Final Action Under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines), 17858-17866 [2019-08462]

Agencies

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

[Federal Register Volume 84, Number 81 (Friday, April 26, 2019)]
[Notices]
[Pages 17858-17866]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-08462]


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

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 of changes to the NIH Guidelines.

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

SUMMARY: This notice sets forth final changes to the NIH Guidelines for 
Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH 
Guidelines) to streamline oversight for human gene transfer clinical 
research protocols and reduce duplicative reporting requirements 
already captured within the existing regulatory framework, as initially 
outlined by the NIH Office of Science Policy (OSP) in a Federal 
Register notice issued on August 17, 2018. Following the solicitation 
of public comment on its original proposal, the NIH is amending the NIH 
Guidelines to: (A) Delete the NIH protocol registration submission and 
reporting requirements under Appendix M of the NIH Guidelines, and (B) 
modify the roles and responsibilities of entities that involve human 
gene transfer and the Recombinant DNA Advisory Committee (RAC).

DATES: Changes outlined in this notice will be effective upon 
publication in the Federal Register.

FOR FURTHER INFORMATION CONTACT: If you have questions, or require 
additional background information about these changes, please contact 
the NIH by email at [email protected], or telephone at 301-496-
9838. You may also contact Jessica Tucker, Ph.D., Director of the 
Division of Biosafety, Biosecurity, and Emerging Biotechnology Policy, 
Office of Science Policy, NIH, at 301-451-4431 or 
[email protected].

SUPPLEMENTARY INFORMATION: In a Federal Register notice issued on 
August 17, 2018 (83 FR 41082), the NIH proposed a series of actions to 
the NIH Guidelines for Research Involving Recombinant or Synthetic 
Nucleic Acid Molecules (NIH Guidelines) to streamline oversight of 
human gene transfer research (HGT), and to focus the NIH Guidelines 
more specifically on biosafety issues associated with research 
involving recombinant or synthetic nucleic acid molecules. The field of 
HGT has recently experienced a series of advances that has resulted in 
the translation of research into clinical practice, including Food and 
Drug Administration (FDA) approvals for licensed products. 
Additionally, oversight mechanisms for ensuring HGT is appropriately 
assessed for safety risks have sufficiently evolved to keep pace with 
new discoveries in this field. At this time, there is duplication in 
submitting protocols, annual reports, amendments, and serious adverse 
events for HGT protocols to both the NIH and the FDA that does not 
exist for other areas of clinical research. It is an opportune time to 
make changes to the NIH Guidelines to make oversight of HGT 
commensurate with oversight afforded to other areas of clinical 
research, given the robust infrastructure in place to oversee this type 
of research.
    After careful consideration of public comments, the NIH is amending 
the NIH Guidelines in the following areas:
    1. Elimination of HGT protocol submission and reporting 
requirements to the NIH, and individual HGT protocol review by the 
Recombinant DNA Advisory Committee (RAC).
    2. Modification of roles and responsibilities of investigators, 
institutions, Institutional Biosafety Committees (IBCs), the RAC, and 
the NIH to be consistent with these goals including:
    a. Modification of roles of IBCs in reviewing HGT to be consistent 
with review of other covered research.
    b. Elimination of roles of the RAC in HGT and biosafety.
    The proposed changes outlined above will require amendment of 
multiple portions of the NIH Guidelines (see section below on 
``Amendments to the NIH Guidelines''). Following deletions, sections 
and appendices will be relabeled to proceed consecutively throughout 
the NIH Guidelines. Language in the ``Amendments to the NIH 
Guidelines'' section below includes updated references to relabeled 
section and appendix names, where relevant. Sections of the NIH 
Guidelines also will be amended to include several minor additional 
changes to provide non-substantive clarifications or for consistency.

Overview of Comments Received in Response to NIH's Proposal To Amend 
the NIH Guidelines (83 FR 41082)

    The NIH received 43 comments (available at https://osp.od.nih.gov/wp-content/uploads/Aug162018_AllComments_r508.pdf) in response to its 
proposal to amend the NIH Guidelines, posted in the Federal Register on 
August 17, 2018, including from individuals from the general public, 
academic institutions, and industry; and professional or membership 
organizations representing the biosafety, gene therapy, biotechnology, 
patient advocacy, academic, medical, and Institutional Review Board 
(IRB) communities. Few comments received in response to the Federal 
Register notice (83 FR 41082) (hereafter referred to as the August 17, 
2018 FRN) reflected views entirely supportive of or in opposition to 
the proposal, but instead indicated support

[[Page 17859]]

or criticism for specific components. A minority of comments indicated 
that the existing system for review and reporting of individual 
protocols and IBC review should remain, as is. All comments, regardless 
of position, were reviewed and considered by the NIH. These comments, 
along with the NIH responses, are summarized below.
    Elimination of submission and reporting requirements to the NIH. In 
general, the majority of favorable comments supported eliminating HGT 
protocol submission and safety reporting requirements to the NIH's 
Office of Science Policy (NIH/OSP) and streamlining HGT oversight to 
eliminate overlapping reporting requirements, though a smaller number 
of comments did not support this proposed change. Some respondents 
indicated that reporting of HGT protocols to both the FDA, which has 
regulatory jurisdiction, and the NIH is no longer necessary. After 
careful analyses of these comments, the NIH will implement the changes 
to protocol submission and reporting requirements as outlined in the 
August 17, 2018 FRN. Related to this issue, some comments indicated an 
interest in maintaining the Genetic Modification Clinical Research 
Information System (GeMCRIS) or ensuring vector information gets added 
to ClinicalTrials.gov to provide IBCs with a resource for use during 
their reviews. Of note, the operation of GeMCRIS and its maintenance 
are not specified in the NIH Guidelines; because NIH/OSP will no longer 
receive HGT protocols and associated reports, GeMCRIS will no longer be 
updated. The NIH will continue to consider appropriate mechanisms to 
facilitate information-sharing, and ClinicalTrials.gov provides some 
useful data for those in the HGT community. The NIH notes that the 
level of detailed information that is currently housed in GeMCRIS is 
not standard for other clinical research, or other non-clinical 
research subject to the NIH Guidelines.
    IBC Roles and Responsibilities. Most comments received from 
individuals self-identifying as members of the biosafety community were 
supportive of continued review and oversight of HGT by IBCs. However, 
many comments noted concerns about the appropriate roles and 
responsibilities for IBCs, especially in the area of HGT oversight, in 
light of these proposed changes. In general, the NIH agrees that 
further consideration of the roles and responsibilities of IBCs in the 
assessment of biosafety issues associated with HGT is warranted, and 
the NIH anticipates exploring these issues with the community in more 
detail. However, the NIH notes that biosafety oversight of HGT 
protocols has always been the responsibility of IBCs, and they should 
continue to serve that function. Local oversight is an important 
component of the NIH Guidelines, and IBCs are expected to continue to 
have the necessary expertise and processes in place to consider 
biosafety issues associated with HGT protocols, as they do for other 
research covered under the NIH Guidelines. Upon assessment of the 
comments, the NIH will implement the changes outlined in the August 17, 
2018 FRN regarding IBC roles and responsibilities with two exceptions 
noted below. Specific sub-topics raised in comments received included 
the duration of IBC oversight, IBC responsibilities and documents to 
review, and the scope of biosafety review for HGT protocols.
    Several comments requested additional clarity from the NIH 
regarding the expected duration of IBC oversight and whether this 
oversight should extend beyond the proposed final administration of 
product. Specifically, some comments questioned whether oversight 
should be extended until it is reasonable to expect that the vector 
will no longer be shed, until there is no product at the site of the 
study, until the trial is no longer enrolling, or throughout handling 
of biospecimens taken from individuals after the final dose. The NIH 
acknowledges these issues and notes that biosafety issues that extend 
beyond product administration should be considered by IBCs during 
review, but any such risks should generally be addressed and managed by 
IBCs prior to administration (e.g., establishing monitoring plans for 
shedding). Additionally, the NIH Guidelines set a baseline for IBC 
oversight requirements, and institutions regularly choose to expand 
this scope based upon research oversight needs; for example, many IBCs 
extend oversight to all pathogen research, regardless of whether this 
research is recombinant or synthetic in origin. As such, institutions 
and IBCs may always choose to expand the purview of their oversight as 
needed to maintain appropriate oversight over biosafety issues. The NIH 
Guidelines will be amended in Section IV-B-2-b-(1) to clarify that 
oversight may conclude after the final administration of product to the 
final research participant, but institutions and IBCs are permitted to 
identify an end point for the conclusion of oversight that extends 
after the final administration of the product to the final research 
participant.
    Many comments requested additional guidance on what documents IBCs 
should review regarding HGT protocols; a majority of these comments 
were received from individuals self-identifying as associated with 
research institutions or biosafety professionals. Specific 
recommendations included retaining Appendix M-1-A in the NIH Guidelines 
or, as a resource, providing a checklist of documents or developing 
another guidance document. The NIH Guidelines, in general, are intended 
to provide sufficient clarity, but also sufficient flexibility, to all 
institutions to establish policies that accommodate local needs while 
adhering to the principles and expectations detailed in the policy. For 
both basic research and HGT, institutions should establish policies to 
ensure that documentation is sufficient for oversight bodies, including 
IBCs, to conduct review and approval. Because NIH/OSP sometimes issues 
guidance or points to consider on specific topics relevant to the NIH 
Guidelines when requested by the community, NIH/OSP will make available 
the parts of Appendix M-1-A that are still relevant, in light of the 
final changes to the NIH Guidelines, as a separate resource for 
institutions, IBCs, and investigators on the types of information that 
institutions and IBCs may wish to consider in the review of HGT 
protocols.
    Similarly, many comments requested more guidance on what IBCs 
should consider when reviewing HGT protocols for biosafety 
considerations. A small number of respondents suggested that the 
biosafety review of HGT protocols is no longer needed, is very low 
risk, or reflects substantial burden without a commensurate benefit. 
Others indicated that reporting of adverse events to IBCs and IBC 
review of informed consent documents should be required to enable IBCs 
to conduct sufficient biosafety reviews. A few comments indicated the 
proposed changes will more clearly delineate the roles of IBCs and IRBs 
and supported the notion that review of informed consent documents or 
adverse events should not be a responsibility of IBCs but is instead 
the purview of IRBs. Others expressed confusion about whether reporting 
biosafety incidents to NIH/OSP would be affected by the proposed 
amendments to the NIH Guidelines. The proposed changes ensure that the 
scope and responsibilities of IBCs reviewing HGT protocols are 
consistent with their responsibilities for other research covered by 
the NIH Guidelines. As noted previously, institutions may expand the 
scope of IBC review of

[[Page 17860]]

protocols and safety reports beyond that outlined by the NIH 
Guidelines, but in general, review of adverse events and informed 
consent documents is the purview of other oversight entities. The 
topics for IBC biosafety review for HGT protocols are articulated in 
Section IV-B-2-b-(1). No changes were proposed regarding the reporting 
of biosafety incidents to NIH/OSP for HGT protocols, and this reporting 
will continue to be required under the NIH Guidelines as articulated in 
Sections IV-B-1-j, IV-B-2-b-(7), and IV-B-7-a-(3).
    Some comments indicated that the proposal to eliminate certain 
protocols conducted under individual patient expanded access 
investigational new drug applications (INDs) as research subject to the 
NIH Guidelines is not justifiable from a biosafety perspective, since 
the biohazard risks are not different from those under a conventional 
human gene therapy IND. This change was proposed to harmonize the NIH 
Guidelines with current FDA policies, which do not require review by 
the full IRB membership of physician-sponsored individual patient 
expanded access INDs. Some modifications to the original proposed 
language will be made to ensure greater consistency with existing FDA 
guidance. Specific guidance regarding FDA requirements is provided at 
https://www.fda.gov/downloads/drugs/guidances/ucm351261.pdf. Section 
III-C-1 will be amended to clearly state that any deliberate transfer 
of recombinant or synthetic nucleic acids into one human participant, 
when conducted under an FDA-regulated individual patient expanded 
access IND or protocol, including for emergency use, is not research 
subject to the NIH Guidelines.
    Elimination of RAC's Roles in HGT Protocol Review and Biosafety 
Oversight from the NIH Guidelines, and Future of the RAC. A topic that 
generated many comments concerned the proposed changes to the role of 
the RAC as specified in the NIH Guidelines. Some comments indicated 
support for eliminating RAC review of individual HGT protocols and 
focusing the committee's attention on a broader scope of emerging 
biotechnologies, whether or not such research involves recombinant or 
synthetic nucleic acid molecules, because IBCs can adequately perform 
their HGT oversight independently and the FDA has regulatory authority. 
Upon assessment of the comments, the NIH will implement the changes 
outlined in the August 17, 2018 FRN regarding RAC roles with two 
additions noted below. Specific sub-topics raised in comments received 
included removal of references to the role of the RAC from the NIH 
Guidelines, the need for a transparent forum for discussion on various 
scientific, ethical, legal and social issues related to emerging 
biotechnologies, the loss of the RAC as a biosafety guidance resource 
for IBCs, potential future roles of the RAC, and which entities should 
perform current roles of the RAC.
    Some respondents indicated that the biosafety roles of the RAC in 
the NIH Guidelines should remain, with some suggesting that the 
articulation of RAC functions in the NIH Guidelines protects the 
committee's core functions more than a committee charter. The NIH notes 
that, in general, functions of discretionary Federal Advisory Committee 
Act (FACA) committees, such as the RAC, are routinely articulated in 
their charters rather than in policy documents. The NIH is committed to 
transitioning the RAC in ways that preserve its current forum for 
public discourse and advice to the NIH Director on the emerging 
biotechnology issues of today and the future. The NIH will release the 
revised charter of the committee, which will be renamed the Novel and 
Exceptional Technology and Research Advisory Committee (NExTRAC), to 
reflect the shift in focus of the committee while embracing the 
continuity of this important advisory board. Some historical references 
to the RAC will remain in the NIH Guidelines.
    Some comments, particularly those from individuals self-identifying 
as members of the ethics and oversight communities, indicated the 
importance of a transparent forum for discourse and advice regarding 
HGT, Major Actions, biosafety issues, and any changes needed to the NIH 
Guidelines. Some respondents argued that there are still unknown 
aspects of HGT, especially given the advent of genome editing 
technologies, and that the existing system of oversight and other 
relevant mechanisms (i.e., the FDA, IRBs, and ClinicalTrials.gov) do 
not replace the RAC's functions and mission of transparency. 
Additionally, one commenter suggested that although few individual 
protocols have been publicly reviewed since the 2016 amendments to the 
NIH Guidelines, the RAC members may have chosen to review more 
protocols had they been given the opportunity. While no longer 
specified as responsibilities in the NIH Guidelines, the NIH will 
continue to consult, as needed, with the NExTRAC or other relevant 
advisory committees regarding issues of emerging biotechnologies, 
biosafety, or when proposing changes to the NIH Guidelines or other 
relevant policies. The NIH consistently seeks out diverse input, 
including expert opinions, when considering changes to existing 
policies, and transparent and open discourse is a critical part of the 
policy-making process, whether through requests for public comment, 
workshops, or charges to advisory committees. Integral to the NIH 
mission is to exemplify and promote the highest level of scientific 
integrity, public accountability, and social responsibility in the 
conduct of science, and the NIH has and will continue to rely on 
mechanisms that allow for advice and public discourse, including review 
and discussion by FACA committees, when appropriate.
    Several comments indicated that the public discussion of HGT 
protocols by the RAC provided guidance to IBCs in conducting biosafety 
reviews of these protocols. A few comments indicated that IBCs do not 
have the necessary expertise to conduct biosafety reviews for clinical 
protocols and therefore rely on the RAC. Some commenters requested that 
IBCs should retain flexibility to request RAC review for certain 
individual HGT protocols, especially those involving pediatric 
populations. Alternatively, other respondents suggested that the NIH 
should establish a panel of HGT experts to provide guidance, upon 
request. While the NIH is sensitive to these concerns and acknowledges 
that risks are always present in clinical research, the NIH argues that 
there is not sufficient evidence to justify the unique oversight 
afforded to this area of research. The NIH maintains, however, that the 
NExTRAC will continue to serve as a forum for public discourse and 
discussions on emerging biotechnology issues, which may include--but is 
not limited to--emerging trends in HGT, rather than the discussion of 
individual HGT protocols. Furthermore, the NIH emphasizes that all HGT 
protocols, regardless of whether RAC review was performed, were and are 
to be reviewed by IBCs. To assert that this function cannot be 
performed in the absence of RAC review undermines the authority of the 
IBC and the underlying rationale for establishing the oversight 
infrastructure. IBCs are expected to include and, as needed, supplement 
their discussions with ad hoc expertise for the local biosafety review 
of all protocols under their purview, including HGT protocols. For 
Major Actions and other biosafety issues of significance, the NIH will 
continue to, as needed, consult with subject matter experts and, if 
necessary, provide a forum for public discussion to facilitate the 
review and approval process.

[[Page 17861]]

    Several comments suggested support for the NIH's intent to continue 
to utilize the RAC as an emerging biotechnology committee but requested 
more information about these plans. Similarly, some comments requested 
that the NIH identify a point of contact to assist in navigating 
questions that previously would have been considered by the RAC. 
Regarding the future of the RAC, as noted, the NIH will issue a revised 
charter and intends to use the NExTRAC as a board for public discussion 
and advice on the scientific, safety, ethical, legal, and social issues 
associated with emerging biotechnologies. NIH/OSP continues to serve as 
a resource for guidance, which it provides to investigators, 
institutions, biosafety professionals, and members of the public on a 
daily basis. Questions regarding the NIH Guidelines should continue to 
be directed to [email protected].
    Two references to the RAC that also should have been proposed for 
elimination from the NIH Guidelines were not included in amendments 
proposed in the August 17, 2018 FRN. These references will be included 
for elimination in the final changes; otherwise, all changes outlined 
in the August 17, 2018 FRN regarding the RAC will be implemented.
    Other Topics Outside of this Policy Proposal. Some comments 
requested additional guidance in the NIH Guidelines on specific areas 
of emerging technology, including CRISPR/Cas9 genome editing and T cell 
immunotherapy, perhaps by utilizing a task force to provide such 
guidance. Additionally, a few comments requested further assessment of 
mature areas of technology to determine if they should still be subject 
to the NIH Guidelines. A small number of comments requested further 
guidance regarding in utero gene therapy. These types of amendments 
were not the purview of this policy change, but the NIH is undertaking 
a long-term effort to consider further updates to the NIH Guidelines, 
building upon the July 2017 workshop, NIH Guidelines: Honoring the 
Past, Charting the Future. The NIH will continue to solicit input and 
facilitate transparent discourse to consider these and similar issues.
    Other comments outside the purview of this proposed policy change, 
but which may be addressed in future efforts, were related to requested 
modifications of the IBC review and approval process, including 
allowing expedited review, eliminating the requirement for IBC review 
at sites lacking IBCs, and greater guidance for coordination between 
various oversight committees (e.g., IBCs, IRBs, and Institutional 
Animal Care and Use Committees) or coordination on multisite trials. As 
noted previously, the NIH is committed to considering the appropriate 
roles of IBCs in biosafety review of clinical research and will 
continue to consider these issues.

Amendments to the NIH Guidelines

    Section I-A will be amended as follows:

Section I-A. Purpose

    The purpose of the NIH Guidelines is to specify the biosafety 
practices and containment principles for constructing and handling: (i) 
Recombinant nucleic acid molecules, (ii) synthetic nucleic acid 
molecules, including those that are chemically or otherwise modified 
but can base pair with naturally occurring nucleic acid molecules, and 
(iii) cells, organisms, and viruses containing such molecules.
    Section I-A-1 will be amended as follows:
    Section I-A-1. Any nucleic acid molecule experiment, which 
according to the NIH Guidelines requires approval by NIH, must be 
submitted to NIH or to another Federal agency that has jurisdiction for 
review and approval. Once approvals, or other applicable clearances, 
have been obtained from a Federal agency other than NIH (whether the 
experiment is referred to that agency by NIH or sent directly there by 
the submitter), the experiment may proceed without the necessity for 
NIH review or approval.
    Section I-A-1-a will be amended as follows:
    Section I-A-1-a. For 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 
human research participants (human gene transfer), no human gene 
transfer experiment shall be initiated (see definition of initiation in 
Section I-E-4) until Institutional Biosafety Committee (IBC) approval 
(from the clinical trial site) has been obtained and all other 
applicable institutional and regulatory authorization(s) and approvals 
have been obtained.
    Section I-E. General Definitions will be amended to delete the 
current definitions I-E-4, and I-E-7 through I-E-12 and to include a 
new definition for ``initiation.''
    Section I-E-4 will be amended to define initiation as follows: 
``Initiation'' of research is the introduction of recombinant or 
synthetic nucleic acid molecules into organisms, cells, or viruses.
    None of the other sub-sections under Section I. Scope of the NIH 
Guidelines will be amended.
    Section III will be amended as follows:

Section III. Experiments Covered by the NIH Guidelines

    This section describes six categories of experiments involving 
recombinant or synthetic nucleic acid molecules: (i) Those that require 
NIH Director approval and Institutional Biosafety Committee (IBC) 
approval before initiation (see Section III-A), (ii) those that require 
NIH OSP approval and Institutional Biosafety Committee approval before 
initiation (see Section III-B), (iii) those that require Institutional 
Biosafety Committee approval before initiation of human gene transfer 
(see Section III-C), (iv) those that require Institutional Biosafety 
Committee approval before initiation (see Section III-D), (v) those 
that require Institutional Biosafety Committee notification 
simultaneous with initiation (see Section III-E), and (vi) those that 
are exempt from the NIH Guidelines (see Section III-F).

    Note: If an experiment falls into Sections III-A, III-B, or III-
C and one of the other sections, the rules pertaining to Sections 
III-A, III-B, or III-C shall be followed. If an experiment falls 
into Section III-F and into either Sections III-D or III-E as well, 
the experiment is considered exempt from the NIH Guidelines.

    Any change in containment level, which is different from that which 
is specified in the NIH Guidelines, may not be initiated without the 
express approval of NIH OSP (see Section IV-C-1-b-(2) and its 
subsections, Minor Actions).
    Section III-A will be amended as follows:

Section III-A. Experiments That Require NIH Director Approval and 
Institutional Biosafety Committee Approval Before Initiation (See 
Section IV-C-1-b-(1), Major Actions)

Section III-A-1. Major Actions Under the NIH Guidelines

    Experiments considered as Major Actions as defined in Section III-
A-1-a under the NIH Guidelines cannot be initiated without submission 
of relevant information on the proposed experiment to the Office of 
Science Policy, National Institutes of Health, preferably by email to: 
[email protected], the publication of the proposal in the 
Federal Register for a minimum of 15 days of comment, and notice of 
specific approval by NIH. The containment

[[Page 17862]]

conditions or stipulation requirements for such experiments will be set 
by NIH at the time of approval. Such experiments require Institutional 
Biosafety Committee approval before initiation. Specific experiments 
already approved are included in Appendix D, Major Actions Taken under 
the NIH Guidelines.
    Section III-A-1-a. The deliberate transfer of a drug resistance 
trait to microorganisms that are not known to acquire the trait 
naturally (see Section V-B, Footnotes and References of Sections I-IV), 
if such acquisition could compromise the ability to control disease 
agents in humans, veterinary medicine, or agriculture, will require NIH 
Director approval.
    Consideration should be given as to whether the drug resistance 
trait to be used in the experiment would render that microorganism 
resistant to the primary drug available to and/or indicated for certain 
populations, for example children or pregnant women.
    At the request of an Institutional Biosafety Committee, NIH OSP 
will make a determination regarding whether a specific experiment 
involving the deliberate transfer of a drug resistance trait falls 
under Section III-A-1-a and therefore requires NIH Director approval. 
An Institutional Biosafety Committee may also consult with NIH OSP 
regarding experiments that do not meet the requirements of Section III-
A-1-a but nonetheless raise important public health issues.
    Section III-C will be amended as follows:

Section III-C. Experiments Involving Human Gene Transfer That Require 
Institutional Biosafety Committee Approval Prior to Initiation

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 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.
    Research cannot be initiated until Institutional Biosafety 
Committee and all other applicable institutional and regulatory 
authorization(s) and approvals have been obtained.
    The deliberate transfer of recombinant or synthetic nucleic acids 
into one human research participant, conducted under an FDA-regulated 
individual patient expanded access IND or protocol, including for 
emergency use, is not research subject to the NIH Guidelines and thus 
does not need to be submitted to an IBC for review and approval.
    Section III-D-7-b will be amended as follows:
    Section III-D-7-b. Highly Pathogenic Avian Influenza H5N1 strains 
within the Goose/Guangdong/96-like H5 lineage (HPAI H5N1). Experiments 
involving influenza viruses containing a majority of genes and/or 
segments from a HPAI H5N1 influenza virus shall be conducted at BL3 
enhanced containment, (see Appendix G-II-C-5, Biosafety Level 3 
Enhanced for Research Involving Risk Group 3 Influenza Viruses). 
Experiments involving influenza viruses containing a minority of genes 
and/or segments from a HPAI H5N1 influenza virus shall be conducted at 
BL3 enhanced unless a risk assessment performed by the IBC determines 
that they can be conducted safely at BL2 and after they have been 
excluded pursuant to 9 CFR 121.3(e). NIH OSP is available to IBCs to 
provide consultation with influenza virus experts when risk assessments 
are being made to determine the appropriate biocontainment for 
experiments with influenza viruses containing a minority of gene/
segments from HPAI H5N1. Such experiments may be performed at BL3 
enhanced containment or containment may be lowered to BL2, the level of 
containment for most research with other influenza viruses. (USDA/APHIS 
regulations and decisions on lowering containment also apply.) In 
deciding to lower containment, the IBC should consider whether, in at 
least two animal models (e.g., ferret, mouse, Syrian golden hamster, 
cotton rat, non-human primate), there is evidence that the resulting 
influenza virus shows reduced replication and virulence compared to the 
parental RG3 virus at relevant doses. This should be determined by 
measuring biological indices appropriate for the specific animal model 
(e.g., severe weight loss, elevated temperature, mortality or 
neurological symptoms).
    Section III-D-7-d will be amended as follows:
    Section III-D-7-d. Antiviral Susceptibility and Containment. The 
availability of antiviral drugs as preventive and therapeutic measures 
is an important safeguard for experiments with 1918 H1N1, HPAI H5N1, 
and human H2N2 (1957-1968). If an influenza virus containing genes from 
one of these viruses is resistant to both classes of current antiviral 
agents, adamantanes and neuraminidase inhibitors, higher containment 
may be required based on the risk assessment considering 
transmissibility to humans, virulence, pandemic potential, alternative 
antiviral agents if available, etc.
    Experiments with 1918 H1N1, human H2N2 (1957-1968) or HPAI H5N1 
that are designed to create resistance to neuraminidase inhibitors or 
other effective antiviral agents (including investigational antiviral 
agents being developed for influenza) would be subject to Section III-
A-1 (Major Actions). As per Section I-A-1 of the NIH Guidelines, if the 
agent is a Select Agent, the NIH will defer to the appropriate Federal 
agency (HHS or USDA Select Agent Divisions) on such experiments.
    Section III-F-6 will be amended as follows:
    Section III-F-6. Those that consist entirely of DNA segments from 
different species that exchange DNA by known physiological processes, 
though one or more of the segments may be a synthetic equivalent. A 
list of such exchangers will be prepared and periodically revised by 
the NIH Director after appropriate notice and opportunity for public 
comment (see Section IV-C-1-b-(1)-(c), Major Actions). See Appendices 
A-I through A-VI, Exemptions under Section III-F-6--Sublists of Natural 
Exchangers, for a list of natural exchangers that are exempt from the 
NIH Guidelines.
    Section III-F-8 will be amended as follows:
    Section III-F-8. Those that do not present a significant risk to 
health or the environment (see Section IV-C-1-b-(1)-(c), Major 
Actions), as determined by the NIH Director following appropriate 
notice and opportunity for public comment. See Appendix C, Exemptions 
under Section III-F-8 for other classes of experiments which are exempt 
from the NIH Guidelines.
    None of the other sub-sections under Section III. Experiments 
Covered by the NIH Guidelines will be amended.
    Section IV-B-1-f will be amended as follows:

[[Page 17863]]

    Section IV-B-1-f. Ensure that when the institution participates in 
or sponsors recombinant or synthetic nucleic acid molecule research 
involving human participants: (i) The Institutional Biosafety Committee 
has adequate expertise and training (using ad hoc consultants as deemed 
necessary), and (ii) no human gene transfer experiment shall be 
initiated until Institutional Biosafety Committee approval has been 
obtained, and all other applicable institutional and regulatory 
authorization(s) and approvals have been obtained. Institutional 
Biosafety Committee approval must be obtained from the clinical trial 
site.
    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 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.

    Note: Individuals, corporations, and institutions not otherwise 
covered by the NIH Guidelines, are encouraged to adhere to the 
standards and procedures set forth in Sections I through IV (see 
Section IV-D, Voluntary Compliance. The policy and procedures for 
establishing an Institutional Biosafety Committee under Voluntary 
Compliance, are specified in Section IV-D-2, Institutional Biosafety 
Committee Approval).

    Section IV-B-2-b-(1) will be amended as follows:
    Section IV-B-2-b-(1). Reviewing recombinant or synthetic nucleic 
acid molecule research conducted at or sponsored by the institution for 
compliance with the NIH Guidelines as specified in Section III, 
Experiments Covered by the NIH Guidelines, and approving those research 
projects that are found to conform with the NIH Guidelines. This review 
shall include: (i) Independent assessment of the containment levels 
required by the NIH Guidelines for the proposed research; (ii) 
assessment of the facilities, procedures, practices, and training and 
expertise of personnel involved in recombinant or synthetic nucleic 
acid molecule research; (iii) for recombinant or synthetic nucleic acid 
molecule research involving human research participants, assessment 
focused on biosafety issues (e.g., administration, shedding). IBC 
oversight may conclude after the last participant is administered the 
final dose of product. However, IBCs may choose to establish other end 
points for oversight, based on their biosafety assessment of the 
proposed research.
    Section IV-B-2-b-(8) will be amended as follows:
    Section IV-B-2-b-(8). The Institutional Biosafety Committee may not 
authorize initiation of experiments which are not explicitly covered by 
the NIH Guidelines until NIH establishes the containment requirement.
    Section IV-B-6 will be amended as follows:

Section IV-B-6. Human Gene Transfer Expertise

    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).
    Section IV-B-7 will be amended as follows:

Section IV-B-7. Principal Investigator (PI)

    On behalf of the institution, the Principal Investigator is 
responsible for full compliance with the NIH Guidelines in the conduct 
of recombinant or synthetic nucleic acid molecule research.
    Section IV-B-7-b-(6) will be deleted in its entirety.
    Section IV-B-7-e-(5) will be deleted in its entirety.
    Section IV-C will be amended as follows:

Section IV-C. Responsibilities of the National Institutes of Health 
(NIH)

Section IV-C-1. NIH Director

    The NIH Director is responsible for: (i) Establishment of the NIH 
Guidelines, (ii) oversight of their implementation, and (iii) their 
final interpretation. The NIH Director has responsibilities under the 
NIH Guidelines that involve OSP. OSP's responsibilities under the NIH 
Guidelines are administrative. In certain circumstances, there is 
specific opportunity for public comment with published response prior 
to final action.

Section IV-C-1-a. General Responsibilities

    The NIH Director is responsible for:
    Section IV-C-1-a-(1). Promulgating requirements as necessary to 
implement the NIH Guidelines;
    Section IV-C-1-a-(2). Establishing and maintaining NIH OSP to carry 
out the responsibilities defined in Section IV-C-2, Office of Science 
Policy;
    Section IV-C-1-a-(3). Conducting and supporting training programs 
in laboratory safety for Institutional Biosafety Committee members, 
Biological Safety Officers and other institutional experts (if 
applicable), Principal Investigators, and laboratory staff.

Section IV-C-1-b. Specific Responsibilities

    In carrying out the responsibilities set forth in this section, the 
NIH Director or a designee shall weigh each proposed

[[Page 17864]]

action through appropriate analysis and consultation to determine 
whether it complies with the NIH Guidelines and presents no significant 
risk to health or the environment.

Section IV-C-1-b-(1). Major Actions

    To execute Major Actions, the NIH Director shall provide an 
opportunity for public and Federal agency comment. The NIH Director's 
decision/recommendation (at his/her discretion) may be published in the 
Federal Register for a minimum of 15 days of comment before final 
action is taken. The NIH Director's final decision/recommendation, 
along with responses to public comments, shall be published in the 
Federal Register. Institutional Biosafety Committee Chairs shall be 
notified of the following decisions:
    Section IV-C-1-b-(1)-(a). Changing containment levels for types of 
experiments that are specified in the NIH Guidelines when a Major 
Action is involved;
    Section IV-C-1-b-(1)-(b). Assigning containment levels for types of 
experiments that are not explicitly considered in the NIH Guidelines 
when a Major Action is involved;
    Section IV-C-1-b-(1)-(c). Promulgating and amending a list of 
classes of recombinant or synthetic nucleic acid molecules to be exempt 
from the NIH Guidelines because they consist entirely of DNA segments 
from species that exchange DNA by known physiological processes or 
otherwise do not present a significant risk to health or the 
environment;
    Section IV-C-1-b-(1)-(d). Permitting experiments specified by 
Section III-A, Experiments that Require NIH Director Approval and 
Institutional Biosafety Committee Approval Before Initiation;
    Section IV-C-1-b-(1)-(e). Certifying new host-vector systems with 
the exception of minor modifications (e.g., those of minimal or no 
consequence to the properties relevant to containment) of already 
certified systems (the standards and procedures for certification are 
described in Appendix I-II, Certification of Host-Vector Systems; and
    Section IV-C-1-b-(1)-(f). Adopting other changes in the NIH 
Guidelines.

Section IV-C-1-b-(2). Minor Actions

    NIH OSP shall carry out certain functions as delegated to it by the 
NIH Director (see Section IV-C-2, Office of Science Policy). Minor 
Actions will be transmitted to Institutional Biosafety Committee 
Chairs:
    Section IV-C-1-b-(2)-(a). Changing containment levels for 
experiments that are specified in Section III, Experiments Covered by 
the NIH Guidelines (except when a Major Action is involved);
    Section IV-C-1-b-(2)-(b). Assigning containment levels for 
experiments not explicitly considered in the NIH Guidelines;
    Section IV-C-1-b-(2)-(c). Revising the Classification of Etiologic 
Agents for the purpose of these NIH Guidelines (see Section V-A, 
Footnotes and References of Sections I-IV);
    Section IV-C-1-b-(2)-(d). Interpreting the NIH Guidelines for 
experiments to which the NIH Guidelines do not specifically assign 
containment levels;
    Section IV-C-1-b-(2)-(e). Setting containment under Sections III-D-
1-d, Experiments Using Risk Group 2, Risk Group 3, Risk Group 4, or 
Restricted Agents as Host-Vector Systems, and III-D-2-b, Experiments in 
which DNA from Risk Group 2, Risk Group 3, Risk Group 4, or Restricted 
Agents is Cloned into Nonpathogenic Prokaryotic or Lower Eukaryotic 
Host-Vector Systems;
    Section IV-C-1-b-(2)-(f). Approving minor modifications of already 
certified host-vector systems (the standards and procedures for such 
modifications are described in Appendix I-II, Certification of Host-
Vector Systems);
    Section IV-C-1-b-(2)-(g). Decertifying already certified host-
vector systems;
    Section IV-C-1-b-(2)-(h). Adding new entries to the list of 
molecules toxic for vertebrates (see Appendix F, Containment Conditions 
for Cloning of Genes Coding for the Biosynthesis of Molecules Toxic for 
Vertebrates); and
    Section IV-C-1-b-(2)-(i). Determining appropriate containment 
conditions for experiments according to case precedents developed under 
Section IV-C-1-b-(2)-(c).
    Section IV-C-2. Recombinant DNA Advisory Committee (RAC) will be 
deleted in its entirety.
    Section IV-C-3 will be amended as follows:

Section IV-C-2. Office of Science Policy (OSP)

    OSP shall serve as a focal point for information on recombinant or 
synthetic nucleic acid molecule activities and provide advice to all 
within and outside NIH including institutions, Biological Safety 
Officers, Principal Investigators, Federal agencies, state and local 
governments, and institutions in the private sector. OSP shall carry 
out such other functions as may be delegated to it by the NIH Director. 
OSP's responsibilities include (but are not limited to) the following:
    Section IV-C-2-a. Reviewing and approving experiments involving the 
cloning of genes encoding for toxin molecules that are lethal for 
vertebrates at an LD50 of less than or equal to 100 
nanograms per kilogram body weight in organisms other than Escherichia 
coli K-12 (see Section III-B-1, Experiments Involving the Cloning of 
Toxin Molecules with LD50 of Less than 100 Nanograms Per Kilogram Body 
Weight, Appendix F, Containment Conditions for Cloning of Genes Coding 
for the Biosynthesis of Molecules Toxic for Vertebrates);
    Section IV-C-2-b. Publishing in the Federal Register, as needed;
    Section IV-C-2-c. Reviewing and approving the membership of an 
institution's Institutional Biosafety Committee, and where it finds the 
Institutional Biosafety Committee meets the requirements set forth in 
Section IV-B-2, Institutional Biosafety Committee (IBC), giving its 
approval to the Institutional Biosafety Committee membership.
    Section IV-D-5-a will be amended as follows:

Section IV-D-5-a. General

    In general, the Freedom of Information Act requires Federal 
agencies to make their records available to the public upon request. 
However, this requirement does not apply to, among other things, 
``trade secrets and commercial or financial information that is 
obtained from a person and that is privileged or confidential.'' Under 
18 U.S.C. 1905, it is a criminal offense for an officer or employee of 
the U.S. or any Federal department or agency to publish, divulge, 
disclose, or make known ``in any manner or to any extent not authorized 
by law any information coming to him in the course of his employment or 
official duties or by reason of any examination or investigation made 
by, or return, report or record made to or filed with, such department 
or agency or officer or employee thereof, which information concerns or 
relates to the trade secrets, (or) processes . . . of any person, firm, 
partnership, corporation, or association.'' This provision applies to 
all employees of the Federal Government, including special Government 
employees.
    In submitting to NIH for purposes of voluntary compliance with the 
NIH Guidelines, an institution may designate those items of information 
which the institution believes constitute trade secrets, privileged, 
confidential, commercial, or financial information. If NIH receives a 
request under the Freedom of Information Act for information so 
designated, NIH will promptly contact the institution to secure its 
views as to whether the information (or some portion) should be

[[Page 17865]]

released. If NIH decides to release this information (or some portion) 
in response to a Freedom of Information request or otherwise, the 
institution will be advised and the actual release will be delayed in 
accordance with 45 Code of Federal Regulations, Section 5.65(d) and 
(e).
    None of the other sub-sections under Section IV. Roles and 
Responsibilities will be amended.
    Section V will be amended as follows:

Section V. Footnotes and References of Sections I Through IV

    Section V-A. The NIH Director may revise the classification for the 
purposes of the NIH Guidelines (see Section IV-C-1-b-(2)-(e), Minor 
Actions). The revised list of organisms in each Risk Group is reprinted 
in Appendix B, Classification of Human Etiologic Agents on the Basis of 
Hazard.
    Section V-B. Section III, Experiments Covered by the NIH 
Guidelines, describes a number of places where judgments are to be 
made. In all these cases, the Principal Investigator shall make the 
judgment on these matters as part of his/her responsibility to ``make 
an initial determination of the required levels of physical and 
biological containment in accordance with the NIH Guidelines'' (see 
Section IV-B-7-c-(1)). For cases falling under Sections III-A through 
III-E, Experiments Covered by the NIH Guidelines, this judgment is to 
be reviewed and approved by the Institutional Biosafety Committee as 
part of its responsibility to make an ``independent assessment of the 
containment levels required by the NIH Guidelines for the proposed 
research'' (see Section IV-B-2-b-(1), Institutional Biosafety 
Committee). The Institutional Biosafety Committee may refer specific 
cases to NIH OSP as part of NIH OSP's functions to ``provide advice to 
all within and outside NIH'' (see Section IV-C-2).
    None of the other sub-sections under Section V. Footnotes and 
References of Sections I Through IV will be amended.
    Appendix A will be amended as follows:

Appendix A. Exemptions Under Section III-F-6--Sublists of Natural 
Exchangers

    Certain specified recombinant or synthetic nucleic acid 
molecules that consist entirely of DNA segments from different 
species that exchange DNA by known physiological processes, though 
one or more of the segments may be a synthetic equivalent are exempt 
from these NIH Guidelines (see Section III-F-6, Exempt Experiments). 
Institutional Biosafety Committee registration is not required for 
these exempt experiments. A list of such exchangers will be prepared 
and periodically revised by the NIH Director after appropriate 
notice and opportunity for public comment (see Section IV-C-1-b-(1)-
(c), NIH Director--Specific Responsibilities). For a list of natural 
exchangers that are exempt from the NIH Guidelines, see Appendices 
A-I through A-VI, Exemptions under Section III-F-6 Sublists of 
Natural Exchangers. Section III-F-6, Exempt Experiments, describes 
recombinant or synthetic nucleic acid molecules that are: (1) 
Composed entirely of DNA segments from one or more of the organisms 
within a sublist, and (2) to be propagated in any of the organisms 
within a sublist (see Bergey's Manual of Systematic Bacteriology; 
2nd edition, Springer-Verlag; New York, NY). Although these 
experiments are exempt, it is recommended that they be performed at 
the appropriate biosafety level for the host or recombinant/
synthetic organism (see Biosafety in Microbiological and Biomedical 
Laboratories, 5th edition, 2009, U.S. DHHS, Public Health Service, 
Centers for Disease Control and Prevention, and National Institutes 
of Health).

    None of the sub-sections under Appendix A. Exemptions Under III-F-
6--Sublists of Natural Exchangers will be amended.
    Appendix B will be amended as follows:

Appendix B. Classification of Human Etiologic Agents on the Basis of 
Hazard

    This appendix includes those biological agents known to infect 
humans as well as selected animal agents that may pose theoretical 
risks if inoculated into humans. Included are lists of 
representative genera and species known to be pathogenic; mutated, 
recombined, and non-pathogenic species and strains are not 
considered. Non-infectious life cycle stages of parasites are 
excluded.
    This appendix reflects the current state of knowledge and should 
be considered a resource document. Included are the more commonly 
encountered agents and is not meant to be all-inclusive. Information 
on agent risk assessment may be found in the Agent Summary 
Statements of the CDC/NIH publication, Biosafety in Microbiological 
and Biomedical Laboratories (see Sections V-C, V-D, V-E, and V-F, 
Footnotes and References of Sections I through IV). Further guidance 
on agents not listed in Appendix B may be obtained through: Centers 
for Disease Control and Prevention, Biosafety Branch, Atlanta, 
Georgia 30333, Phone: (404) 639-3883, Fax: (404) 639-2294; National 
Institutes of Health, Division of Safety, Bethesda, Maryland 20892, 
Phone: (301) 496-1357; Biosafety Manager, National Animal Disease 
Center, U.S. Department of Agriculture--ARS, Ames, Iowa 50010, 
Phone: (515) 337-7772.

    None of the sub-sections under Appendix B. Classification of Human 
Etiologic Agents on the Basis of Hazard nor Table 1 will be amended.
    Appendix C will be amended as follows:

Appendix C. Exemptions Under Section III-F-8

    Section III-F-8 states that exempt from these NIH Guidelines are 
``those that do not present a significant risk to health or the 
environment (see Section IV-C-1-b-(1)-(c), Major Actions), as 
determined by the NIH Director following appropriate notice and 
opportunity for public comment. See Appendix C, Exemptions under 
Sections III-F-8, for other classes of experiments which are exempt 
from the NIH Guidelines.'' The following classes of experiments are 
exempt under Section III-F-8:

    Appendix C-IX-A. will be amended as follows:
    Appendix C-IX-A. The NIH Director may revise the classification for 
the purposes of these NIH Guidelines (see Section IV-C-1-b-(2)-(b), 
Minor Actions). The revised list of organisms in each Risk Group is 
located in Appendix B.
    None of the other sub-sections under Appendix C. Exemptions Under 
Section III-F-8 will be amended.
    Appendix D will be amended as follows:

Appendix D. Major Actions Taken Under The NIH Guidelines

    As noted in the subsections of Section IV-C-1-b-(1), the 
Director, NIH, may take certain actions with regard to the NIH 
Guidelines. (Entries up to and including D-118 were approved using a 
process that involved the Recombinant DNA Advisory Committee.) Some 
of the actions taken to date include the following:

    None of the sub-sections under Appendix D. Major Actions Taken 
Under The NIH Guidelines will be amended.
    Appendix I-II will be amended as follows:

Appendix I-II. Certification of Host-Vector Systems

Appendix I-II-A. Responsibility

    Host-Vector 1 systems (other than Escherichia coli K-12) and 
Host-Vector 2 systems may not be designated as such until they have 
been certified by the NIH Director. Requests for certification of 
host-vector systems may be submitted to the Office of Science 
Policy, National Institutes of Health, preferably by email to: 
[email protected]; additional contact information is also 
available here and on the OSP website (www.osp.od.nih.gov). Proposed 
host-vector systems will be reviewed based on the construction, 
properties, and testing of the proposed host-vector system by ad hoc 
experts. The NIH Director is responsible for certification of host-
vector systems. Minor modifications to existing host-vector systems 
(i.e., those that are of minimal or no consequence to the properties 
relevant to containment) may be certified by the NIH Director (see 
Section IV-C-1-b-(2)-(f), Minor Actions). Once a host-vector system 
has been

[[Page 17866]]

certified by the NIH Director, a notice of certification will be 
sent by NIH OSP to the applicant and to the Institutional Biosafety 
Committee Chairs. A list of all currently certified host-vector 
systems is available from the Office of Science Policy, National 
Institutes of Health, preferably by submitting a request for this 
information to: [email protected]; additional contact 
information is also available here and on the OSP website 
(www.osp.od.nih.gov). The NIH Director may rescind the certification 
of a host-vector system (see Section IV-C-1-b-(2)-(g), Minor 
Actions). If certification is rescinded, NIH will instruct 
investigators to transfer cloned DNA into a different system or use 
the clones at a higher level of physical containment level, unless 
NIH determines that the already constructed clones incorporate 
adequate biological containment. Certification of a host-vector 
system does not extend to modifications of either the host or vector 
component of that system. Such modified systems shall be 
independently certified by the NIH Director. If modifications are 
minor, it may only be necessary for the investigator to submit data 
showing that the modifications have either improved or not impaired 
the major phenotypic traits on which the containment of the system 
depends. Substantial modifications to a certified host-vector system 
require submission of complete testing data.

Appendix I-II-B. Data To Be Submitted for Certification

Appendix I-II-B-1. Host-Vector 1 Systems Other Than Escherichia coli K-
12

    The following types of data shall be submitted, modified as 
appropriate for the particular system under consideration: (i) A 
description of the organism and vector; the strain's natural habitat 
and growth requirements; its physiological properties, particularly 
those related to its reproduction, survival, and the mechanisms by 
which it exchanges genetic information; the range of organisms with 
which this organism normally exchanges genetic information and the 
type of information exchanged; and any relevant information about 
its pathogenicity or toxicity; (ii) a description of the history of 
the particular strains and vectors to be used, including data on any 
mutations which render this organism less able to survive or 
transmit genetic information; and (iii) a general description of the 
range of experiments contemplated with emphasis on the need for 
developing such an Host-Vector 1 system.

Appendix I-II-B-2. Host-Vector 2 Systems

    Investigators planning to request Host-Vector 2 systems 
certification may obtain instructions from NIH OSP concerning data 
to be submitted (see Appendices I-III-N and O, Footnotes and 
References of Appendix I). In general, the following types of data 
are required: (i) Description of construction steps with indication 
of source, properties, and manner of introduction of genetic traits; 
(ii) quantitative data on the stability of genetic traits that 
contribute to the containment of the system; (iii) data on the 
survival of the host-vector system under non-permissive laboratory 
conditions designed to represent the relevant natural environment; 
(iv) data on transmissibility of the vector and/or a cloned DNA 
fragment under both permissive and non-permissive conditions; (v) 
data on all other properties of the system which affect containment 
and utility, including information on yields of phage or plasmid 
molecules, ease of DNA isolation, and ease of transfection or 
transformation; and (vi) in some cases, the investigator may be 
asked to submit data on survival and vector transmissibility from 
experiments in which the host-vector is fed to laboratory animals or 
one or more human subjects. Such in vivo data may be required to 
confirm the validity of predicting in vivo survival on the basis of 
in vitro experiments. Data shall be submitted to the Office of 
Science Policy, National Institutes of Health, preferably by email 
to: [email protected]; additional contact information is also 
available here and on the OSP website (www.osp.od.nih.gov). 
Investigators are encouraged to publish their data on the 
construction, properties, and testing of proposed Host-Vector 2 
systems prior to consideration of the system by NIH. Specific 
instructions concerning the submission of data for proposed 
Escherichia coli K-12 Host-Vector 2 system (EK2) involving either 
plasmids or bacteriophage in Escherichia coli K-12, are available 
from the Office of Science Policy, National Institutes of Health, 
preferably by submitting a request for this information to: 
[email protected]; additional contact information is also 
available here and on the OSP website (www.osp.od.nih.gov).

    None of the other sub-sections under Appendix I. Biological 
Containment will be amended.
    Appendix L. Gene Therapy Policy Conferences (GTPCS) will be deleted 
in its entirety.
    Appendix M. Points to Consider in the Design and Submission of 
Protocols for the Transfer of Recombinant or Synthetic Nucleic Acid 
Molecules into One or More Human Research Participants (Points to 
Consider) will be deleted in its entirety.

    Dated: April 10, 2019.
Lawrence A. Tabak,
Principal Deputy Director, National Institutes of Health.
[FR Doc. 2019-08462 Filed 4-25-19; 8:45 am]
 BILLING CODE 4140-01-P