[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 [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: 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: [email protected],
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:
[email protected]; 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:
[email protected], 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:
[email protected]; 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 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-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:
[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 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: [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
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: [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 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: [email protected];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:
[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. 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:
[email protected];
[[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: [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).
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