution
conducts recombinant or synthetic nucleic acid molecule research at
BL3, BL4, or Large Scale (greater than 10 liters) or research involving
gene drive modified organisms, a Biological Safety Officer is mandatory
and shall be a member of the Institutional Biosafety Committee (see
Section IV-B-3, Biological Safety Officer). When the institution
conducts research with gene drive modified organisms, the impact on
ecosystems should be assessed by the Institutional Biosafety Committee
(see Section V-N, Footnotes and References of Sections I-IV). When the
institution participates in or sponsors recombinant or synthetic
nucleic acid molecule research involving human research participants,
the institution must ensure that the Institutional Biosafety Committee
has adequate expertise and training (using ad hoc consultants if
necessary). Institutional Biosafety Committee approval must be obtained
from the clinical trial site.
Section IV-B-3, Biological Safety Officer (BSO), states in part:
Section IV-B-3-a. The institution shall appoint a Biological Safety
Officer if it engages in large-scale research or

[[Page 54339]]

production activities involving viable organisms containing recombinant
or synthetic nucleic acid molecules.
Section IV-B-3-a is proposed to be amended to clarify the
requirement for a BSO to be a member of the IBC. A new Section IV-B-3-c
is proposed to be added to require a BSO for research involving GDMOs.
The current IV-B-3-c sections will be re-lettered to IV-B-3-d.
Section IV-B-3-a. The institution shall appoint a Biological Safety
Officer if it engages in large-scale research or production activities
involving viable organisms containing recombinant or synthetic nucleic
acid molecules. The Biological Safety Officer shall be a member of the
Institutional Biosafety Committee.
Section IV-B-3-c. The institution shall appoint a Biological Safety
Officer if it engages in recombinant or synthetic nucleic acid molecule
research that involves gene drive modified organisms. The Biological
Safety Officer shall be a member of the Institutional Biosafety
Committee.
To emphasize that GDMOs may have an impact on ecosystems, a new
footnote and reference for Sections I through IV is proposed to be
added.
Section V-N is proposed to state:
Section V-N Determination of whether a gene drive modified organism
has a potential for serious detrimental impact on managed
(agricultural, forest, grassland) or natural ecosystems should be made
by the Principal Investigator and the Institutional Biosafety
Committee, in consultation with scientists knowledgeable of gene drive
technology, the environment, and ecosystems in the geographic area of
the research.
Since research with GDMOs shall be conducted at a minimum of
Biosafety Level 2, research involving host vector system organisms
modified by a gene drive will not be exempt. Therefore, the exceptions
(Appendices C-III-A and C-IV-A) to Appendices C-III and C-IV,
Saccharomyces and Kluyveromyces Host-Vector Systems, respectively, are
proposed to be amended.
Appendices C-III-A Exceptions and C-IV-A Exceptions currently
state:
The following categories are not exempt from the NIH Guidelines:
(i) experiments described in Section III-B which require NIH OSP and
Institutional Biosafety Committee approval before initiation, (ii)
experiments involving DNA from Risk Groups 3, 4, or restricted
organisms (see Appendix B, Classification of Human Etiologic Agents on
the Basis of Hazard, and Sections V-G and V-L, Footnotes and References
of Sections I through IV) or cells known to be infected with these
agents may be conducted under containment conditions specified in
Section III-D-2 with prior Institutional Biosafety Committee review and
approval, (iii) large-scale experiments (e.g., more than 10 liters of
culture), and (iv) experiments involving the deliberate cloning of
genes coding for the biosynthesis of molecules toxic for vertebrates
(see Appendix F, Containment Conditions for Cloning of Genes Coding for
the Biosynthesis of Molecules Toxic for Vertebrates).
Appendices C-III-A Exceptions and C-IV-A Exceptions are proposed to
be amended to state:
The following categories are not exempt from the NIH Guidelines:
(i) experiments described in Section III-B, which require NIH OSP and
Institutional Biosafety Committee approval before initiation; (ii)
experiments involving DNA from Risk Groups 3, 4, or restricted
organisms (see Appendix B, Classification of Human Etiologic Agents on
the Basis of Hazard, and Sections V-G and V-L, Footnotes and References
of Sections I through IV) or cells known to be infected with these
agents may be conducted under containment conditions specified in
Section III-D-2 with prior Institutional Biosafety Committee review and
approval; (iii) large-scale experiments (e.g., more than 10 liters of
culture), (iv) experiments involving the deliberate cloning of genes
coding for the biosynthesis of molecules toxic for vertebrates (see
Appendix F, Containment Conditions for Cloning of Genes Coding for the
Biosynthesis of Molecules Toxic for Vertebrates), and (v) experiments
involving gene drive modified organisms (Section III-D-8). To provide
additional guidance on containment for work with arthropods, Appendices
G, L, and M are proposed to reference the Arthropod Containment
Guidelines, which specifically outline practices and procedures for
arthropod research, and the addendum Arthropod Containment Guidelines,
which articulates containment practices for gene drive modified
arthropods. Appendix G-III and Footnotes and References of Appendix G
will also be modified to reference the current edition of the reference
source BMBL and to correct an erroneous second citation of the BMBL.
Appendix G-III-A currently states:
Appendix G-III-A. Biosafety in Microbiological and Biomedical
Laboratories, 5th edition, U.S. Department of Health and Human
Services, Public Health Service, Centers for Disease Control and
Prevention, Atlanta, Georgia, and National Institutes of Health,
Bethesda, Maryland.
Appendix G-III-A is proposed to be amended to state:
Appendix G-III-A. Biosafety in Microbiological and Biomedical
Laboratories, 6th edition, U.S. Department of Health and Human
Services, Public Health Service, Centers for Disease Control and
Prevention, Atlanta, Georgia, and National Institutes of Health,
Bethesda, Maryland.
Appendix G-III-B currently states:
Appendix G-III-B. Biosafety in Microbiological and Biomedical
Laboratories, 3rd edition, May 1993, U.S. DHHS, Public Health Service,
Centers for Disease Control and Prevention, Atlanta, Georgia, and NIH,
Bethesda, Maryland.
Appendix G-III-B is proposed to be amended to state:
Appendix G-III-B. Arthropod Containment Guidelines, Version 3.2,
2019, and Addendum 1 Containment Practices for Arthropods Modified with
Engineered Transgenes Capable of Gene Drive, 2022, American Committee
of Medical Entomology, American Society of Tropical Medicine and
Hygiene, Arlington, Virginia. Appendices L and M specify containment
conditions and practices for plants and animals, respectively, that
preclude the use of containment as specified in Appendix G. Both
Appendices L and M will be modified to incorporate the Arthropod
Containment Guidelines and cross-reference to Appendix G-III-B.
Appendix L-III-C currently states:

Appendix L-III-C. Biological Containment Practices (Macroorganisms)

Appendix L-III-C-1. Effective dissemination of arthropods and other
small animals can be prevented by using one or more of the following
procedures: (i) use non-flying, flight-impaired, or sterile arthropods;
(ii) use non-motile or sterile strains of small animals; (iii) conduct
experiments at a time of year that precludes the survival of escaping
organisms; (iv) use animals that have an obligate association with a
plant that is not present within the dispersal range of the organism;
or (v) prevent the escape of organisms present in run-off water by
chemical treatment or evaporation of run-off water.
Appendix L-III-C is proposed to be amended to:

Appendix L-III-C. Biological Containment Practices (Macroorganisms)

Appendix L-III-C-1. Effective dissemination of arthropods and other
small animals can be prevented by using

[[Page 54340]]

one or more of the following procedures: (i) use non-flying, flight-
impaired, or sterile arthropods; (ii) use non-motile or sterile strains
of small animals; (iii) conduct experiments at a time of year that
precludes the survival of escaping organisms; (iv) use animals that
have an obligate association with a plant that is not present within
the dispersal range of the organism; or (v) prevent the escape of
organisms present in run-off water by chemical treatment or evaporation
of run-off water. Containment for arthropods is described in the
Arthropod Containment Guidelines and Addendum 1 Containment Practices
for Arthropods Modified with Engineered Transgenes Capable of Gene
Drive (see Appendix G-III-B).
Appendix M-III-D currently states:
Appendix M-III-D. Other research with non-laboratory animals, which
may not appropriately be conducted under conditions described in
Appendix M, may be conducted safely by applying practices routinely
used for controlled culture of these biota. In aquatic systems, for
example, BL1 equivalent conditions could be met by utilizing growth
tanks that provide adequate physical means to avoid the escape of the
aquatic species, its gametes, and introduced exogenous genetic
material. A mechanism shall be provided to ensure that neither the
organisms nor their gametes can escape into the supply or discharge
system of the rearing container (e.g., tank, aquarium, etc.) Acceptable
barriers include appropriate filtration, irradiation, heat treatment,
chemical treatment, etc. Moreover, the top of the rearing container
shall be covered to avoid escape of the organism and its gametes. In
the event of tank rupture, leakage, or overflow, the construction of
the room containing these tanks should prevent the organisms and
gametes from entering the building's drains before the organism and its
gametes have been inactivated.
Other types of non-laboratory animals (e.g., nematodes, arthropods,
and certain forms of smaller animals) may be accommodated by using the
appropriate BL1 through BL4 or BL1-P through BL4-P containment
practices and procedures as specified in Appendices G and L.
Appendix M-III-D is proposed to be amended to:
Appendix M-III-D. Research with animals, which may not
appropriately be conducted under conditions described in Appendix M,
may be conducted safely by applying practices routinely used for
controlled culture of these biota. In aquatic systems, for example, BL1
equivalent conditions could be met by utilizing growth tanks that
provide adequate physical means to avoid the escape of the aquatic
species, its gametes, and introduced exogenous genetic material. A
mechanism shall be provided to ensure that neither the organisms nor
their gametes can escape into the supply or discharge system of the
rearing container (e.g., tank, aquarium, etc.) Acceptable barriers
include appropriate filtration, irradiation, heat treatment, chemical
treatment, etc. Moreover, the top of the rearing container shall be
covered to avoid escape of the organism and its gametes. In the event
of tank rupture, leakage, or overflow, the construction of the room
containing these tanks should prevent the organisms and gametes from
entering the building's drains before the organism and its gametes have
been inactivated.
Other types of animals (e.g., nematodes, arthropods, and certain
forms of smaller animals) may be accommodated by using the appropriate
BL1 through BL4 or BL1-P through BL4-P containment practices and
procedures as specified in Appendices G and L. Containment for
arthropods is described in the Arthropod Containment Guidelines and
Addendum 1 Containment Practices for Arthropods Modified with
Engineered Transgenes Capable of Gene Drive (see Appendix G-III-B).
The term ``helper virus'' is used in multiple sections of the NIH
Guidelines to refer to the missing functions provided to a defective
virus. However, helper systems (e.g., transient transfection systems,
packaging cell lines, replicon systems, etc.) are more commonly used
than a helper virus. NIH OSP has interpreted the term ``helper virus''
to extend to the use of helper systems because they are also associated
with the risk of generation of replication competent virus. To clarify
the language in the NIH Guidelines, the term ``helper virus'' will be
replaced in Sections III-D-3, and III-E-1 with the term ``helper
systems''.
The risk group classification in Appendix B of two viruses, West
Nile virus and St. Louis encephalitis virus, are proposed to be changed
from RG3 to RG2 to be consistent with the risk assessment that is
articulated in the current edition of the BMBL.
Appendix B-III-D currently states in part:
Appendix B-III-D. Risk Group 3 (RG3)--Viruses and Prions.
Alphaviruses (Togaviruses)--Group A Arboviruses currently states in
part:
--St. Louis encephalitis virus.
Flaviviruses--Group B Arboviruses currently states in part:
--West Nile virus (WNV).
Appendix B-II-D is proposed to be amended to state:
Appendix B-II-D. Risk Group 2 (RG2)--Viruses.
Alphaviruses (Togaviruses)--Group A Arboviruses.
--St. Louis encephalitis virus.
Flaviviruses--Group B Arboviruses.
--West Nile virus (WNV).

Dated: August 3, 2023.
Tara A. Schwetz,
Acting Principal Deputy Director, National Institutes of Health.
[FR Doc. 2023-17178 Filed 8-9-23; 8:45 am]
BILLING CODE 4140-01-P

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