Final Action Under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines)
| Published date | 05 April 2024 |
| Record Number | 2024-07082 |
| Citation | 89 FR 24016 |
| Court | National Institutes Of Health |
| Section | Notices |
Federal Register, Volume 89 Issue 67 (Friday, April 5, 2024)
[Federal Register Volume 89, Number 67 (Friday, April 5, 2024)]
[Notices]
[Pages 24016-24022]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-07082]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
Final Action Under the NIH Guidelines for Research Involving
Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines)
AGENCY: National Institutes of Health, HHS.
ACTION: Notice.
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SUMMARY: This notice sets forth final changes to NIH Guidelines for
Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH
Guidelines) as initially outlined in a Federal Register notice issued
on August 10, 2023. Following solicitation of public comments, the NIH
is amending the NIH Guidelines to include specific considerations and
requirements for conducting research
[[Page 24017]]
involving gene drive modified organisms (GDMOs) in contained research
settings. NIH is updating the NIH Guidelines to clarify minimum
containment requirements, provide considerations for performing risk
assessments, and define additional institutional responsibilities
regarding Institutional Biosafety Committees (IBCs) and Biological
Safety Officers (BSOs).
DATES: Changes outlined in this notice will be implemented on September
30, 2024.
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 email at
[email protected].
SUPPLEMENTARY INFORMATION: In a Federal Register notice issued on
August 10, 2023 (88 FR 54332), NIH proposed a series of actions to the
NIH Guidelines for public comment. NIH is amending the NIH Guidelines
to ensure the continued responsible research involving GDMOs in
contained research settings. Specifically, the NIH Guidelines will be
amended to:
1. clarify minimum containment requirements for research involving
GDMOs;
2. provide considerations for risk assessment;
3. define additional institutional responsibilities for IBCs and
BSOs.
In addition to the amendments related to contained research
involving GDMOs, the NIH Guidelines will also be amended 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 BMBL.
The revisions apply to GDMO research in contained settings, which
is subject to the NIH Guidelines. These revisions are consistent with
the recommendations of the Novel and Exceptional Technology Research
Advisory Committee report, Gene Drives in Biomedical Research (NExTRAC
Report). NIH does not currently support research involving field
release of GDMOs and the NIH Guidelines pertain to contained research;
accordingly, no changes regarding potential field release are included
in this Notice. NIH is also revising the NIH Guidelines to harmonize
with the 6th edition of the Biosafety in Microbiological and Biomedical
Laboratories (BMBL) regarding the Risk Group (RG) categorization of
West Nile Virus (WNV) and Saint Louis Encephalitis Virus (SLEV).
Overview of Comments Received in Response to NIH's Proposal To Amend
the NIH Guidelines (88 FR 54332)
The NIH received 28 comments (available at https://osp.od.nih.gov/wp-content/uploads/2023/11/RFI_Nucleic_Final_508.pdf) submitted by
individuals from the general public, academic institutions, and
professional or membership organizations in response to the proposal to
amend the NIH Guidelines posted to the Federal Register on August 10,
2023. All comments were reviewed and considered by the NIH. Most
comments did not express general concerns with the proposed amendments,
but many included comments or questions on specific sections. These
comments, along with NIH responses, are summarized below.
Several of the comments requested additional guidance or resources
to accompany any changes. As a source of information in addition to
that in the NIH Guidelines, the NIH will provide a supplementary
reference document, Biosafety Considerations for Contained Research
Involving Gene Drive Modified Organisms, that institutions,
investigators, and the biosafety community can reference as they
consider conducting contained gene drive research. The reference
document is intended to organize the relevant sections of the NIH
Guidelines in an accessible format and to provide some additional
information and resources. It will be available on the NIH Office of
Science Policy (OSP) NIH Guidelines website, along with Frequently
Asked Questions.
Definition of ``gene drive'' in Section I-E-7. Several comments
requested additional clarification of the definition and that the
definition specify ``engineered'' gene drives to exclude natural gene
drives. Under the scope of NIH Guidelines, only contained research with
gene drives involving recombinant or synthetic nucleic acids would be
subject to the NIH Guidelines. The definition language is based on the
definition in the NExTRAC report, Gene Drives in Biomedical Research.
Other comments asked whether certain research with prokaryotes or
viruses could be considered to involve GDMOs. While gene drive
technologies are usually applied to sexually reproducing organisms, the
risk assessment section of the NIH Guidelines will include guidance on
the consideration of modifications with properties similar to a gene
drive. The supplementary reference document will include sources for
additional information on gene drive technologies and capabilities.
Section II-A-3 Risk Assessment. In response to comments seeking
additional risk assessment guidance, in particular regarding relevant
biosafety data, the reference document will include links to sources
with additional information including the NExTRAC report, the National
Academy of Sciences report, Gene Drives on the Horizon, and other
relevant literature sources.
Section III-D Containment
Regarding the requirement of a minimum of biosafety level 2 (BL2)
containment for work with GDMOs, several comments asked about
appropriate BL2 containment for specific species. Gene drive research
may be conducted in a broad range of species, and institutions may wish
to consult containment guidance tailored to the specific species or
type of organism utilized in a particular protocol. For work with
arthropods, the NIH Guidelines will be amended to reference the
Arthropod Containment Guidelines and Addendum 1 Containment Practices
for Arthropods Modified with Engineered Transgenes Capable of Gene
Drive. The reference document will include sources for additional
species. In particular, there were comments about Saccharomyces and
Kluyveromyces Host-Vector Systems. The amendments will only affect
research involving host vector systems modified by a gene drive and
does not pertain to other yeast research.
Other comments requested a process for handling requests to lower
containment levels for research involving GDMOs. As with requests to
lower containment for research involving infectious agents outlined in
Section IV-C-b-(2)-(a), OSP will consider containment lowering requests
for research involving GDMO on a case-by-case basis.
Section III-D and III-E. Comments were supportive of the
terminology shift from ``helper virus'' to ``helper system,'' but
several asked that the examples of helper systems that were included in
the Federal Register notice also be included in the NIH Guidelines. To
provide that information, the preamble to III-D-3 will state: ``The
potential for reversion or generation of replication competent virus
should be considered when generating or using defective viruses or
vectors in the presence of helper systems (e.g., helper viruses,
packaging cell lines, transient transfection systems, replicon
systems).''
[[Page 24018]]
Section III-E-3 Experiments Involving Transgenic Rodents
Several comments asked whether NIH was proposing to expand Section
III-E-3 to include the use of transgenic rodents. There are two
instances where transgenic rodents are specifically exempted from the
NIH Guidelines. Appendix C-VII exempts the purchase or transfer of
transgenic rodents and Appendix C-VIII exempts the generation of BL1
rodents by breeding. The use of exempt rodents remains exempt unless
the subsequent research involves the use of recombinant or synthetic
nucleic acid molecules. The language added to III-E-3 is not an
expansion to include the use of de novo generated rodents covered under
that section. Rodents covered under III-E-3 are not exempt and, as
such, their subsequent use is not exempt. The inclusion of the language
referring to the use of such rodents is intended to clarify that their
subsequent use is not exempt.
Section IV Roles and Responsibilities and V-N. Several comments
asked for clarification regarding the requirement for adequate
expertise on IBCs reviewing GDMO research including consideration of
ecological impacts. Consistent with expectations in the NIH Guidelines
for the review of research with plants, animals, or human research
participants, appropriate expertise regarding ecological impacts may be
provided by members of the IBC or ad hoc consultants. An ad hoc
consultant with expertise in ecological impacts would only be needed
for review of specific GDMO research and, if an institution has
multiple IBCs, would only be required to serve on the specific IBC
reviewing such research. An ad hoc consultant may be from a partner or
unrelated institution and does not need to be local to the institution.
Several comments addressed the additional requirement for a
biological safety officer (BSO) to be appointed if research involving
GDMOs is to be conducted. Some commenters interpreted this language to
mean that a BSO must be appointed if the institution engages in any BL2
research. To clarify, a BSO must be appointed if the institution
engages in recombinant or synthetic nucleic acid molecule research that
involves GDMOs. Section IV-B-1-c will be revised to clarify this
requirement. Others commented on the qualifications of a BSO and the
reference to the Laboratory Safety Monograph. The duties of a BSO are
specifically outlined in Section IV-B-3 of the NIH Guidelines.
Appendix B Classification of Human Etiologic Agents on the Basis of
Hazard. All comments regarding this proposed change supported the
reclassification of West Nile Virus and Saint Louis Encephalitis virus
(SLEV) as risk group 2 agents to harmonize with guidance provided by
the BMBL. One comment noted that SLEV was improperly classified as an
alphavirus. Appendix B will be amended to classify SLEV as a
flavivirus. As minor actions under the NIH Guidelines, Appendix B-IV-D
Risk Group 4 Viral Agents will be amended from ``Hemorrhagic fever
agents and viruses as yet undefined'' to ``Hemorrhagic fever viruses as
yet undefined'' to prevent possible misinterpretation that all
undefined viruses require RG4 containment, and the listing of Ebola and
Marburg virus will be pluralized to harmonize with recent changes in
taxonomy nomenclature to cover multiple viruses. The amendment to
``Ebola viruses'' and ``Marburg viruses'' will clarify that the virus
name applies to the multiple species.
Amendments to the NIH Guidelines
Section I-E will be amended as follows:
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 will be amended as follows:
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 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
[[Page 24019]]
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.
A portion of Section III-C-1 will be amended as follows:
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
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 will be amended as follows:
Section III-F-1 Exempt Experiments
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.
Section III-D-4 will be amended as follows:
Section III-D-4. Experiments Involving Whole Animals
This section covers experiments involving deliberate transfer of
recombinant or synthetic nucleic acid 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
[[Page 24020]]
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.
A portion of Section III-D-5 will be amended as follows:
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 will be added as follows:
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.
A portion of Section III-E-3 will be amended as follows:
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.
Section IV-B-1-c will be amended as follows:
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 any research involving gene
drive modified organisms, which all must be conducted at BL2 or higher
containment. The Biological Safety Officer carries out the duties
specified in Section IV-B-3.
Section IV-B-2-a-(1) will be amended as follows:
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
[[Page 24021]]
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), will be amended as below in Section IV-B-3-a along with the
addition of a new Section IV-B-3-c and re-lettering of the current
Section IV-B-3-c to IV-B-3-d as follows:
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.
A new footnote and reference for Sections I through IV will be to
be added as follows:
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, and of the environment, and ecosystems in the geographic
area of the research.
Appendices C-III-A Exceptions and C-IV-A Exceptions will be amended
as follows:
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).
Appendix G-III-A will be amended as follows:
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 will be amended as follows:
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.
Appendix L-III-C will be amended as follows:
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. 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 will be amended as follows:
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).
Section III-D-3 will be amended as follows:
[[Page 24022]]
Section III-D-3. Experiments Involving the Use of Infectious DNA or RNA
Viruses or Defective DNA or RNA Viruses in the Presence of a Helper
System in Tissue Culture Systems
Caution: The potential for reversion or generation of replication
competent virus should be considered when generating or using defective
viruses or vectors in the presence of helper systems (e.g., helper
viruses, packaging cell lines, transient transfection systems, replicon
systems). Special care should be used in the evaluation of containment
levels for experiments which are likely to either enhance the
pathogenicity (e.g., insertion of a host oncogene) or to extend the
host range (e.g., introduction of novel control elements) of viral
vectors under conditions that permit a productive infection. In such
cases, serious consideration should be given to increasing physical
containment by at least one level.
Note: Recombinant or synthetic nucleic acid molecules or nucleic
acid molecules derived therefrom, which contain less than two-thirds of
the genome of any eukaryotic virus (all viruses from a single Family
(see Section V-J, Footnotes and References of Sections I-IV) being
considered identical (see Section V-K, Footnotes and References of
Sections I-IV)), are considered defective and may be used in the
absence of helper systems under the conditions specified in Section
III-E-1, Experiments Involving the Formation of Recombinant or
Synthetic Molecules Containing No More than Two-Thirds of the Genome of
any Eukaryotic Virus.
Section III-D-3-a. Experiments involving the use of infectious or
defective Risk Group 2 viruses (see Appendix B-II, Risk Group 2 Agents)
in the presence of a helper system may be conducted at BL2.
Section III-D-3-b. Experiments involving the use of infectious or
defective Risk Group 3 viruses (see Appendix B-III-D, Risk Group 3
(RG3)--Viruses and Prions) in the presence of a helper system may be
conducted at BL3.
Section III-D-3-c. Experiments involving the use of infectious or
defective Risk Group 4 viruses (see Appendix B-IV-D, Risk Group 4
(RG4)--Viral Agents) in the presence of a helper system may be
conducted at BL4.
Section III-D-3-d. Experiments involving the use of infectious or
defective restricted poxviruses (see Sections V-A and V-L, Footnotes
and References of Sections I-IV) in the presence of a helper system
shall be determined on a case-by-case basis following NIH OSP review. 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-3-e. Experiments involving the use of infectious or
defective viruses in the presence of a helper system which are not
covered in Sections III-D-3-a through III-D-3-d may be conducted at
BL1.
Section III-E-1 will be amended as follows:
Section III-E-1. Experiments Involving the Formation of Recombinant or
Synthetic Nucleic Acid Molecules Containing No More Than Two-Thirds of
the Genome of Any Eukaryotic Virus
Recombinant or synthetic nucleic acid molecules containing no more
than two-thirds of the genome of any eukaryotic virus (all viruses from
a single Family being considered identical [see Section V-J, Footnotes
and References of Sections I-IV]) may be propagated and maintained in
cells in tissue culture using BL1 containment. For such experiments, it
must be demonstrated that the cells lack a helper system for the
specific Families of defective viruses being used. If a helper system
is present, procedures specified under Section III-D-3, Experiments
Involving the Use of Infectious Animal or Plant DNA or RNA Viruses or
Defective Animal or Plant DNA or RNA Viruses in the Presence of Helper
Systems in Tissue Culture Systems, should be used. The DNA may contain
fragments of the genome of viruses from more than one Family but each
fragment shall be less than two-thirds of a genome.
Appendix B-II-D will be amended as follows:
Appendix B-II-D. Risk Group 2 (RG2)--Viruses
Flaviviruses--Group B Arboviruses
--Saint Louis Encephalitis Virus (SLEV)
--West Nile virus (WNV)
Appendix B-IV-D Risk Group 4 (RG4)--Viruses
Filoviruses
--Ebola viruses
--Marburg viruses
Hemorrhagic fever viruses as yet undefined
Dated: March 25, 2024.
Lawrence A. Tabak,
Principal Deputy Director, National Institutes of Health.
[FR Doc. 2024-07082 Filed 4-4-24; 8:45 am]
BILLING CODE 4140-01-P
