Final Action Under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines), 24016-24022 [2024-07082]

Agencies

• DEPARTMENT OF HEALTH AND HUMAN SERVICES
• National Institutes of Health

[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).''

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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

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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

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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

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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