[Federal Register Volume 83, Number 160 (Friday, August 17, 2018)]
[Notices]
[Pages 41082-41093]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-17760]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


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

AGENCY: National Institutes of Health, HHS.

ACTION: Notice.

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SUMMARY: The National Institutes of Health (NIH) seeks public comment 
on its proposal to amend 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. Specifically, NIH 
proposes amendments to: Delete the NIH protocol registration submission 
and reporting requirements under Appendix M of the NIH Guidelines, and 
modify the roles and responsibilities of entities that involve human 
gene transfer or the Recombinant DNA Advisory Committee (RAC).

DATES: To ensure consideration, comments must be submitted in writing 
by October 16, 2018.

ADDRESSES: Comments may be submitted electronically by visiting: 
https://osp.od.nih.gov/comment-form-nih-guidelines/. Comments may also 
be sent via fax to 301-496-9839, or by mail to the Office of Science 
Policy, National Institutes of Health, 6705 Rockledge Drive, Suite 750, 
Bethesda, Maryland 20892-7985. All written comments received in 
response to this notice will be available for public inspection at NIH 
Office of Science Policy (OSP), 6705 Rockledge Drive, Suite 750, 
Bethesda, MD 20892-7985, weekdays between the hours of 8:30 a.m. and 5 
p.m. and may be posted without change, including any personal 
information, to the NIH OSP website.

FOR FURTHER INFORMATION CONTACT: If you have questions, or require 
additional background information about these proposed changes, please 
contact the NIH by email at <a href="/cdn-cgi/l/email-protection#87d4e4eee2e9e4e2d7e8ebeee4fec7e8e3a9e9eeefa9e0e8f1"><span class="__cf_email__" data-cfemail="0d5e6e6468636e685d6261646e744d626923636465236a627b">[email protected]</span></a>, 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 
<a href="/cdn-cgi/l/email-protection#0b416e787862686a255f7e68606e794b656263256c647d"><span class="__cf_email__" data-cfemail="a1ebc4d2d2c8c2c08ff5d4c2cac4d3e1cfc8c98fc6ced7">[email protected]</span></a>.

SUPPLEMENTARY INFORMATION: NIH is proposing 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 have resulted in the 
translation of research into clinical practice, including U.S. Food and 
Drug Administration (FDA) approvals for licensed products. 
Additionally, oversight mechanisms for ensuring HGT proceeds safely 
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 clinical 
protocols to both NIH and FDA that does not exist for other areas of 
clinical research. Historically, this duplication was conceived as 
harmonized reporting, enabling FDA to provide regulatory oversight 
while NIH provided a forum for open dialogue and transparency. However, 
since these complementary functions were first envisioned, we have now 
seen several converging systems emerge that provide some of these 
functions. For instance, ClinicalTrials.gov has been instituted, which 
provides a transparent and searchable database for clinical trials. In 
addition, the protection of human research subjects was improved 
through changes that updated provisions of the Common Rule. In 2018, 
FDA released a suite of draft guidance documents pertaining to gene 
therapy that includes new guidance on manufacturing issues, long-term 
follow-up, and pathways for clinical development in certain areas, 
including hemophilia, ophthalmologic indications, and rare diseases.
    While the science and oversight system have evolved, HGT protocols 
continue to receive special oversight that is not afforded to other 
areas of clinical research. This observation was also noted in a 2014 
Institute of Medicine of the National Academies report, Oversight and 
Review of Clinical Gene Transfer Protocols: Assessing the Role of the 
Recombinant DNA Advisory Committee, in which it was recommended that 
NIH begin to limit RAC review to only exceptional HGT protocols that 
meet certain criteria and that would significantly benefit from RAC 
review. As very few protocols have been assessed by NIH to merit review 
under this new system, NIH asserts 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.
    Briefly to summarize, NIH proposes amending the NIH Guidelines to:
    1. Eliminate RAC review and reporting requirements to NIH for HGT 
protocols.
    2. Modify roles and responsibilities of investigators, 
institutions, IBCs, the RAC, and NIH to be consistent with these goals 
including:
    a. Modifying roles of IBCs in reviewing HGT to be consistent with 
review of other covered research, and
    b. Eliminating references to the RAC, including its roles in HGT 
and biosafety.
    NIH suggests that the series of changes proposed in this Notice is 
a rational next step in the process of considering appropriate 
oversight of HGT. Consistent with these proposed changes to the NIH 
Guidelines, Section I-A, the Purpose of the NIH Guidelines, is proposed 
to be amended to clarify that the focus of the policy is biosafety

[[Page 41083]]

oversight of research involving recombinant or synthetic nucleic acid 
molecules. NIH notes that some of the duties of Institutional Biosafety 
Committees (IBCs) as currently written in the NIH Guidelines (e.g., 
review of informed consent documents) are duplicative with the 
oversight provided by FDA or Institutional Review Boards (IRBs). NIH 
proposes that IBCs retain responsibility to review and approve HGT 
protocols; however, NIH proposes that these responsibilities be 
modified to be similar to those responsibilities IBCs currently have 
for review and approval of other research subject to the NIH 
Guidelines.
    With the proposed elimination of the requirements for safety 
reporting under Appendix M, IBC oversight should be completed 
immediately after the last participant is administered the final dose 
of product. Additionally, the role of IBC review is proposed to be 
amended to be consistent with FDA's current guidance regarding 
individual patient expanded access to investigational drugs. In this 
way, the role of the IBCs will be focused on providing local biosafety 
oversight of basic and clinical research involving recombinant or 
synthetic nucleic acids. In particular, NIH seeks comment on whether 
the expectations of IBCs, in light of these proposed changes, have been 
articulated clearly in the proposed revisions to the NIH Guidelines.
    Notably, the roles and responsibilities of the RAC are proposed to 
be removed from the NIH Guidelines. NIH recognizes the value of the RAC 
in discussions of science, safety, and ethics. In an effort to use the 
RAC as a public forum to advise on issues associated with emerging 
biotechnologies, the RAC's charter will be modified to change the 
committee's focus from research solely involving recombinant or 
synthetic nucleic acids to emerging biotechnologies research. In light 
of this modification to the committee, NIH proposes eliminating 
references to the RAC in the NIH Guidelines, though NIH may continue to 
seek advice from the RAC on biosafety issues that fall under the 
purview of the NIH Guidelines. Similarly, NIH may choose to seek advice 
from internal working groups or Federal Advisory Committees on a 
variety of issues, when warranted.
    The proposed changes outlined above will require amendment of 
multiple portions of the NIH Guidelines. Sections and appendices 
proposed to be deleted from the current NIH Guidelines may be accessed 
at https://osp.od.nih.gov/biotechnology/nih-guidelines/. Following 
deletions, sections and appendices will be relabeled to proceed 
consecutively throughout the NIH Guidelines.

Proposed Amendments to the NIH Guidelines

    Section I-A currently states:

Section I-A. Purpose

    The purpose of the NIH Guidelines is to specify the practices 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 is proposed to 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 currently states:
    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. (See exception in Section I-A-1-a regarding 
requirement for human gene transfer protocol registration.)
    Section I-A-1 is proposed to 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 currently states:
    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 research 
participant shall be enrolled (see definition of enrollment in Section 
I-E-7) until the NIH protocol registration process has been completed 
(see Appendix M-I-B, Selection of Individual Protocols for Public RAC 
Review and Discussion); Institutional Biosafety Committee (IBC) 
approval (from the clinical trial site) has been obtained; 
Institutional Review Board (IRB) approval has been obtained; and all 
applicable regulatory authorization(s) have been obtained.
    For a clinical trial site that is added after the completion of the 
NIH protocol registration process, no research participant shall be 
enrolled (see definition of enrollment in Section I-E-7) at the 
clinical trial site until IBC approval and IRB approval from that site 
have been obtained. Within 30 days of enrollment (see definition of 
enrollment in Section I-E-7) at a clinical trial site, the following 
documentation shall be submitted to NIH OSP: (1) Institutional 
Biosafety Committee approval (from the clinical trial site); (2) 
Institutional Review Board approval; (3) Institutional Review Board-
approved informed consent document(s); and (4) NIH grant number(s) if 
applicable.
    Section I-A-1-a is proposed to 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-7) 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 is proposed to be amended to 
delete the current definitions I-E-4, I-E-7 through I-E-12 and to 
include a new definition for ``initiation.''
    Section I-E-4 is proposed to be amended to define initiation as the 
following: ``Initiation'' of research is the introduction of 
recombinant or synthetic nucleic acid molecules into organisms, cells, 
or viruses.
    Section III currently states:

[[Page 41084]]

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 
Institutional Biosafety Committee (IBC) approval, RAC review, and NIH 
Director approval before initiation (see Section III-A), (ii) those 
that require NIH OSP and Institutional Biosafety Committee approval 
before initiation (see Section III-B), (iii) those that require 
Institutional Biosafety Committee and Institutional Review Board 
approvals and RAC review before research participant enrollment (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 those 
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 is proposed to 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 
Institutional Biosafety Committee (IBC) approval and NIH Director 
approval before initiation (see Section III-A), (ii) those that require 
NIH OSP 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 those 
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 currently states:

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

    Experiments considered as Major Actions 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: <a href="/cdn-cgi/l/email-protection#400e090807352924252c292e2533002f246e2e29286e272f36"><span class="__cf_email__" data-cfemail="9bd5d2d3dceef2fffef7f2f5fee8dbf4ffb5f5f2f3b5fcf4ed">[email protected]</span></a>, 
the publication of the proposal in the Federal Register for 15 days of 
comment, review by RAC, and specific approval by NIH. The containment 
conditions or stipulation requirements for such experiments will be 
recommended by RAC and 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, which may be 
obtained from the Office of Science Policy, National Institutes of 
Health, preferably by submitting a request for this information to: 
<a href="/cdn-cgi/l/email-protection#b5fbfcfdf2c0dcd1d0d9dcdbd0c6f5dad19bdbdcdd9bd2dac3"><span class="__cf_email__" data-cfemail="cf81868788baa6abaaa3a6a1aabc8fa0abe1a1a6a7e1a8a0b9">[email protected]</span></a>; additional contact information is also 
available here and on the OSP website (www.osp.od.nih.gov).
    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 be reviewed 
by the RAC.
    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 RAC review and 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. NIH OSP will consult, as needed, with one or more 
experts, which may include the RAC.
    Section III-A is proposed to be amended as follows:

Section III-A. Experiments That Require Institutional Biosafety 
Committee Approval and NIH Director 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: 
<a href="/cdn-cgi/l/email-protection#e8a6a1a0af9d818c8d8481868d9ba8878cc6868180c68f879e"><span class="__cf_email__" data-cfemail="ce80878689bba7aaaba2a7a0abbd8ea1aae0a0a7a6e0a9a1b8">[email protected]</span></a>, the publication of the proposal in the 
Federal Register for 15 days of comment, and specific approval by NIH. 
The containment 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, which may be 
obtained from the Office of Science Policy, National Institutes of 
Health, preferably by submitting a request for this information to: 
<a href="/cdn-cgi/l/email-protection#501e191817253934353c393e3523103f347e3e39387e373f26"><span class="__cf_email__" data-cfemail="98d6d1d0dfedf1fcfdf4f1f6fdebd8f7fcb6f6f1f0b6fff7ee">[email protected]</span></a>; additional contact information is also 
available here and on the OSP website (www.osp.od.nih.gov).
    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

[[Page 41085]]

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 currently states:
    Section III-C. Experiments that Require Institutional Biosafety 
Committee and Institutional Review Board Approvals and RAC Review (if 
applicable) Before Research Participant Enrollment
    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.
    No research participant shall be enrolled (see definition of 
enrollment in Section I-E-7) until the NIH protocol registration 
process has been completed (see Appendix M-I-B, Selection of Individual 
Protocols for Public RAC Review and Discussion).
    In its evaluation of human gene transfer protocols, NIH will make a 
determination, following a request from one or more oversight bodies 
involved in the review at an initial site(s), whether a proposed human 
gene transfer experiment meets the requirements for selecting protocols 
for public RAC review and discussion (See Appendix M-I-B). The process 
of public RAC review and discussion is intended to foster the safe and 
ethical conduct of human gene transfer experiments. Public review and 
discussion of a human gene transfer experiment (and access to relevant 
information) also serves to inform the public about the technical 
aspects of the proposal, the meaning and significance of the research, 
and any significant safety, social, and ethical implications of the 
research.
    Public RAC review and discussion of a human gene transfer 
experiment will be initiated in two exceptional circumstances: (1) 
Following a request for public RAC review from one or more oversight 
bodies involved in the review at an initial site(s), the NIH concurs 
that (a) the individual protocol would significantly benefit from RAC 
review and (b) that the submission meets one or more of the following 
NIH RAC review criteria: (i) The protocol uses a new vector, genetic 
material, or delivery methodology that represents a first-in-human 
experience, thus presenting an unknown risk; (ii) the protocol relies 
on preclinical safety data that were obtained using a new preclinical 
model system of unknown and unconfirmed value; or (iii) the proposed 
vector, gene construct, or method of delivery is associated with 
possible toxicities that are not widely known and that may render it 
difficult for oversight and federal regulatory bodies to evaluate the 
protocol rigorously. However, if one or more oversight bodies involved 
in the review at an initial site(s) requests public RAC review, but NIH 
does not concur that (a) the individual protocol would significantly 
benefit from RAC review and (b) that the submission meets one or more 
of the RAC review criteria (listed in i, ii, or iii), then the NIH OSP 
will inform, within 10 working days, the requesting and other oversight 
bodies involved in the review at an initial site(s) that public RAC 
review is not warranted. (2) The NIH Director, in consultation (if 
needed) with appropriate regulatory authorities, determines that the 
submission: (a) Meets one or more of the NIH RAC review criteria 
(listed in i, ii, or iii) and that public RAC review and discussion 
would provide a clear and obvious benefit to the scientific community 
or the public; or (b) raises significant scientific, societal, or 
ethical concerns.
    For a clinical trial site that is added after the completion of the 
NIH protocol registration process, no research participant shall be 
enrolled (see definition of enrollment in Section I-E-7) at the 
clinical trial site until IBC approval and IRB approval from that site 
have been obtained. Within 30 days of enrollment (see definition of 
enrollment in Section I-E-7) at a clinical trial site, the following 
documentation shall be submitted to NIH OSP: (1) Institutional 
Biosafety Committee approval (from the clinical trial site); (2) 
Institutional Review Board approval; (3) Institutional Review Board-
approved informed consent document(s); and (4) NIH grant number(s) if 
applicable.
    In order to maintain public access to information regarding human 
gene transfer (including protocols that are not publicly reviewed by 
the RAC), the NIH OSP will maintain the documentation described in 
Appendices M-I through M-II. The information provided in response to 
Appendix M should not contain any confidential commercial or financial 
information or trade secrets, enabling all aspects of RAC review to be 
open to the public.

    Note:  For specific directives concerning the use of retroviral 
vectors for gene delivery, consult Appendix B-V-1, Murine Retroviral 
Vectors.

    Section III-C is proposed to 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.
    An individual patient expanded access IND is not research subject 
to the NIH Guidelines and thus does not need to be submitted to an IBC, 
if the following conditions are met: (i) A PI is submitting an 
individual patient expanded access IND using Form FDA 3926; (ii) the PI 
selects the appropriate box on that form to request a waiver under 21 
CFR 56.105 of the requirements in 21 CFR 56.108(c); and (iii) the FDA 
concludes that such a waiver is appropriate.

[[Page 41086]]

    Section III-D-7-b currently states:
    Section III-D-7-b. Highly Pathogenic Avian Influenza H5N1 strains 
within the Goose/Guangdong/96-like H5 lineage (HPAI H5N1). Experiments 
involving influenza viruses containing a majority of genes and/or 
segments from a HPAI H5N1 influenza virus shall be conducted at BL3 
enhanced containment, (see Appendix G-II-C-5, Biosafety Level 3 
Enhanced for Research Involving Risk Group 3 Influenza Viruses). 
Experiments involving influenza viruses containing a minority of genes 
and/or segments from a HPAI H5N1 influenza virus shall be conducted at 
BL3 enhanced unless a risk assessment performed by the IBC determines 
that they can be conducted safely at biosafety level 2 and after they 
have been excluded pursuant to 9 CFR 121.3(e). NIH OSP is available to 
IBCs to provide consultation with the RAC and influenza virus experts 
when risk assessments are being made to determine the appropriate 
biocontainment for experiments with influenza viruses containing a 
minority of gene/segments from HPAI H5N1. Such experiments may be 
performed at BL3 enhanced containment or containment may be lowered to 
biosafety level 2, the level of containment for most research with 
other influenza viruses. (USDA/APHIS regulations and decisions on 
lowering containment also apply). In deciding to lower containment, the 
IBC should consider whether, in at least two animal models (e.g., 
ferret, mouse, Syrian golden hamster, cotton rat, non-human primates), 
there is evidence that the resulting influenza virus shows reduced 
replication and virulence compared to the parental RG3 virus at 
relevant doses. This should be determined by measuring biological 
indices appropriate for the specific animal model (e.g., severe weight 
loss, elevated temperature, mortality or neurological symptoms).
    Section III-D-7-b is proposed to 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 biosafety level 2 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 biosafety level 
2, the level of containment for most research with other influenza 
viruses. (USDA/APHIS regulations and decisions on lowering containment 
also apply). In deciding to lower containment, the IBC should consider 
whether, in at least two animal models (e.g., ferret, mouse, Syrian 
golden hamster, cotton rat, non-human primates), there is evidence that 
the resulting influenza virus shows reduced replication and virulence 
compared to the parental RG3 virus at relevant doses. This should be 
determined by measuring biological indices appropriate for the specific 
animal model (e.g., severe weight loss, elevated temperature, mortality 
or neurological symptoms).
    Section III-D-7-d currently states:
    Section III-D-7-d. Antiviral Susceptibility and Containment. The 
availability of antiviral drugs as preventive and therapeutic measures 
is an important safeguard for experiments with 1918 H1N1, HPAI H5N1, 
and human H2N2 (1957-1968). If an influenza virus containing genes from 
one of these viruses is resistant to both classes of current antiviral 
agents, adamantanes and neuraminidase inhibitors, higher containment 
may be required based on the risk assessment considering 
transmissibility to humans, virulence, pandemic potential, alternative 
antiviral agents if available, etc.
    Experiments with 1918 H1N1, human H2N2 (1957-1968) or HPAI H5N1 
that are designed to create resistance to neuraminidase inhibitors or 
other effective antiviral agents (including investigational antiviral 
agents being developed for influenza) would be subject to Section III-
A-1 (Major Actions) and require RAC review and NIH Director approval. 
As per Section I-A-1 of the NIH Guidelines, if the agent is a Select 
Agent, the NIH will defer to the appropriate federal agency (HHS or 
U.S. Department of Agriculture (USDA) Select Agent Divisions) on such 
experiments.
    Section III-D-7-d is proposed to 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) and NIH Director approval. As per Section I-A-1 of 
the NIH Guidelines, if the agent is a Select Agent, NIH will defer to 
the appropriate Federal agency (HHS or USDA Select Agent Divisions) on 
such experiments.
    Section III-F-6 currently states:
    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 with advice of the RAC 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-6 is proposed to 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 currently states:
    Section III-F-8. Those that do not present a significant risk to 
health or the

[[Page 41087]]

environment (see Section IV-C-1-b-(1)-(c), Major Actions), as 
determined by the NIH Director, with the advice of the RAC, and 
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.
    Section III-F-8 is proposed to 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, and 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.
    Section IV-B-1-f currently states:
    Section IV-B-1-f. Ensure that when the institution participates in 
or sponsors recombinant or synthetic nucleic acid molecule research 
involving human subjects: (i) The Institutional Biosafety Committee has 
adequate expertise and training (using ad hoc consultants as deemed 
necessary), (ii) all aspects of Appendix M have been appropriately 
addressed by the Principal Investigator; and (iii) no research 
participant shall be enrolled (see definition of enrollment in Section 
I-E-7) in a human gene transfer experiment until the NIH protocol 
registration process has been completed (see Appendix M-I-B, Selection 
of Individual Protocols for Public RAC Review and Discussion), 
Institutional Biosafety Committee approval has been obtained, 
Institutional Review Board approval has been obtained, and all 
applicable regulatory authorizations have been obtained. Institutional 
Biosafety Committee approval must be obtained from the clinical trial 
site.
    Section IV-B-1-f is proposed to be amended as follows:
    Section IV-B-1-f. Ensure that when the institution participates in 
or sponsors recombinant or synthetic nucleic acid molecule research 
involving human subjects: (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.
    None of the other sub-sections under Section IV-B-1. General 
Information are proposed to be amended.
    Section IV-B-2-a-(1) currently states:
    Section IV-B-2-a-(1). The Institutional Biosafety Committee must be 
comprised of 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 P, 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 Q, 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: (i) The Institutional Biosafety Committee has adequate expertise 
and training (using ad hoc consultants as deemed necessary); (ii) all 
aspects of Appendix M have been appropriately addressed by the 
Principal Investigator; (iii) no research participant shall be enrolled 
(see definition of enrollment in Section I-E-7) in a human gene 
transfer experiment until the NIH protocol registration process has 
been completed (see Appendix M-I-B, Selection of Individual Protocols 
for Public RAC Review and Discussion); and (iv) final IBC approval is 
granted only after the NIH protocol registration process has been 
completed (see Appendix M-I-B, Selection of Individual Protocols for 
Public RAC Review and Discussion). Institutional Biosafety Committee 
approval must be obtained from the clinical trial site.
    Section IV-B-2-a-(1) is proposed to be amended as follows:
    Section IV-B-2-a-(1). The Institutional Biosafety Committee must be 
comprised of 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 P, 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 Q, 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

[[Page 41088]]

recombinant or synthetic nucleic acid molecule research involving human 
research participants, the institution must ensure that the 
Institutional Biosafety Committee has adequate expertise and training 
(using ad hoc consultants as deemed necessary). Institutional Biosafety 
Committee approval must be obtained from the clinical trial site.
    Section IV-B-2-b-(1) currently states:
    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) ensuring that all aspects of Appendix M 
have been appropriately addressed by the Principal Investigator; (iv) 
ensuring that no research participant is enrolled (see definition of 
enrollment in Section I-E-7) in a human gene transfer experiment until 
the NIH protocol registration process has been completed (see Appendix 
M-I-B, Selection of Individual Protocols for Public RAC Review and 
Discussion), Institutional Biosafety Committee approval (from the 
clinical trial site) has been obtained, Institutional Review Board 
approval has been obtained, and all applicable regulatory 
authorizations have been obtained; (v) for human gene transfer 
protocols selected for public RAC review and discussion, consideration 
of the issues raised and recommendations made as a result of this 
review and consideration of the Principal Investigator's response to 
the recommendations; (vi) ensuring that final IBC approval is granted 
only after the NIH protocol registration process has been completed 
(see Appendix M-I-B, Selection of Individual Protocols for Public RAC 
Review and Discussion); and (vii) ensuring compliance with all 
surveillance, data reporting, and adverse event reporting requirements 
set forth in the NIH Guidelines.
    Section IV-B-2-b-(1) is proposed to 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).
    Section IV-B-2-b-(8) currently states:
    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 (with the advice of the RAC when required) 
establishes the containment requirement.
    Section IV-B-2-b-(8) is proposed to 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.
    None of the other sub-sections under Section IV-B-2. Institutional 
Biosafety Committee (IBC) are proposed to be amended.
    Section IV-B-6 currently states:

Section IV-B-6. Human Gene Therapy Expertise

    When the institution participates in or sponsors recombinant or 
synthetic nucleic acid molecule research involving human subjects, the 
institution must ensure that: (i) The Institutional Biosafety Committee 
has adequate expertise and training (using ad hoc consultants as deemed 
necessary) and (ii) all aspects of 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 Subjects 
(Points to Consider), have been appropriately addressed by the 
Principal Investigator prior to its approval.
    Section IV-B-6 is proposed to 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 subjects, 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 currently states:

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. A Principal 
Investigator engaged in human gene transfer research may delegate to 
another party, such as a corporate sponsor, the reporting functions set 
forth in Appendix M, with written notification to the NIH OSP of the 
delegation and of the name(s), address, telephone, and fax numbers of 
the contact. The Principal Investigator is responsible for ensuring 
that the reporting requirements are fulfilled and will be held 
accountable for any reporting lapses.
    Section IV-B-7 is proposed to 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) is proposed to be deleted in its entirety
    Section IV-B-7-e-(5) is proposed to be deleted in its entirety
    None of the other sub-sections under Section IV-B-7. Principal 
Investigator are proposed to be amended.
    Section IV-C currently states:

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

Section IV-C-1. NIH Director

    The NIH Director is responsible for: (i) Establishing the NIH 
Guidelines, (ii) overseeing their implementation, and (iii) their final 
interpretation. The NIH Director has responsibilities under the NIH 
Guidelines that involve OSP and RAC. OSP's responsibilities under the 
NIH Guidelines are administrative. Advice from RAC is primarily 
scientific, technical, and ethical. 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:

[[Page 41089]]

    Section IV-C-1-a-(1). Promulgating requirements as necessary to 
implement the NIH Guidelines;
    Section IV-C-1-a-(2). Establishing and maintaining RAC to carry out 
the responsibilities set forth in Section IV-C-2, Recombinant DNA 
Advisory Committee (RAC membership is specified in its charter and in 
Section IV-C-2);
    Section IV-C-1-a-(3). Establishing and maintaining NIH OSP to carry 
out the responsibilities defined in Section IV-C-3, Office of Science 
Policy;
    Section IV-C-1-a-(4). 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-a-(5). Establishing and convening Gene Therapy 
Policy Conferences as described in Appendix L, Gene Therapy Policy 
Conferences.

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 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 seek the advice of 
RAC and provide an opportunity for public and federal agency comment. 
Specifically, the Notice of Meeting and Proposed Actions shall be 
published in the Federal Register at least 15 days before the RAC 
meeting. The NIH Director's decision/recommendation (at his/her 
discretion) may be published in the Federal Register for 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. The RAC and 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 Institutional Biosafety 
Committee Approval, RAC Review, and NIH Director Approval Before 
Initiation;
    Section IV-C-1-b-(1)-(e). Certifying new host-vector systems with 
the exception of minor modifications of already certified systems (the 
standards and procedures for certification are described in Appendix I-
II, Certification of Host-Vector Systems). Minor modifications 
constitute (e.g., those of minimal or no consequence to the properties 
relevant to containment); 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-3, Office of Science Policy). Minor 
Actions (as determined by NIH OSP in consultation with the RAC Chair 
and one or more RAC members, as necessary) will be transmitted to RAC 
and 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 is proposed to 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) Establishing the NIH 
Guidelines, (ii) overseeing 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-3, 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 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.

[[Page 41090]]

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 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 Institutional Biosafety 
Committee Approval, and NIH Director 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-3, 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) is 
proposed to be deleted in its entirety.
    Section IV-C-3. Office of Science Policy (OSP) is proposed to be 
amended as follows:
    Sections IV-C-3-a through IV-C-3-f are proposed to be deleted in 
their entirety. Section IV-C-3-h is proposed to be deleted in its 
entirety. Section IV-C-3-g will be renumbered to Section IV-C-3-a. 
Section IV-C-i will be renumbered to Section IV-C-3-b; Section IV-C-3-
i-(1), Section IV-C-3-i-(2) and Section IV-C-3-i-(3) are proposed to be 
deleted in their entirety. Section IV-C-3-j will be renumbered to 
Section IV-C-3-c.
    Section IV-C-3 is proposed to be amended as follows:

Section IV-C-3. 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-3-a. Reviewing and approving experiments involving the 
cloning of genes encoding for toxin molecules that are lethal for 
vertebrates at an LD<INF>50</INF> 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-3-b. Publishing in the Federal Register, as needed.
    Section IV-C-3-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 currently states:

Section IV-D-5. Protection of Proprietary Data--Voluntary Compliance

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

[[Page 41091]]

employees. Members of RAC are ``special Government employees.''
    Section IV-D-5 is proposed to 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 United States 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.
    None of the other sub-sections under Section IV are proposed to be 
amended.
    Section V currently states:

Section V. Footnotes and References of Sections I through IV

    Section V-A. The NIH Director, with advice of the RAC, 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 
the 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-3). NIH OSP may request 
advice from the RAC as part of the RAC's responsibility for 
``interpreting the NIH Guidelines for experiments to which the NIH 
Guidelines do not specifically assign containment levels'' (see Section 
IV-C-1-b-(2)-(f), Minor Actions).
    Section V is proposed to be amended as follows:
    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 
the 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-3).
    Appendix A currently states:

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 with advice from the 
RAC 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 Classification of 
Bergey's Manual of Determinative Bacteriology; 8th edition, R.E. 
Buchanan and N.E. Gibbons, editors, Williams and Wilkins Company; 
Baltimore, Maryland 1984). 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, 2007, 
U.S. DHHS, Public Health Service, Centers for Disease Control and 
Prevention, Atlanta, Georgia, and NIH Office of Biosafety, Bethesda, 
Maryland).

    Appendix A is proposed to 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, 2007, U.S. DHHS, Public Health Service, 
Centers for Disease Control and Prevention, Atlanta, Georgia, and 
NIH Office of Biosafety, Bethesda, Maryland).

    Appendix C-IX-A currently states:

Appendix C-IX-A

    The NIH Director, with advice of the RAC, may revise the 
classification for the purposes of these NIH Guidelines (see Section 
IV-C-

[[Page 41092]]

1-b-(2)-(b), Minor Actions). The revised list of organisms in each 
Risk Group is located in Appendix B.

    Appendix C-IX-A is proposed to 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-IX. Footnotes and 
References of Appendix C are proposed to be amended.
    Appendix D currently states in part:

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 after the issues have been considered by the RAC. Some of 
the actions taken to date include the following:

    Appendix D is proposed to 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 RAC.) Some of the actions taken to date 
include the following:

    Appendix I-II currently states:

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: 
<a href="/cdn-cgi/l/email-protection#185651505f6d717c7d7471767d6b58777c36767170367f776e"><span class="__cf_email__" data-cfemail="91dfd8d9d6e4f8f5f4fdf8fff4e2d1fef5bffff8f9bff6fee7">[email protected]</span></a>; additional contact information is also 
available here and on the OSP website (www.osp.od.nih.gov). Proposed 
host-vector systems will be reviewed by the RAC (see Section IV-C-1-
b-(1)-(f), Major Actions). Initial review will based on the 
construction, properties, and testing of the proposed host-vector 
system by a subcommittee composed of one or more RAC members and/or 
ad hoc experts. The RAC will evaluate the subcommittee's report and 
any other available information at the next scheduled RAC meeting. 
The NIH Director is responsible for certification of host-vector 
systems, following advice of the RAC. 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 without prior RAC review (see Section 
IV-C-1-b-(2)-(f), Minor Actions). Once a host-vector system has been 
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: <a href="/cdn-cgi/l/email-protection#76383f3e31031f12131a1f18130536191258181f1e58111900"><span class="__cf_email__" data-cfemail="054b4c4d42706c6160696c6b6076456a612b6b6c6d2b626a73">[email protected]</span></a>; 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 
requires 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 is 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 12 weeks prior to the 
RAC meeting at which such data will be considered by the Office of 
Science Policy, National Institutes of Health, preferably by email 
to: <a href="/cdn-cgi/l/email-protection#733d3a3b34061a17161f1a1d1600331c175d1d1a1b5d141c05"><span class="__cf_email__" data-cfemail="f5bbbcbdb2809c9190999c9b9086b59a91db9b9c9ddb929a83">[email protected]</span></a>; 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 the RAC and its 
subcommittee. 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: <a href="/cdn-cgi/l/email-protection#2d6364656a58444948414443485e6d424903434445034a425b"><span class="__cf_email__" data-cfemail="91dfd8d9d6e4f8f5f4fdf8fff4e2d1fef5bffff8f9bff6fee7">[email protected]</span></a>;additional contact information is also 
available here and on the OSP website (www.osp.od.nih.gov).
    Appendix I-II is proposed to 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: 
<a href="/cdn-cgi/l/email-protection#397770717e4c505d5c5550575c4a79565d17575051175e564f"><span class="__cf_email__" data-cfemail="226c6b6a65574b46474e4b4c4751624d460c4c4b4a0c454d54">[email protected]</span></a>; 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. Once a host-vector system has been 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: 
<a href="/cdn-cgi/l/email-protection#ace2e5e4ebd9c5c8c9c0c5c2c9dfecc3c882c2c5c482cbc3da"><span class="__cf_email__" data-cfemail="d99790919eacb0bdbcb5b0b7bcaa99b6bdf7b7b0b1f7beb6af">[email protected]</span></a>;

[[Page 41093]]

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 
requires 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 is 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: <a href="/cdn-cgi/l/email-protection#eda3a4a5aa98848988818483889ead8289c3838485c38a829b"><span class="__cf_email__" data-cfemail="07494e4f40726e63626b6e69627447686329696e6f29606871">[email protected]</span></a>; 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: 
<a href="/cdn-cgi/l/email-protection#56181f1e11233f32333a3f38332516393278383f3e78313920"><span class="__cf_email__" data-cfemail="87c9cecfc0f2eee3e2ebeee9e2f4c7e8e3a9e9eeefa9e0e8f1">[email protected]</span></a>; additional contact information is also 
available here and on the OSP website (www.osp.od.nih.gov).

    Appendix L, GENE THERAPY POLICY CONFERENCES (GTPCS), is proposed to 
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), is proposed to be deleted in its entirety.

    Dated: August 7, 2018.
Lawrence A. Tabak,
Deputy Director, National Institutes of Health.
[FR Doc. 2018-17760 Filed 8-16-18; 8:45 am]
 BILLING CODE 4140-01-P


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