80_FR_62743 80 FR 62543 - Proposed Action Under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines)

80 FR 62543 - Proposed Action Under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines)

DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health

Federal Register Volume 80, Issue 200 (October 16, 2015)

Page Range62543-62550
FR Document2015-26388

The NIH seeks public comment on its proposal to amend the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) to incorporate the recommendations of the Institute of Medicine (IOM) regarding human gene transfer clinical research protocols. The NIH proposes amendments to the following: (A) The criteria for selecting protocols for in-depth review and public discussion by the NIH Recombinant DNA Advisory Committee (RAC), (B) the process by which human gene transfer protocols are reviewed and registered with the NIH, and (C) the streamlining of the NIH protocol registration submission requirements under Appendix M-I-A of the NIH Guidelines.

Federal Register, Volume 80 Issue 200 (Friday, October 16, 2015)
[Federal Register Volume 80, Number 200 (Friday, October 16, 2015)]
[Notices]
[Pages 62543-62550]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2015-26388]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Proposed Action Under the NIH Guidelines for Research Involving 
Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines)

AGENCY: National Institutes of Health (NIH), HHS.

ACTION: Notice of proposed changes to the NIH Guidelines.

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SUMMARY: The NIH seeks public comment on its proposal to amend the NIH 
Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid 
Molecules (NIH Guidelines) to incorporate the recommendations of the 
Institute of Medicine (IOM) regarding human gene transfer clinical 
research protocols. The NIH proposes amendments to the following: (A) 
The criteria for selecting protocols for in-depth review and public 
discussion by the NIH Recombinant DNA Advisory Committee (RAC), (B) the 
process by which human gene transfer protocols are reviewed and 
registered with the NIH, and (C) the streamlining of the NIH protocol 
registration submission requirements under Appendix M-I-A of the NIH 
Guidelines.

DATES: To ensure consideration, comments must be submitted in writing 
by November 30, 2015.

ADDRESSES: Comments may be submitted by email at OBA-osp@od.nih.gov, by 
fax at 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 the 
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 to the NIH OSP Web site.

FOR FURTHER INFORMATION CONTACT: If you have questions, or require 
additional background information about these proposed changes, please 
contact the NIH by email at OBA-osp@od.nih.gov, or telephone at 301-
496-9838.

SUPPLEMENTARY INFORMATION: The NIH Office of the Director requested 
that the IOM review whether gene transfer research raises issues of 
concern that warrant the current level of RAC oversight of individual 
clinical trials involving gene transfer techniques. The IOM noted that 
the RAC has served a valuable role, but concluded that the current 
level of oversight over individual clinical trials is no longer 
justifiable. In an effort to maximize the benefits of the RAC review 
process, the IOM recommended that the NIH maintain its protocol 
submission and safety reporting requirements, but restrict individual 
gene transfer protocol reviews to exceptional cases that meet specified 
criteria (full recommendations are listed in the IOM report Oversight 
and Review of Clinical Gene Transfer Protocols: Assessing the Role of 
the Recombinant DNA Advisory Committee (http://www.iom.edu/Reports/2013/Oversight-and-Review-of-Clinical-Gene-Transfer-Protocols.aspx)).
    After careful consideration of the IOM's recommendations, the NIH 
proposes amendments to the NIH Guidelines in the following areas:
    A. Criteria and process for selecting protocols for RAC review. The 
following criteria (subsequently referred to as the NIH RAC review 
criteria) are proposed for initiating RAC review of individual human 
gene transfer protocols (criteria listed in both items 1 and 2 must be 
met):
    1. An oversight body (an Institutional Biosafety Committee (IBC) or 
an Institutional Review Board (IRB)) determines that a human gene 
transfer protocol submitted to it for approval would significantly 
benefit from RAC review; and
    2. One or more of the criteria below are satisfied:
    a. The protocol uses a new vector, genetic material, or delivery 
methodology that represents a first-in-human experience, thus 
presenting an unknown risk.
    b. The protocol relies on preclinical safety data that were 
obtained using a new preclinical model system of unknown and 
unconfirmed value.
    c. 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 bodies to evaluate the protocol 
rigorously.
    The chair of an oversight body or an authorized oversight body 
representative may submit a request for RAC review by sending the 
request to the NIH as part of the submission materials provided by the 
PI. This request must include the rationale for why the protocol 
satisfies both items 1 and 2 of the NIH RAC review criteria. The NIH 
will review the request and notify the requestor of a decision in no 
more than ten working days.
    1. If the NIH determines that the criteria listed in both 1 and 2 
above are satisfied, the NIH Director will convene the RAC.
    2. If the NIH receives a request for RAC review of a protocol that 
the NIH determines does not meet both of these criteria, the NIH would:
    a. Inform the requestor that RAC review is not warranted, and
    b. offer to provide the requestor with information about previous 
protocols that have used similar products, the outcome of those 
studies, if available, and a summary of relevant safety data.
    3. Even if the protocol does not meet the proposed criteria listed 
in both items 1 and 2 above, the NIH Director, in consultation (if 
necessary) with appropriate regulatory authorities (e.g., the Office 
for Human Research Protections, the Food and Drug Administration), can 
select protocols for review that may present significant scientific, 
societal, or ethical concerns.
    B. Process by which human gene transfer protocols are registered 
with the NIH. All human gene transfer protocols subject to Section III-
C of the NIH Guidelines will continue to be registered with the NIH. 
However, the following changes are being proposed:

[[Page 62544]]

    1. The Principal Investigator (PI) will continue to be responsible 
for submitting documentation regarding a proposed human gene transfer 
protocol to his or her local oversight bodies. The PI will also 
continue to be responsible for submitting documentation as outlined in 
Appendix M-I-A to the NIH. As part of the submission to the NIH, the PI 
shall provide documentation from oversight bodies regarding their 
assessment of whether RAC review is warranted.
    2. Completion of the protocol registration process:
    a. If no oversight body requests RAC review, the IBC may proceed 
with its approval process upon receipt of documentation from the NIH 
indicating that the protocol registration process is complete. No 
research participant shall be enrolled (see definition of enrollment in 
Section I-E-7) in the human gene transfer protocol until the protocol 
registration process has been completed.
    b. If an oversight body requests review and the NIH agrees that the 
submission has met the criteria in A above, the protocol will undergo 
RAC review and public discussion. The IBC may not approve a protocol 
until the RAC review process has been completed. The IBC may proceed 
with its approval process upon receipt of documentation from the NIH 
indicating that the protocol registration process is complete. No 
research participant shall be enrolled (see definition of enrollment in 
Section I-E-7) in the human gene transfer protocol until the protocol 
registration process has been completed.
    C. Streamlining the submission requirements for protocol 
registration. Section III-C-1 and Appendix M of the NIH Guidelines 
specify the requirements for protocol submission, RAC review, and 
reporting requirements for human gene transfer experiments. In an 
effort to streamline the protocol submission process, the NIH proposes 
to reduce the submission requirements as outlined in Appendix M-I-A. 
Specifically, only a subset of the information listed under the current 
Appendices M-II through M-V will be required mainly for oversight 
bodies to determine RAC review eligibility and to support the Genetic 
Modification Clinical Research Information System (GeMCRIS[supreg]), 
which facilitates safety reporting and provides access to information 
about human gene transfer protocols registered with the NIH.
    The proposed changes to the RAC review process, outlined above, 
will require amendment of multiple portions of the NIH Guidelines.

Proposed Amendments to the NIH Guidelines

    Throughout the document the following global changes will be made: 
(i) The NIH OSP will replace the NIH OBA, (ii) the term ``RAC review'' 
will be replaced with the term ``NIH protocol registration process'' as 
appropriate; (iii) the title for Appendix M-I-B will be changed; and 
(iv) the requirement for a CV/biosketch of key personnel will be 
deleted.
    Section I-E is proposed to be amended to include the following new 
definitions:

I-E-11. An ``oversight body'' is an institutional entity (an 
Institutional Biosafety Committee or an Institutional Review Board) 
that must review and approve a human gene transfer trial.
I-E-12. A ``regulatory authority'' is a federal entity that by statute 
has oversight over research involving humans.

    Section III-C-1 currently states:

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 RAC review process has been 
completed (see Appendix M-I-B, RAC Review Requirements).
    In its evaluation of human gene transfer proposals, the RAC will 
consider whether a proposed human gene transfer experiment presents 
characteristics that warrant public RAC review and discussion (See 
Appendix M-I-B-2). 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 may be: (1) Initiated by the NIH Director; or (2) 
initiated by the NIH OBA Director following a recommendation to NIH 
OBA by: (a) Three or more RAC members; or (b) a Federal agency other 
than NIH. After a human gene transfer experiment is reviewed by the 
RAC at a regularly scheduled meeting, NIH OBA will send a letter, 
unless NIH OBA determines that there are exceptional circumstances, 
within 10 working days to the NIH Director, the Principal 
Investigator, the sponsoring institution, and other DHHS components, 
as appropriate, summarizing the RAC recommendations.
    For a clinical trial site that is added after the RAC review 
process, no research participant shall be enrolled (see definition 
of enrollment in Section I-E-7) at the clinical trial site until the 
following documentation has been submitted to NIH OBA: (1) 
Institutional Biosafety Committee approval (from the clinical trial 
site); (2) Institutional Review Board approval; (3) Institutional 
Review Board-approved informed consent document; (4) curriculum 
vitae of the Principal Investigator(s) (no more than two pages in 
biographical sketch format); and (5) 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), NIH OBA will maintain the documentation 
described in Appendices M-I through M-V. The information provided in 
response to Appendix M should not contain any confidential 
commercial 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-1 is proposed to be amended as follows:

Section III-C-1. Experiments Involving the Deliberate Transfer of 
Recombinant or Synthetic Nucleic Acid Molecules, or DNA or RNA Derived 
From Recombinant or Synthetic Nucleic Acid Molecules, Into One or More 
Human Research Participants

    Human gene transfer is the deliberate transfer into human 
research participants of either:
    1. Recombinant nucleic acid molecules, or DNA or RNA derived 
from recombinant nucleic acid molecules, or
    2. Synthetic nucleic acid molecules, or DNA or RNA derived from 
synthetic nucleic acid molecules that meet any one of the following 
criteria:
    a. Contain more than 100 nucleotides; or
    b. Possess biological properties that enable 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, the NIH will 
make a

[[Page 62545]]

determination, following a request from one or more oversight 
bodies, whether a proposed human gene transfer experiment has one or 
more of the characteristics that warrant public RAC review and 
discussion (See Appendix M-1-B-1). 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 may be initiated in two exceptional circumstances: (1) 
The NIH will determine, following a request for RAC public review 
from an oversight body, whether the protocol has one or more of the 
following characteristics: (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 bodies to evaluate the 
protocol rigorously. If an oversight body requests public RAC 
review, but the protocol does not have one or more of the above 
characteristics (listed in i, ii, or iii), then the NIH will inform 
the requesting oversight body that public RAC review is not 
warranted. (2) Public RAC review and discussion of protocols not 
requested for review by an oversight body may be initiated by the 
NIH Director if: (a) The protocol has one or more of the three 
characteristics listed above (i, ii, or iii) and public RAC review 
and discussion would provide a clear and obvious benefit to the 
scientific community or the public; or (b) the protocol otherwise 
raises significant scientific, societal, or ethical concerns.
    For a clinical trial site that is added after 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 the following documentation has been 
submitted to the 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; and (4) the 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 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 RAC review process has been completed (see Appendix M-I-B, 
RAC Review Requirements), 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 each institution at which recombinant or synthetic 
nucleic acids will be administered to human subjects (as opposed to 
each institution involved in the production of vectors for human 
application and each institution at which there is ex vivo 
transduction of recombinant or synthetic nucleic acid molecule 
material into target cells for human application).

    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), (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.

    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 RAC 
review process has been completed (see Appendix M-I-B, RAC Review 
Requirements); and (iv) final IBC approval is granted only after the 
RAC review process has been completed (see Appendix M-I-B, RAC 
Review Requirements). Institutional Biosafety Committee approval 
must be obtained from the institution at which recombinant or 
synthetic nucleic acid molecule material will be administered to 
human research participants (rather than the site involved in 
manufacturing gene transfer products).
    Note: Individuals, corporations, and institutions not otherwise 
covered by the NIH Guidelines, are encouraged to adhere to the 
standards and procedures set forth in Sections I through IV (see 
Section IV-D, Voluntary Compliance. The policy and procedures for 
establishing an Institutional Biosafety Committee under Voluntary 
Compliance, are specified in Section IV-D-2, Institutional Biosafety 
Committee Approval).

    Section IV-B-2-a-(1) is proposed to be amended as follows:


[[Page 62546]]


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

    None of the other sub-sections under Section IV-B2-a. Membership 
and Procedures of the IBC are proposed to be amended.
    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 RAC review process has been 
completed (see Appendix M-I-B, RAC Review Requirements), 
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 RAC 
recommendations; (vi) ensuring that final IBC approval is granted 
only after the RAC review process has been completed (see Appendix 
M-I-B, RAC Review Requirements); 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) 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 RAC 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.

    None of the other sub-sections under Section IV-B-2-b. Functions of 
the 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 submission to NIH/
OBA.

    Section IV-B-6 is proposed to be amended as follows:

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-7-b-(6) currently states:

    Section IV-B-7-b-(6). Ensure that all aspects of Appendix M have 
been appropriately addressed prior to submission of a human gene 
transfer experiment to NIH OBA, and provide a letter signed by the 
Principal Investigator(s) on institutional

[[Page 62547]]

letterhead acknowledging that the documentation being submitted to 
NIH OBA complies with the requirements set forth in Appendix M. No 
research participant shall be enrolled (see definition of enrollment 
in Section I-E-7) in a human gene transfer experiment until the RAC 
review process has been completed (see Appendix M-I-B, RAC Review 
Requirements); 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 RAC review 
process, no research participant shall be enrolled (see definition 
of enrollment in Section I-E-7) at the clinical trial site until the 
following documentation has been submitted to NIH OBA: (1) IBC 
approval (from the clinical trial site); (2) IRB approval; (3) IRB-
approved informed consent document; (4) curriculum vitae of the 
Principal Investigator(s) (no more than two pages in biographical 
sketch format); and (5) NIH grant number(s) if applicable.

    Section IV-B-7-b-(6) is proposed to be amended as follows:

    Section IV-B-7-b-(6). Ensure that all aspects of Appendix M have 
been appropriately addressed prior to submission. 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); 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 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 the following documentation has been 
submitted to the NIH OSP: (1) IBC approval (from the clinical trial 
site); (2) IRB approval; (3) IRB-approved informed consent document; 
and (4) NIH grant number(s) if applicable.

    To implement this new process, the NIH proposes to amend 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).

    Appendix M currently states:
    Appendix M applies to research conducted at or sponsored by an 
institution that receives any support for recombinant or synthetic 
nucleic acid molecule research from NIH. Researchers not covered by 
the NIH Guidelines are encouraged to use Appendix M (see Section I-
C, General Applicability).
    The acceptability of human somatic cell gene transfer has been 
addressed in several public documents as well as in numerous 
academic studies. In November 1982, the President's Commission for 
the Study of Ethical Problems in Medicine and Biomedical and 
Behavioral Research published a report, Splicing Life, which 
resulted from a two-year process of public deliberation and 
hearings. Upon release of that report, a U.S. House of 
Representatives subcommittee held three days of public hearings with 
witnesses from a wide range of fields from the biomedical and social 
sciences to theology, philosophy, and law. In December 1984, the 
Office of Technology Assessment released a background paper, Human 
Gene Therapy, which concluded that civic, religious, scientific, and 
medical groups have all accepted, in principle, the appropriateness 
of gene transfer of somatic cells in humans for specific genetic 
diseases. Somatic cell gene transfer is seen as an extension of 
present methods that might be preferable to other technologies. In 
light of this public support, RAC is prepared to consider proposals 
for somatic cell gene transfer.
    RAC will not at present entertain proposals for germ line 
alterations but will consider proposals involving somatic cell gene 
transfer. The purpose of somatic cell gene transfer is to treat an 
individual patient, e.g., by inserting a properly functioning gene 
into the subject's somatic cells. Germ line alteration involves a 
specific attempt to introduce genetic changes into the germ 
(reproductive) cells of an individual, with the aim of changing the 
set of genes passed on to the individual's offspring.
    The RAC continues to explore the issues raised by the potential 
of in utero gene transfer clinical research. However, the RAC 
concludes that, at present, it is premature to undertake any in 
utero gene transfer clinical trial. Significant additional 
preclinical and clinical studies addressing vector transduction 
efficacy, biodistribution, and toxicity are required before a human 
in utero gene transfer protocol can proceed. In addition, a more 
thorough understanding of the development of human organ systems, 
such as the immune and nervous systems, is needed to better define 
the potential efficacy and risks of human in utero gene transfer. 
Prerequisites for considering any specific human in utero gene 
transfer procedure include an understanding of the pathophysiology 
of the candidate disease and a demonstrable advantage to the in 
utero approach. Once the above criteria are met, the RAC would be 
willing to consider well rationalized human in utero gene transfer 
clinical trials.
    Research proposals involving the deliberate transfer of 
recombinant or synthetic nucleic acid molecules, or DNA or RNA 
derived from such nucleic acid molecules, into human subjects (human 
gene transfer) will be considered through a review process involving 
both NIH/OBA and RAC. Investigators shall submit their relevant 
information on the proposed human gene transfer experiments to NIH/
OBA. Submission of human gene transfer protocols to NIH will be in 
the format described in Appendix M-I-A, Submission Requirements for 
Protocol Submission. Submission to NIH shall be for registration 
purposes and will ensure continued public access to relevant human 
gene transfer information conducted in compliance with the NIH 
Guidelines. Investigational New Drug (IND) applications should be 
submitted to FDA in the format described in 21 CFR, Chapter I, 
Subchapter D, Part 312, Subpart B, Section 23, IND Content and 
Format.
    Institutional Biosafety Committee approval must be obtained from 
each institution at which recombinant or synthetic nucleic acid 
molecule material will be administered to human subjects (as opposed 
to each institution involved in the production of vectors for human 
application and each institution at which there is ex vivo 
transduction of recombinant or synthetic nucleic acid molecule 
material into target cells for human application).
    Factors that may contribute to public discussion of a human gene 
transfer experiment by RAC include: (i) New vectors/new gene 
delivery systems, (ii) new diseases, (iii) unique applications of 
gene transfer, and (iv) other issues considered to require further 
public discussion. Among the experiments that may be considered 
exempt from RAC discussion are those determined not to represent 
possible risk to human health or the environment. Full, public RAC 
review and discussion of a human gene transfer experiment may be (1) 
initiated by the NIH Director; or (2) initiated by the NIH OBA 
Director following a recommendation to NIH OBA by: (a) Three or more 
RAC members, or (b) a Federal agency other than NIH. An individual 
human gene transfer experiment that is recommended for full RAC 
review should represent novel characteristics deserving of public 
discussion. If it is determined that an experiment will undergo full 
RAC discussion, NIH/OBA will immediately notify the Principal 
Investigator. RAC members may forward individual requests for 
additional information relevant to a specific protocol through NIH/
OBA to the Principal Investigator. In making a determination whether 
an experiment is novel, and thus deserving of full RAC discussion, 
reviewers will examine the scientific rationale, scientific context 
(relative to other proposals reviewed by RAC), whether the 
preliminary in vitro and in vivo safety data were obtained in 
appropriate models and are sufficient, and whether questions related 
to relevant social and ethical issues have been resolved. RAC 
recommendations on a specific human gene transfer experiment shall 
be forwarded to the NIH Director, the Principal Investigator, the 
sponsoring institution, and other DHHS components, as appropriate. 
Relevant documentation will be included in the material for the RAC 
meeting at which the experiment is scheduled to be discussed. RAC 
meetings will be open to the public except where trade secrets and 
proprietary information are reviewed (see Section IV-D-5, Protection 
of Proprietary Data--Voluntary Compliance). RAC prefers that 
information provided in response to Appendix M contain no 
proprietary data or trade secrets, enabling all aspects of the 
review to be open to the public.
    Note: Any application submitted to NIH/OBA shall not be 
designated as `confidential'

[[Page 62548]]

in its entirety. In the event that a sponsor determines that 
specific responses to one or more of the items described in Appendix 
M should be considered as proprietary or trade secret, each item 
should be clearly identified as such. The cover letter (attached to 
the submitted material) shall: (1) Clearly indicate that select 
portions of the application contain information considered as 
proprietary or trade secret, (2) a brief explanation as to the 
reason that each of these items is determined proprietary or trade 
secret.
    Public discussion of human gene transfer experiments (and access 
to relevant information) shall serve to inform the public about the 
technical aspects of the proposals, meaning and significance of the 
research, and significant safety, social, and ethical implications 
of the research. RAC discussion is intended to ensure safe and 
ethical conduct of gene transfer experiments and facilitate public 
understanding of this novel area of biomedical research.
    In its evaluation of human gene transfer proposals, RAC will 
consider whether the design of such experiments offers adequate 
assurance that their consequences will not go beyond their purpose, 
which is the same as the traditional purpose of clinical 
investigation, namely, to protect the health and well being of human 
subjects being treated while at the same time gathering 
generalizable knowledge. Two possible undesirable consequences of 
the transfer of recombinant or synthetic nucleic acid molecules 
would be unintentional: (i) Vertical transmission of genetic changes 
from an individual to his/her offspring, or (ii) horizontal 
transmission of viral infection to other persons with whom the 
individual comes in contact. Accordingly, Appendices M-I through M-V 
request information that will enable RAC and NIH/OBA to assess the 
possibility that the proposed experiment(s) will inadvertently 
affect reproductive cells or lead to infection of other people 
(e.g., medical personnel or relatives).
    Appendix M will be considered for revisions as experience in 
evaluating proposals accumulates and as new scientific developments 
occur. This review will be carried out periodically as needed.

    Appendix M is proposed to be amended as follows:

    Appendix M applies to research conducted at or sponsored by an 
institution that receives any support for recombinant or synthetic 
nucleic acid molecule research from NIH. Researchers not covered by 
the NIH Guidelines are encouraged to use Appendix M (see Section I-
C, General Applicability).
    The acceptability of human somatic cell gene transfer has been 
addressed in several public documents as well as in numerous 
academic studies. In November 1982, the President's Commission for 
the Study of Ethical Problems in Medicine and Biomedical and 
Behavioral Research published a report, Splicing Life, which 
resulted from a two-year process of public deliberation and 
hearings. Upon release of that report, a U.S. House of 
Representatives subcommittee held three days of public hearings with 
witnesses from a wide range of fields from the biomedical and social 
sciences to theology, philosophy, and law. In December 1984, the 
Office of Technology Assessment released a background paper, Human 
Gene Therapy, which concluded that civic, religious, scientific, and 
medical groups have all accepted, in principle, the appropriateness 
of gene transfer of somatic cells in humans for specific genetic 
diseases. Somatic cell gene transfer is seen as an extension of 
present methods that might be preferable to other technologies. In 
light of this public support, the NIH is prepared to consider 
proposals for somatic cell gene transfer.
    The NIH will not at present entertain proposals for germ line 
alterations but will consider proposals involving somatic cell gene 
transfer. The purpose of somatic cell gene transfer is to treat an 
individual patient, e.g., by inserting a properly functioning gene 
into the subject's somatic cells. Germ line alteration involves a 
specific attempt to introduce genetic changes into the germ 
(reproductive) cells of an individual, with the aim of changing the 
set of genes passed on to the individual's offspring.
    The NIH continues to explore the issues raised by the potential 
of in utero gene transfer clinical research. However, the NIH 
concludes that, at present, it is premature to undertake any in 
utero gene transfer clinical trial. Significant additional 
preclinical and clinical studies addressing vector transduction 
efficacy, biodistribution, and toxicity are required before a human 
in utero gene transfer protocol can proceed. In addition, a more 
thorough understanding of the development of human organ systems, 
such as the immune and nervous systems, is needed to better define 
the potential efficacy and risks of human in utero gene transfer. 
Prerequisites for considering any specific human in utero gene 
transfer procedure include an understanding of the pathophysiology 
of the candidate disease and a demonstrable advantage to the in 
utero approach. Once the above criteria are met, the NIH would be 
willing to consider well rationalized human in utero gene transfer 
clinical trials.
    Research proposals involving the deliberate transfer of 
recombinant or synthetic nucleic acid molecules, or DNA or RNA 
derived from such nucleic acid molecules, into one or more human 
subjects (human gene transfer) will be considered through a 
registration process involving the NIH, oversight bodies, and 
regulatory authorities, when appropriate. Investigators shall submit 
the relevant information on the proposed human gene transfer 
experiment to the oversight bodies and then to the NIH. The format 
of the submission is described in Appendix M-I-A, Requirements for 
Protocol Submission. Submission to the NIH OSP shall be for 
registration purposes and will ensure continued public access to 
relevant human gene transfer information conducted in compliance 
with the NIH Guidelines.
    Public RAC review and discussion of a human gene transfer 
experiment may be initiated in two exceptional circumstances: (1) 
The NIH will determine, following a request for RAC review from an 
oversight body, whether the protocol has one or more of the 
following characteristics: 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 bodies to evaluate the 
protocol rigorously. If an oversight body requests public RAC 
review, but the NIH determines that the protocol does not have one 
or more of the above characteristics (listed in i, ii, or iii), then 
the NIH will inform the requesting oversight body that public RAC 
review is not warranted. (2) Public RAC review and discussion of 
protocols not requested for review by an oversight body may be 
initiated by the NIH Director, after consultation (if needed) with 
appropriate regulatory authorities, if: (a) The protocol has one or 
more of the three characteristics listed above (i, ii, or iii) and 
public RAC review and discussion would provide a clear and obvious 
benefit to the scientific community or the public; or (b) the 
protocol otherwise raises significant scientific, societal, or 
ethical concerns.
    If it is determined that a human gene transfer trial will 
undergo RAC review, the NIH will immediately notify the Principal 
Investigator. RAC recommendations following public review on a 
specific human gene transfer experiment shall be forwarded to the 
Principal Investigator, oversight bodies, and regulatory 
authorities, as appropriate. Relevant documentation will be included 
in the material for the RAC meeting at which the human gene transfer 
trial is scheduled to be discussed. RAC meetings will be open to the 
public except where trade secrets and proprietary information are 
reviewed (see Section IV-D-5, Protection of Proprietary Data--
Voluntary Compliance). The NIH prefers that information provided in 
response to Appendix M contain no proprietary data or trade secrets, 
enabling all aspects of the review to be open to the public.
    Some but not all sections of Appendix M-I Requirements for 
Protocol Submission, Review, and Reporting--Human Gene Transfer 
Experiments are proposed to be amended to decrease the number and 
amount of supporting documentation that must be submitted upon 
protocol registration, and to modify the timing of the registration 
processes. As proposed, Principal Investigators must submit the 
material as outlined below to oversight bodies at the proposed 
clinical trial sites; however, submission of responses to Appendices 
M-II through M-V or curriculum vitae will no longer be required.

    Appendix M-I-A currently states:

Appendix M-I.A. Requirements for Protocol Submission

    The following documentation must be submitted (see exemption in 
Appendix M-III-A, Footnotes of Appendix M) in printed or electronic 
form to the: Office of Biotechnology Activities, National Institutes

[[Page 62549]]

of Health, 6705 Rockledge Drive, Suite 750, Bethesda, MD 20892-7985 
(20817 for non-USPS mail), 301-496-9838, 301-496-9839 (fax), Email: 
rosenthg@od.nih.gov. NIH OBA will confirm receipt within three 
working days after receiving the submission. Investigators should 
contact NIH OBA if they do not receive this confirmation.
    1. A cover letter on institutional letterhead, signed by the 
Principal Investigator(s), that: (1) Acknowledges that the 
documentation submitted to NIH OBA complies with the requirements 
set forth in Appendix M-I-A, Requirements for Protocol Submission; 
(2) identifies the Institutional Biosafety Committee (IBC) and 
Institutional Review Board (IRB) at the proposed clinical trial 
site(s) responsible for local review and approval of the protocol; 
and (3) acknowledges that no research participant will be enrolled 
(see definition of enrollment in Section I-E-7) until the RAC review 
process has been completed (see Appendix M-I-B, RAC Review 
Requirements); IBC approval (from the clinical trial site) has been 
obtained; IRB approval has been obtained; and all applicable 
regulatory authorizations have been obtained.
    2. The scientific abstract.
    3. The non-technical abstract.
    4. The proposed clinical protocol, including tables, figures, 
and relevant manuscripts.
    5. Responses to Appendices M-II through M-V, Description of the 
Proposal, Informed Consent, Privacy, and Special Issues. Responses 
to Appendices M-II through M-V may be provided either as an appendix 
to the clinical protocol or incorporated in the clinical protocol. 
If responses to Appendices M-II through M-V are incorporated in the 
clinical protocol, each response must refer to the appropriate 
Appendix M-II through M-V.
    6. The proposed informed consent document.
    7. Curriculum vitae of the Principal Investigator(s) (no more 
than two pages in biographical sketch format).
    Note: A human gene transfer experiment submitted to NIH OBA 
should not contain confidential commercial information or trade 
secrets, enabling all aspects of the review to be open to the 
public.

    Appendix M-I-A is proposed to be amended as follows:

Appendix M-I-A. Requirements for Protocol Submission
    The following documentation must be submitted according to 
institutional policy, to the appropriate oversight bodies and 
subsequently in electronic form to the NIH OSP:
    1. A scientific abstract.
    2. The proposed clinical protocol, including tables, figures, 
and any relevant publications.
    3. Summary of preclinical studies conducted in support of the 
proposed clinical trial or reference to the specific section of the 
protocol providing this information.
    4. A description of the product:
    a. Describe the derivation of the delivery vector system 
including the source (e.g., viral, bacterial, or plasmid vector); 
and modifications (e.g., deletions to attenuate or self-inactivate, 
encapsulation in any synthetic complex, changes to tropisms, etc.). 
Please reference any previous clinical experience with this vector 
or similar vectors.
    b. Describe the genetic content of the transgene or nucleic acid 
delivered including the species source of the sequence and whether 
any modifications have been made (e.g. mutations, deletions, and 
truncations). What are the regulatory elements contained in the 
construct?
    c. Describe any other material to be used in preparation of the 
agent (vector and transgene) that will be administered to the human 
research subject (e.g., helper virus, packaging cell line, carrier 
particles).
    d. Describe the methods for replication-competent virus testing, 
if applicable.
    e. Describe the intended ex vivo or in vivo target cells and 
transduction efficiency.
    f. Describe the gene transfer agent delivery method.
    5. The proposed informed consent document.
    6. Specifically for submission to the NIH OSP, the PI shall 
provide additional documentation from oversight bodies regarding 
their assessment of whether RAC review is warranted. In the event 
that review is requested, the documentation shall include a 
justification that the protocol characteristics (see Section III-C-
1) that would warrant RAC public review have been met.
    Note: Any application submitted shall not contain any document 
that is designated as 'confidential' in its entirety. In the event 
that a sponsor determines that a portion of a specific document 
should be considered as proprietary or trade secret, each portion of 
the document should be clearly identified as such. In the event that 
a specific portion of the submission does contain information that a 
sponsor considers to be proprietary or trade secret, the submission 
to the NIH OSP must contain a letter from the sponsor that: (1) 
Clearly indicates what select portions of the application contain 
information considered as proprietary or trade secret, (2) provides 
an adequate and convincing justification as to the reason that this 
information is considered to be proprietary or trade secret. The 
justification must be able to demonstrate with specificity how 
release of that information will reveal a trade secret or will 
result in substantial competitive harm.
    Appendix M-I-B, RAC Review Requirements is proposed to be 
amended to change the process and timing of initial and RAC review. 
Currently, investigators are informed within 15 working days whether 
or not the protocol requires public RAC review. Public discussion of 
selected protocols then occurs at the next quarterly RAC meeting, 
which occurs, at a minimum of, eight weeks after receipt of a 
complete protocol submission. Under the proposal, individual RAC 
members will no longer make a recommendation regarding whether a 
protocol should be selected for review at a public meeting.

    Therefore, Appendix M-1-B-1 and Appendix M-1-B-2 are being amended 
as follows to form a consolidated Appendix M-1-B:
Appendix M-1-B. Selection of Individual Protocols for Public RAC Review 
and Discussion
    As part of the NIH protocol registration process, documentation 
from oversight bodies regarding their assessment of whether RAC 
review is warranted. If no oversight body would significantly 
benefit from public RAC review and discussion, then the Principal 
Investigator shall submit all of the documentation required to 
register the submission (see Appendix M-I-A) to the NIH OSP at any 
time but shall occur not less than three working days prior to the 
anticipated date of enrollment of the first subject (see definition 
of enrollment in Section I-E-7), and shall be provided in electronic 
form to the Office of Science Policy, National Institutes of Health, 
6705 Rockledge Drive, Suite 750, Bethesda, MD 20892-7985 (20817 for 
non-USPS mail), 301-496-9838, 301-496-9839 (fax), Email: 
HGTprotocols@mail.nih.gov. Enrollment may proceed upon 
acknowledgement that the submission is registered.
    If an oversight body determines that: (1) A protocol submission 
would significantly benefit from public RAC review and discussion 
and (2) that one or more of the following NIH RAC review criteria 
are met: (i) The protocol uses a new vector, genetic material, or 
delivery methodology that represents a first-in-human experience, 
thus presenting an unknown risk; or (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 local and federal regulatory bodies to evaluate the 
protocol rigorously, and is therefore requesting RAC review and 
public discussion, the Principal Investigator shall submit the 
documentation as outlined in Appendix M-I-A at least 8 weeks prior 
to the next scheduled meeting in order to be reviewed at that RAC 
meeting. The submission shall include documentation from oversight 
bodies regarding their assessment of whether RAC review is warranted 
and that one or both have justified their request according the NIH 
RAC review criteria listed above. The submission shall be provided 
to the NIH in electronic form to the Office of Science Policy, 
National Institutes of Health, 6705 Rockledge Drive, Suite 750, 
Bethesda, MD 20892-7985 (20817 for non-USPS mail), 301-496-9838, 
301-496-9839 (fax), Email: HGTprotocols@mail.nih.gov. If NIH 
determines that any of the criteria listed in subsections (i), (ii), 
or (iii) above is met, the protocol will undergo public RAC review 
and discussion.
    If an oversight body requests that the RAC review a protocol and 
the NIH determines that the protocol does not satisfy one or more of 
the above NIH RAC review criteria, the NIH OSP will inform the 
Principal Investigator, oversight bodies, and regulatory 
authorities, as appropriate, that RAC review is not warranted.

[[Page 62550]]

    Even if an oversight body does not request that a particular 
protocol be reviewed by the RAC, the NIH Director, after 
consultation (if needed) with appropriate regulatory authorities, 
may initiate RAC review if (a) the protocol has one or more of the 
characteristics listed above (i, ii, or iii) and public RAC review 
and discussion would provide a clear and obvious benefit to the 
scientific community or public; or (b) the protocol otherwise raises 
significant scientific, societal, or ethical concerns.
    Completion of the registration process is defined as: (1) 
Receipt by the Principal Investigator of a letter from the NIH OSP 
indicating that protocol registration process is complete and that 
enrollment may proceed; or (2) receipt by the Principal Investigator 
of a letter from the NIH after public RAC review that summarizes the 
committee's key comments and recommendations (if any).
    A complete human gene transfer protocol package must be 
submitted at least eight weeks before a scheduled RAC meeting to be 
reviewed at that upcoming meeting.
    After a human gene transfer experiment is publicly reviewed by 
the full RAC at a regularly scheduled meeting, the NIH OSP will send 
a letter summarizing the RAC's key comments and recommendations (if 
any) regarding the protocol to the Principal Investigator(s), 
oversight bodies, and regulatory authorities as appropriate. 
Completion of RAC review is defined as receipt by the Principal 
Investigator(s) of a letter from the NIH OSP summarizing the 
committee's findings. Unless the NIH determines that there are 
exceptional circumstances, the letter containing recommendations and 
comments made following public review will be sent within 10 working 
days after the completion of the RAC meeting at which the protocol 
was reviewed.
    RAC meetings will be open to the public except where trade 
secrets or confidential commercial information are reviewed. To 
enable all aspects of the protocol review process to be open to the 
public, information provided in response to Appendix M-I-A should 
not contain trade secrets or confidential commercial or financial 
information. An application submitted to the NIH OSP shall not 
contain any document that is designated as `confidential' in its 
entirety. In the event that a determination has been made that a 
specific portion of a document submitted as one of the items 
described in Appendix M should be considered as confidential 
commercial or financial information or a trade secret, each item 
must be clearly identified as such. The cover letter (attached to 
the submitted material) shall: (1) Clearly designate the information 
that is considered as confidential commercial or financial 
information or a trade secret; and (2) explain and justify each 
designation to demonstrate with specificity how release of that 
information will reveal a trade secret or will result in substantial 
competitive harm.
    There are no proposed amendments to Appendix M-I-C, Reporting 
Requirements and Appendix M-I-D, Safety Assessments in Human Gene 
Transfer Research.
    The current appendices Appendix M-II, Description of the 
Proposal; Appendix M-III, Informed Consent; Appendix M-IV, Privacy; 
and Appendix M-V, Special Issues are proposed to be deleted in their 
entirety, except for Appendix M-III-B-2-b, Long Term Follow-Up which 
will be updated to include a reference to FDA's current guidance on 
this issue and will become Appendix M-II.

    Appendix M-II is proposed to be amended as follows:
Appendix M-II. Long Term Follow-Up
    To permit evaluation of long-term safety and efficacy of gene 
transfer, prospective subjects should be informed that they are 
expected to cooperate in long-term follow-up that extends beyond the 
active phase of the study. A list of persons who can be contacted in 
the event that questions arise during the follow-up period should be 
provided to the investigator. In addition, the investigator should 
request that subjects continue to provide a current address and 
telephone number.
    The subjects should be informed that any significant findings 
resulting from the study will be made known in a timely manner to 
them and/or their parent or guardian including new information about 
the experimental procedure, the harms and benefits experienced by 
other individuals involved in the study, and any long-term effects 
that have been observed.
    Additional guidance is available in the FDA Guidance for 
Industry: Gene Therapy Clinical Trials--Observing Subjects for 
Delayed Adverse Events (available at the following URL: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/default.htm).
    Appendix M-VI Footnotes of Appendix M will be renumbered to 
Appendix M-III. Footnotes of Appendix M. There will be no amendment 
to the language.


    Dated: October 9, 2015.
Francis S. Collins,
Director, National Institutes of Health.
[FR Doc. 2015-26388 Filed 10-15-15; 8:45 am]
 BILLING CODE 4140-01-P



                                                                              Federal Register / Vol. 80, No. 200 / Friday, October 16, 2015 / Notices                                           62543

                                                people with disabilities are represented                are reviewed and registered with the                     1. An oversight body (an Institutional
                                                on HHS Federal advisory committees,                     NIH, and (C) the streamlining of the NIH              Biosafety Committee (IBC) or an
                                                and the Department therefore,                           protocol registration submission                      Institutional Review Board (IRB))
                                                encourages nominations of qualified                     requirements under Appendix M–I–A of                  determines that a human gene transfer
                                                candidates from these groups. The                       the NIH Guidelines.                                   protocol submitted to it for approval
                                                Department also encourages geographic                   DATES: To ensure consideration,                       would significantly benefit from RAC
                                                diversity in the composition of the                     comments must be submitted in writing                 review; and
                                                Committee. Appointment to this                          by November 30, 2015.                                    2. One or more of the criteria below
                                                Committee shall be made without                         ADDRESSES: Comments may be                            are satisfied:
                                                discrimination on the basis of age, race,               submitted by email at OBA-osp@                           a. The protocol uses a new vector,
                                                ethnicity, gender, sexual orientation,                  od.nih.gov, by fax at 301–496–9839, or                genetic material, or delivery
                                                disability, and cultural, religious, or                 by mail to the Office of Science Policy,              methodology that represents a first-in-
                                                socioeconomic status.                                   National Institutes of Health, 6705                   human experience, thus presenting an
                                                   The Department is soliciting                         Rockledge Drive, Suite 750, Bethesda,                 unknown risk.
                                                nominations for two non-federal                         Maryland 20892–7985. All written                         b. The protocol relies on preclinical
                                                members from among scientists,                          comments received in response to this                 safety data that were obtained using a
                                                physicians, and other health                            notice will be available for public                   new preclinical model system of
                                                professionals and for one non-federal                   inspection at the NIH Office of Science               unknown and unconfirmed value.
                                                member of the general public who is a                   Policy (OSP), 6705 Rockledge Drive,                      c. The proposed vector, gene
                                                representative of a leading research,                   Suite 750, Bethesda, MD 20892–7985,                   construct, or method of delivery is
                                                advocacy, or service organization for                   weekdays between the hours of 8:30                    associated with possible toxicities that
                                                people with pain-related conditions.                    a.m. and 5 p.m. and may be posted to                  are not widely known and that may
                                                These candidates will be considered to                  the NIH OSP Web site.                                 render it difficult for oversight bodies to
                                                fill positions opened through                           FOR FURTHER INFORMATION CONTACT: If                   evaluate the protocol rigorously.
                                                completion of current member terms.                     you have questions, or require                           The chair of an oversight body or an
                                                Nominations are due by 5 p.m. on                        additional background information                     authorized oversight body
                                                November 19, 2015, using the IPRCC                      about these proposed changes, please                  representative may submit a request for
                                                nomination web form: http://                            contact the NIH by email at OBA-osp@                  RAC review by sending the request to
                                                iprcc.nih.gov/about/IPRCC-                              od.nih.gov, or telephone at 301–496–                  the NIH as part of the submission
                                                Nomination.htm.                                         9838.                                                 materials provided by the PI. This
                                                  Dated: October 8, 2015.                               SUPPLEMENTARY INFORMATION: The NIH                    request must include the rationale for
                                                Walter J. Koroshetz,                                    Office of the Director requested that the             why the protocol satisfies both items 1
                                                Director, National Institute of Neurological            IOM review whether gene transfer                      and 2 of the NIH RAC review criteria.
                                                Disorders and Stroke, National Institutes of            research raises issues of concern that                The NIH will review the request and
                                                Health.                                                 warrant the current level of RAC                      notify the requestor of a decision in no
                                                [FR Doc. 2015–26408 Filed 10–15–15; 8:45 am]            oversight of individual clinical trials               more than ten working days.
                                                BILLING CODE 4140–01–P                                  involving gene transfer techniques. The                  1. If the NIH determines that the
                                                                                                        IOM noted that the RAC has served a                   criteria listed in both 1 and 2 above are
                                                                                                        valuable role, but concluded that the                 satisfied, the NIH Director will convene
                                                DEPARTMENT OF HEALTH AND                                current level of oversight over                       the RAC.
                                                HUMAN SERVICES                                          individual clinical trials is no longer                  2. If the NIH receives a request for
                                                                                                        justifiable. In an effort to maximize the             RAC review of a protocol that the NIH
                                                National Institutes of Health                           benefits of the RAC review process, the               determines does not meet both of these
                                                                                                        IOM recommended that the NIH                          criteria, the NIH would:
                                                Proposed Action Under the NIH                                                                                    a. Inform the requestor that RAC
                                                                                                        maintain its protocol submission and
                                                Guidelines for Research Involving                                                                             review is not warranted, and
                                                                                                        safety reporting requirements, but
                                                Recombinant or Synthetic Nucleic Acid                                                                            b. offer to provide the requestor with
                                                                                                        restrict individual gene transfer protocol
                                                Molecules (NIH Guidelines)                                                                                    information about previous protocols
                                                                                                        reviews to exceptional cases that meet
                                                AGENCY: National Institutes of Health                   specified criteria (full recommendations              that have used similar products, the
                                                (NIH), HHS.                                             are listed in the IOM report Oversight                outcome of those studies, if available,
                                                ACTION: Notice of proposed changes to                   and Review of Clinical Gene Transfer                  and a summary of relevant safety data.
                                                the NIH Guidelines.                                     Protocols: Assessing the Role of the                     3. Even if the protocol does not meet
                                                                                                        Recombinant DNA Advisory Committee                    the proposed criteria listed in both
                                                SUMMARY:    The NIH seeks public                        (http://www.iom.edu/Reports/2013/                     items 1 and 2 above, the NIH Director,
                                                comment on its proposal to amend the                    Oversight-and-Review-of-Clinical-Gene-                in consultation (if necessary) with
                                                NIH Guidelines for Research Involving                   Transfer-Protocols.aspx)).                            appropriate regulatory authorities (e.g.,
                                                Recombinant or Synthetic Nucleic Acid                      After careful consideration of the                 the Office for Human Research
                                                Molecules (NIH Guidelines) to                           IOM’s recommendations, the NIH                        Protections, the Food and Drug
                                                incorporate the recommendations of the                  proposes amendments to the NIH                        Administration), can select protocols for
                                                Institute of Medicine (IOM) regarding                   Guidelines in the following areas:                    review that may present significant
                                                human gene transfer clinical research                      A. Criteria and process for selecting              scientific, societal, or ethical concerns.
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                                                protocols. The NIH proposes                             protocols for RAC review. The following                  B. Process by which human gene
                                                amendments to the following: (A) The                    criteria (subsequently referred to as the             transfer protocols are registered with the
                                                criteria for selecting protocols for in-                NIH RAC review criteria) are proposed                 NIH. All human gene transfer protocols
                                                depth review and public discussion by                   for initiating RAC review of individual               subject to Section III–C of the NIH
                                                the NIH Recombinant DNA Advisory                        human gene transfer protocols (criteria               Guidelines will continue to be registered
                                                Committee (RAC), (B) the process by                     listed in both items 1 and 2 must be                  with the NIH. However, the following
                                                which human gene transfer protocols                     met):                                                 changes are being proposed:


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                                                62544                         Federal Register / Vol. 80, No. 200 / Friday, October 16, 2015 / Notices

                                                   1. The Principal Investigator (PI) will              Proposed Amendments to the NIH                        Initiated by the NIH Director; or (2) initiated
                                                continue to be responsible for                          Guidelines                                            by the NIH OBA Director following a
                                                submitting documentation regarding a                                                                          recommendation to NIH OBA by: (a) Three or
                                                                                                           Throughout the document the                        more RAC members; or (b) a Federal agency
                                                proposed human gene transfer protocol                   following global changes will be made:                other than NIH. After a human gene transfer
                                                to his or her local oversight bodies. The               (i) The NIH OSP will replace the NIH                  experiment is reviewed by the RAC at a
                                                PI will also continue to be responsible                 OBA, (ii) the term ‘‘RAC review’’ will be             regularly scheduled meeting, NIH OBA will
                                                for submitting documentation as                         replaced with the term ‘‘NIH protocol                 send a letter, unless NIH OBA determines
                                                outlined in Appendix M–I–A to the                       registration process’’ as appropriate; (iii)          that there are exceptional circumstances,
                                                NIH. As part of the submission to the                                                                         within 10 working days to the NIH Director,
                                                                                                        the title for Appendix M–I–B will be                  the Principal Investigator, the sponsoring
                                                NIH, the PI shall provide documentation                 changed; and (iv) the requirement for a               institution, and other DHHS components, as
                                                from oversight bodies regarding their                   CV/biosketch of key personnel will be                 appropriate, summarizing the RAC
                                                assessment of whether RAC review is                     deleted.                                              recommendations.
                                                warranted.                                                 Section I–E is proposed to be                         For a clinical trial site that is added after
                                                   2. Completion of the protocol                        amended to include the following new                  the RAC review process, no research
                                                registration process:                                   definitions:                                          participant shall be enrolled (see definition
                                                                                                                                                              of enrollment in Section I–E–7) at the clinical
                                                   a. If no oversight body requests RAC                 I–E–11. An ‘‘oversight body’’ is an                   trial site until the following documentation
                                                review, the IBC may proceed with its                       institutional entity (an Institutional             has been submitted to NIH OBA: (1)
                                                approval process upon receipt of                           Biosafety Committee or an                          Institutional Biosafety Committee approval
                                                documentation from the NIH indicating                      Institutional Review Board) that must              (from the clinical trial site); (2) Institutional
                                                that the protocol registration process is                  review and approve a human gene                    Review Board approval; (3) Institutional
                                                complete. No research participant shall                    transfer trial.                                    Review Board-approved informed consent
                                                                                                        I–E–12. A ‘‘regulatory authority’’ is a               document; (4) curriculum vitae of the
                                                be enrolled (see definition of enrollment                                                                     Principal Investigator(s) (no more than two
                                                in Section I–E–7) in the human gene                        federal entity that by statute has
                                                                                                                                                              pages in biographical sketch format); and (5)
                                                transfer protocol until the protocol                       oversight over research involving                  NIH grant number(s) if applicable.
                                                registration process has been completed.                   humans.                                               In order to maintain public access to
                                                   b. If an oversight body requests review                 Section III–C–1 currently states:                  information regarding human gene transfer
                                                                                                                                                              (including protocols that are not publicly
                                                and the NIH agrees that the submission                  Section III–C–1. Experiments Involving the            reviewed by the RAC), NIH OBA will
                                                has met the criteria in A above, the                    Deliberate Transfer of Recombinant or                 maintain the documentation described in
                                                protocol will undergo RAC review and                    Synthetic Nucleic Acid Molecules, or DNA or           Appendices M–I through M–V. The
                                                public discussion. The IBC may not                      RNA Derived From Recombinant or                       information provided in response to
                                                approve a protocol until the RAC review                 Synthetic Nucleic Acid Molecules, Into One            Appendix M should not contain any
                                                                                                        or More Human Research Participants                   confidential commercial information or trade
                                                process has been completed. The IBC
                                                may proceed with its approval process                      Human gene transfer is the deliberate              secrets, enabling all aspects of RAC review to
                                                upon receipt of documentation from the                  transfer into human research participants of          be open to the public.
                                                                                                        either:                                                  Note: For specific directives concerning the
                                                NIH indicating that the protocol                           1. Recombinant nucleic acid molecules, or          use of retroviral vectors for gene delivery,
                                                registration process is complete. No                    DNA or RNA derived from recombinant                   consult Appendix B–V–1, Murine, Retroviral
                                                research participant shall be enrolled                  nucleic acid molecules, or                            Vectors.
                                                (see definition of enrollment in Section                   2. Synthetic nucleic acid molecules, or             Section III–C–1 is proposed to be
                                                I–E–7) in the human gene transfer                       DNA or RNA derived from synthetic nucleic
                                                                                                        acid molecules that meet any one of the
                                                                                                                                                              amended as follows:
                                                protocol until the protocol registration
                                                process has been completed.                             following criteria:                                   Section III–C–1. Experiments Involving the
                                                                                                           a. Contain more than 100 nucleotides; or           Deliberate Transfer of Recombinant or
                                                   C. Streamlining the submission                          b. Possess biological properties that enable       Synthetic Nucleic Acid Molecules, or DNA or
                                                requirements for protocol registration.                 integration into the genome (e.g., cis                RNA Derived From Recombinant or
                                                Section III–C–1 and Appendix M of the                   elements involved in integration); or                 Synthetic Nucleic Acid Molecules, Into One
                                                NIH Guidelines specify the                                 c. Have the potential to replicate in a cell;      or More Human Research Participants
                                                requirements for protocol submission,                   or                                                       Human gene transfer is the deliberate
                                                RAC review, and reporting requirements                     d. Can be translated or transcribed.               transfer into human research participants of
                                                for human gene transfer experiments. In                    No research participant shall be enrolled          either:
                                                                                                        (see definition of enrollment in Section I–E–            1. Recombinant nucleic acid molecules, or
                                                an effort to streamline the protocol                    7) until the RAC review process has been
                                                submission process, the NIH proposes to                                                                       DNA or RNA derived from recombinant
                                                                                                        completed (see Appendix M–I–B, RAC                    nucleic acid molecules, or
                                                reduce the submission requirements as                   Review Requirements).                                    2. Synthetic nucleic acid molecules, or
                                                outlined in Appendix M–I–A.                                In its evaluation of human gene transfer           DNA or RNA derived from synthetic nucleic
                                                Specifically, only a subset of the                      proposals, the RAC will consider whether a            acid molecules that meet any one of the
                                                information listed under the current                    proposed human gene transfer experiment               following criteria:
                                                Appendices M–II through M–V will be                     presents characteristics that warrant public             a. Contain more than 100 nucleotides; or
                                                required mainly for oversight bodies to                 RAC review and discussion (See Appendix                  b. Possess biological properties that enable
                                                                                                        M–I–B–2). The process of public RAC review            integration into the genome (e.g., cis
                                                determine RAC review eligibility and to                 and discussion is intended to foster the safe         elements involved in integration); or
                                                support the Genetic Modification                        and ethical conduct of human gene transfer               c. Have the potential to replicate in a cell;
                                                Clinical Research Information System                    experiments. Public review and discussion of          or
                                                (GeMCRIS®), which facilitates safety                    a human gene transfer experiment (and                    d. Can be translated or transcribed.
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                                                reporting and provides access to                        access to relevant information) also serves to           No research participant shall be enrolled
                                                information about human gene transfer                   inform the public about the technical aspects         (see definition of enrollment in Section I–E–
                                                protocols registered with the NIH.                      of the proposal, the meaning and significance         7) until the NIH protocol registration process
                                                                                                        of the research, and any significant safety,          has been completed (see Appendix M–I–B,
                                                   The proposed changes to the RAC                      social, and ethical implications of the               Selection of Individual Protocols for Public
                                                review process, outlined above, will                    research.                                             RAC Review and Discussion).
                                                require amendment of multiple portions                     Public RAC review and discussion of a                 In its evaluation of human gene transfer
                                                of the NIH Guidelines.                                  human gene transfer experiment may be: (1)            protocols, the NIH will make a



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                                                                              Federal Register / Vol. 80, No. 200 / Friday, October 16, 2015 / Notices                                              62545

                                                determination, following a request from one             consult Appendix B–V–1, Murine, Retroviral             shall not be affiliated with the institution
                                                or more oversight bodies, whether a proposed            Vectors.                                               (apart from their membership on the
                                                human gene transfer experiment has one or                                                                      Institutional Biosafety Committee) and who
                                                more of the characteristics that warrant
                                                                                                              Section IV–B–1–f currently states:
                                                                                                                                                               represent the interest of the surrounding
                                                public RAC review and discussion (See                      Section IV–B–1–f. Ensure that when the              community with respect to health and
                                                Appendix M–1–B–1). The process of public                institution participates in or sponsors                protection of the environment (e.g., officials
                                                RAC review and discussion is intended to                recombinant or synthetic nucleic acid                  of state or local public health or
                                                foster the safe and ethical conduct of human            molecule research involving human subjects:            environmental protection agencies, members
                                                gene transfer experiments. Public review and            (i) The Institutional Biosafety Committee has          of other local governmental bodies, or
                                                discussion of a human gene transfer                     adequate expertise and training (using ad hoc          persons active in medical, occupational
                                                experiment (and access to relevant                      consultants as deemed necessary), (ii) all             health, or environmental concerns in the
                                                information) also serves to inform the public           aspects of Appendix M have been                        community). The Institutional Biosafety
                                                about the technical aspects of the proposal,            appropriately addressed by the Principal               Committee shall include at least one
                                                the meaning and significance of the research,           Investigator; and (iii) no research participant        individual with expertise in plant, plant
                                                and any significant safety, social, and ethical         shall be enrolled (see definition of                   pathogen, or plant pest containment
                                                implications of the research.                           enrollment in Section I–E–7) in a human                principles when experiments utilizing
                                                   Public RAC review and discussion of a                gene transfer experiment until the RAC                 Appendix P, Physical and Biological
                                                human gene transfer experiment may be                   review process has been completed (see                 Containment for Recombinant or Synthetic
                                                initiated in two exceptional circumstances:             Appendix M–I–B, RAC Review                             Nucleic Acid Molecule Research Involving
                                                (1) The NIH will determine, following a                 Requirements), Institutional Biosafety                 Plants, require prior approval by the
                                                request for RAC public review from an                   Committee approval has been obtained,                  Institutional Biosafety Committee. The
                                                oversight body, whether the protocol has one            Institutional Review Board approval has been           Institutional Biosafety Committee shall
                                                or more of the following characteristics: (i)           obtained, and all applicable regulatory                include at least one scientist with expertise
                                                The protocol uses a new vector, genetic                 authorizations have been obtained.                     in animal containment principles when
                                                material, or delivery methodology that                  Institutional Biosafety Committee approval             experiments utilizing Appendix Q, Physical
                                                represents a first-in-human experience, thus            must be obtained from each institution at
                                                presenting an unknown risk; (ii) the protocol                                                                  and Biological Containment for Recombinant
                                                                                                        which recombinant or synthetic nucleic acids           or Synthetic Nucleic Acid Molecule Research
                                                relies on preclinical safety data that were             will be administered to human subjects (as
                                                obtained using a new preclinical model                                                                         Involving Animals, require Institutional
                                                                                                        opposed to each institution involved in the            Biosafety Committee prior approval. When
                                                system of unknown and unconfirmed value;                production of vectors for human application
                                                or (iii) the proposed vector, gene construct,                                                                  the institution conducts recombinant or
                                                                                                        and each institution at which there is ex vivo         synthetic nucleic acid molecule research at
                                                or method of delivery is associated with                transduction of recombinant or synthetic
                                                possible toxicities that are not widely known                                                                  BL3, BL4, or Large Scale (greater than 10
                                                                                                        nucleic acid molecule material into target             liters), a Biological Safety Officer is
                                                and that may render it difficult for oversight          cells for human application).
                                                bodies to evaluate the protocol rigorously. If                                                                 mandatory and shall be a member of the
                                                an oversight body requests public RAC                    Section IV–B–1–f is proposed to be                    Institutional Biosafety Committee (see
                                                review, but the protocol does not have one              amended as follows:                                    Section IV–B–3, Biological Safety Officer).
                                                or more of the above characteristics (listed in                                                                When the institution participates in or
                                                                                                           Section IV–B–1–f. Ensure that when the              sponsors recombinant or synthetic nucleic
                                                i, ii, or iii), then the NIH will inform the            institution participates in or sponsors
                                                requesting oversight body that public RAC                                                                      acid molecule research involving human
                                                                                                        recombinant or synthetic nucleic acid                  research participants, the institution must
                                                review is not warranted. (2) Public RAC
                                                                                                        molecule research involving human subjects:            ensure that: (i) The Institutional Biosafety
                                                review and discussion of protocols not
                                                                                                        (i) The Institutional Biosafety Committee has          Committee has adequate expertise and
                                                requested for review by an oversight body
                                                                                                        adequate expertise and training (using ad hoc          training (using ad hoc consultants as deemed
                                                may be initiated by the NIH Director if: (a)
                                                                                                        consultants as deemed necessary), (ii) all             necessary); (ii) all aspects of Appendix M
                                                The protocol has one or more of the three
                                                                                                        aspects of Appendix M have been                        have been appropriately addressed by the
                                                characteristics listed above (i, ii, or iii) and
                                                                                                        appropriately addressed by the Principal               Principal Investigator; (iii) no research
                                                public RAC review and discussion would
                                                                                                        Investigator; and (iii) no research participant        participant shall be enrolled (see definition
                                                provide a clear and obvious benefit to the
                                                                                                        shall be enrolled (see definition of                   of enrollment in Section I–E–7) in a human
                                                scientific community or the public; or (b) the
                                                                                                        enrollment in Section I–E–7) in a human                gene transfer experiment until the RAC
                                                protocol otherwise raises significant
                                                scientific, societal, or ethical concerns.              gene transfer experiment until the NIH                 review process has been completed (see
                                                   For a clinical trial site that is added after        protocol registration process has been                 Appendix M–I–B, RAC Review
                                                completion of the NIH protocol registration             completed (see Appendix M–I–B, Selection               Requirements); and (iv) final IBC approval is
                                                process, no research participant shall be               of Individual Protocols for Public RAC                 granted only after the RAC review process
                                                enrolled (see definition of enrollment in               Review and Discussion), Institutional                  has been completed (see Appendix M–I–B,
                                                Section I–E–7) at the clinical trial site until         Biosafety Committee approval has been                  RAC Review Requirements). Institutional
                                                the following documentation has been                    obtained, Institutional Review Board                   Biosafety Committee approval must be
                                                submitted to the NIH OSP: (1) Institutional             approval has been obtained, and all                    obtained from the institution at which
                                                Biosafety Committee approval (from the                  applicable regulatory authorizations have              recombinant or synthetic nucleic acid
                                                clinical trial site); (2) Institutional Review          been obtained. Institutional Biosafety                 molecule material will be administered to
                                                Board approval; (3) Institutional Review                Committee approval must be obtained from               human research participants (rather than the
                                                Board-approved informed consent document;               the clinical trial site.                               site involved in manufacturing gene transfer
                                                and (4) the NIH grant number(s) if applicable.            None of the other sub-sections under                 products).
                                                   In order to maintain public access to                Section IV–B–1. General Information are                   Note: Individuals, corporations, and
                                                information regarding human gene transfer               proposed to be amended.                                institutions not otherwise covered by the NIH
                                                (including protocols that are not publicly                                                                     Guidelines, are encouraged to adhere to the
                                                                                                          Section IV–B–2–a–(1) currently states:
                                                reviewed by the RAC), the NIH OSP will                                                                         standards and procedures set forth in
                                                maintain the documentation described in                   Section IV–B–2–a–(1). The Institutional              Sections I through IV (see Section IV–D,
                                                Appendices M–I through M–II. The                        Biosafety Committee must be comprised of               Voluntary Compliance. The policy and
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                                                information provided in response to                     no fewer than five members so selected that            procedures for establishing an Institutional
                                                Appendix M should not contain any                       they collectively have experience and                  Biosafety Committee under Voluntary
                                                confidential commercial or financial                    expertise in recombinant or synthetic nucleic          Compliance, are specified in Section IV–D–
                                                information or trade secrets, enabling all              acid molecule technology and the capability            2, Institutional Biosafety Committee
                                                aspects of RAC review to be open to the                 to assess the safety of recombinant or                 Approval).
                                                public.                                                 synthetic nucleic acid molecule research and
                                                   Note: For specific directives concerning the         to identify any potential risk to public health          Section IV–B–2–a–(1) is proposed to
                                                use of retroviral vectors for gene delivery,            or the environment. At least two members               be amended as follows:


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                                                62546                         Federal Register / Vol. 80, No. 200 / Friday, October 16, 2015 / Notices

                                                   Section IV–B–2–a–(1). The Institutional              procedures for establishing an Institutional          enrollment in Section I–E–7) in a human
                                                Biosafety Committee must be comprised of                Biosafety Committee under Voluntary                   gene transfer experiment until the NIH
                                                no fewer than five members so selected that             Compliance, are specified in Section IV–D–            protocol registration process has been
                                                they collectively have experience and                   2, Institutional Biosafety Committee                  completed (see Appendix M–I–B, Selection
                                                expertise in recombinant or synthetic nucleic           Approval).                                            of Individual Protocols for Public RAC
                                                acid molecule technology and the capability                                                                   Review and Discussion), Institutional
                                                                                                          None of the other sub-sections under
                                                to assess the safety of recombinant or                                                                        Biosafety Committee approval (from the
                                                synthetic nucleic acid molecule research and            Section IV–B2–a. Membership and                       clinical trial site) has been obtained,
                                                to identify any potential risk to public health         Procedures of the IBC are proposed to be              Institutional Review Board approval has been
                                                or the environment. At least two members                amended.                                              obtained, and all applicable regulatory
                                                shall not be affiliated with the institution              Section IV–B–2–b–(1) currently states:              authorizations have been obtained; (v) for
                                                (apart from their membership on the                        Section IV–B–2–b–(1). Reviewing                    human gene transfer protocols selected for
                                                Institutional Biosafety Committee) and who              recombinant or synthetic nucleic acid                 public RAC review and discussion,
                                                represent the interest of the surrounding               molecule research conducted at or sponsored           consideration of the issues raised and
                                                community with respect to health and                    by the institution for compliance with the            recommendations made as a result of this
                                                protection of the environment (e.g., officials          NIH Guidelines as specified in Section III,           review and consideration of the Principal
                                                of state or local public health or                      Experiments Covered by the NIH Guidelines,            Investigator’s response to the RAC
                                                environmental protection agencies, members              and approving those research projects that            recommendations; (vi) ensuring that final IBC
                                                of other local governmental bodies, or                  are found to conform with the NIH                     approval is granted only after the NIH
                                                persons active in medical, occupational                 Guidelines. This review shall include: (i)            protocol registration process has been
                                                health, or environmental concerns in the                Independent assessment of the containment             completed (see Appendix M–I–B, Selection
                                                community). The Institutional Biosafety                 levels required by the NIH Guidelines for the         of Individual Protocols for Public RAC
                                                Committee shall include at least one                    proposed research; (ii) assessment of the             Review and Discussion); and (vii) ensuring
                                                individual with expertise in plant, plant               facilities, procedures, practices, and training       compliance with all surveillance, data
                                                pathogen, or plant pest containment                     and expertise of personnel involved in                reporting, and adverse event reporting
                                                principles when experiments utilizing                   recombinant or synthetic nucleic acid                 requirements set forth in the NIH Guidelines.
                                                Appendix P, Physical and Biological                     molecule research; (iii) ensuring that all
                                                Containment for Recombinant or Synthetic                                                                        None of the other sub-sections under
                                                                                                        aspects of Appendix M have been
                                                Nucleic Acid Molecule Research Involving                appropriately addressed by the Principal              Section IV–B–2–b. Functions of the IBC
                                                Plants, require prior approval by the                   Investigator; (iv) ensuring that no research          are proposed to be amended.
                                                Institutional Biosafety Committee. The                  participant is enrolled (see definition of              Section IV–B–6 currently states:
                                                Institutional Biosafety Committee shall                 enrollment in Section I–E–7) in a human               Section IV–B–6. Human Gene Therapy
                                                include at least one scientist with expertise           gene transfer experiment until the RAC                Expertise
                                                in animal containment principles when                   review process has been completed (see
                                                experiments utilizing Appendix Q, Physical                                                                      When the institution participates in or
                                                                                                        Appendix M–I–B, RAC Review
                                                and Biological Containment for Recombinant                                                                    sponsors recombinant or synthetic nucleic
                                                                                                        Requirements), Institutional Biosafety
                                                or Synthetic Nucleic Acid Molecule Research             Committee approval (from the clinical trial           acid molecule research involving human
                                                Involving Animals, require Institutional                site) has been obtained, Institutional Review         subjects, the institution must ensure that: (i)
                                                Biosafety Committee prior approval. When                Board approval has been obtained, and all             the Institutional Biosafety Committee has
                                                the institution conducts recombinant or                 applicable regulatory authorizations have             adequate expertise and training (using ad hoc
                                                synthetic nucleic acid molecule research at             been obtained; (v) for human gene transfer            consultants as deemed necessary) and (ii) all
                                                BL3, BL4, or Large Scale (greater than 10               protocols selected for public RAC review and          aspects of Appendix M, Points to Consider in
                                                liters), a Biological Safety Officer is                 discussion, consideration of the issues raised        the Design and Submission of Protocols for
                                                mandatory and shall be a member of the                  and recommendations made as a result of               the Transfer of Recombinant or Synthetic
                                                Institutional Biosafety Committee (see                  this review and consideration of the                  Nucleic Acid Molecules into One or More
                                                Section IV–B–3, Biological Safety Officer).             Principal Investigator’s response to the RAC          Human Subjects (Points to Consider), have
                                                When the institution participates in or                 recommendations; (vi) ensuring that final IBC         been appropriately addressed by the
                                                sponsors recombinant or synthetic nucleic               approval is granted only after the RAC review         Principal Investigator prior to submission to
                                                acid molecule research involving human                  process has been completed (see Appendix              NIH/OBA.
                                                research participants, the institution must             M–I–B, RAC Review Requirements); and (vii)             Section IV–B–6 is proposed to be
                                                ensure that: (i) The Institutional Biosafety            ensuring compliance with all surveillance,            amended as follows:
                                                Committee has adequate expertise and                    data reporting, and adverse event reporting
                                                training (using ad hoc consultants as deemed            requirements set forth in the NIH Guidelines.         Section IV–B–6. Human Gene Therapy
                                                necessary); (ii) all aspects of Appendix M                                                                    Expertise
                                                                                                          Section IV–B–2–b–(1) is proposed to
                                                have been appropriately addressed by the                                                                        When the institution participates in or
                                                Principal Investigator; (iii) no research               be amended as follows:                                sponsors recombinant or synthetic nucleic
                                                participant shall be enrolled (see definition             Section IV–B–2–b–(1). Reviewing                     acid molecule research involving human
                                                of enrollment in Section I–E–7) in a human              recombinant or synthetic nucleic acid                 subjects, the institution must ensure that: (i)
                                                gene transfer experiment until the NIH                  molecule research conducted at or sponsored           the Institutional Biosafety Committee has
                                                protocol registration process has been                  by the institution for compliance with the            adequate expertise and training (using ad hoc
                                                completed (see Appendix M–I–B, Selection                NIH Guidelines as specified in Section III,           consultants as deemed necessary) and (ii) all
                                                of Individual Protocols for Public RAC                  Experiments Covered by the NIH Guidelines,            aspects of Appendix M, Points to Consider in
                                                Review and Discussion); and (iv) final IBC              and approving those research projects that            the Design and Submission of Protocols for
                                                approval is granted only after the NIH                  are found to conform with the NIH                     the Transfer of Recombinant or Synthetic
                                                protocol registration process has been                  Guidelines. This review shall include: (i)            Nucleic Acid Molecules into One or More
                                                completed (see Appendix M–I–B, Selection                Independent assessment of the containment             Human Subjects (Points to Consider), have
                                                of Individual Protocols for Public RAC                  levels required by the NIH Guidelines for the         been appropriately addressed by the
                                                Review and Discussion). Institutional                   proposed research; (ii) assessment of the             Principal Investigator prior to its approval.
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                                                Biosafety Committee approval must be                    facilities, procedures, practices, and training
                                                obtained from the clinical trial site.                  and expertise of personnel involved in                   Section IV–B–7–b–(6) currently states:
                                                   Note: Individuals, corporations, and                 recombinant or synthetic nucleic acid                   Section IV–B–7–b–(6). Ensure that all
                                                institutions not otherwise covered by the NIH           molecule research; (iii) ensuring that all            aspects of Appendix M have been
                                                Guidelines, are encouraged to adhere to the             aspects of Appendix M have been                       appropriately addressed prior to submission
                                                standards and procedures set forth in                   appropriately addressed by the Principal              of a human gene transfer experiment to NIH
                                                Sections I through IV (see Section IV–D,                Investigator (iv) ensuring that no research           OBA, and provide a letter signed by the
                                                Voluntary Compliance. The policy and                    participant is enrolled (see definition of            Principal Investigator(s) on institutional



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                                                                              Federal Register / Vol. 80, No. 200 / Friday, October 16, 2015 / Notices                                              62547

                                                letterhead acknowledging that the                       academic studies. In November 1982, the               ensure continued public access to relevant
                                                documentation being submitted to NIH OBA                President’s Commission for the Study of               human gene transfer information conducted
                                                complies with the requirements set forth in             Ethical Problems in Medicine and                      in compliance with the NIH Guidelines.
                                                Appendix M. No research participant shall be            Biomedical and Behavioral Research                    Investigational New Drug (IND) applications
                                                enrolled (see definition of enrollment in               published a report, Splicing Life, which              should be submitted to FDA in the format
                                                Section I–E–7) in a human gene transfer                 resulted from a two-year process of public            described in 21 CFR, Chapter I, Subchapter
                                                experiment until the RAC review process has             deliberation and hearings. Upon release of            D, Part 312, Subpart B, Section 23, IND
                                                been completed (see Appendix M–I–B, RAC                 that report, a U.S. House of Representatives          Content and Format.
                                                Review Requirements); IBC approval (from                subcommittee held three days of public                   Institutional Biosafety Committee approval
                                                the clinical trial site) has been obtained;             hearings with witnesses from a wide range of          must be obtained from each institution at
                                                Institutional Review Board (IRB) approval               fields from the biomedical and social                 which recombinant or synthetic nucleic acid
                                                has been obtained; and all applicable                   sciences to theology, philosophy, and law. In         molecule material will be administered to
                                                regulatory authorization(s) have been                   December 1984, the Office of Technology               human subjects (as opposed to each
                                                obtained.                                               Assessment released a background paper,               institution involved in the production of
                                                   For a clinical trial site that is added after        Human Gene Therapy, which concluded that              vectors for human application and each
                                                the RAC review process, no research                     civic, religious, scientific, and medical             institution at which there is ex vivo
                                                participant shall be enrolled (see definition           groups have all accepted, in principle, the           transduction of recombinant or synthetic
                                                of enrollment in Section I–E–7) at the clinical         appropriateness of gene transfer of somatic           nucleic acid molecule material into target
                                                trial site until the following documentation            cells in humans for specific genetic diseases.        cells for human application).
                                                has been submitted to NIH OBA: (1) IBC                  Somatic cell gene transfer is seen as an                 Factors that may contribute to public
                                                approval (from the clinical trial site); (2) IRB        extension of present methods that might be            discussion of a human gene transfer
                                                approval; (3) IRB-approved informed consent             preferable to other technologies. In light of         experiment by RAC include: (i) New vectors/
                                                document; (4) curriculum vitae of the                   this public support, RAC is prepared to               new gene delivery systems, (ii) new diseases,
                                                Principal Investigator(s) (no more than two             consider proposals for somatic cell gene              (iii) unique applications of gene transfer, and
                                                pages in biographical sketch format); and (5)           transfer.                                             (iv) other issues considered to require further
                                                NIH grant number(s) if applicable.                         RAC will not at present entertain proposals        public discussion. Among the experiments
                                                                                                        for germ line alterations but will consider           that may be considered exempt from RAC
                                                  Section IV–B–7–b–(6) is proposed to                   proposals involving somatic cell gene                 discussion are those determined not to
                                                be amended as follows:                                  transfer. The purpose of somatic cell gene            represent possible risk to human health or
                                                   Section IV–B–7–b–(6). Ensure that all                transfer is to treat an individual patient, e.g.,     the environment. Full, public RAC review
                                                aspects of Appendix M have been                         by inserting a properly functioning gene into         and discussion of a human gene transfer
                                                appropriately addressed prior to submission.            the subject’s somatic cells. Germ line                experiment may be (1) initiated by the NIH
                                                No research participant shall be enrolled (see          alteration involves a specific attempt to             Director; or (2) initiated by the NIH OBA
                                                definition of enrollment in Section I–E–7) in           introduce genetic changes into the germ               Director following a recommendation to NIH
                                                a human gene transfer experiment until the              (reproductive) cells of an individual, with the       OBA by: (a) Three or more RAC members, or
                                                NIH protocol registration process has been              aim of changing the set of genes passed on            (b) a Federal agency other than NIH. An
                                                completed (see Appendix M–I–B, Selection                to the individual’s offspring.                        individual human gene transfer experiment
                                                of Individual Protocols for Public RAC                     The RAC continues to explore the issues            that is recommended for full RAC review
                                                Review and Discussion); IBC approval (from              raised by the potential of in utero gene              should represent novel characteristics
                                                the clinical trial site) has been obtained;             transfer clinical research. However, the RAC          deserving of public discussion. If it is
                                                Institutional Review Board (IRB) approval               concludes that, at present, it is premature to        determined that an experiment will undergo
                                                has been obtained; and all applicable                   undertake any in utero gene transfer clinical         full RAC discussion, NIH/OBA will
                                                regulatory authorization(s) have been                   trial. Significant additional preclinical and         immediately notify the Principal Investigator.
                                                obtained.                                               clinical studies addressing vector                    RAC members may forward individual
                                                   For a clinical trial site that is added after        transduction efficacy, biodistribution, and           requests for additional information relevant
                                                completion of the NIH protocol registration             toxicity are required before a human in utero         to a specific protocol through NIH/OBA to
                                                process, no research participant shall be               gene transfer protocol can proceed. In                the Principal Investigator. In making a
                                                enrolled (see definition of enrollment in               addition, a more thorough understanding of            determination whether an experiment is
                                                Section I–E–7) at the clinical trial site until         the development of human organ systems,               novel, and thus deserving of full RAC
                                                the following documentation has been                    such as the immune and nervous systems, is            discussion, reviewers will examine the
                                                submitted to the NIH OSP: (1) IBC approval              needed to better define the potential efficacy        scientific rationale, scientific context
                                                (from the clinical trial site); (2) IRB approval;       and risks of human in utero gene transfer.            (relative to other proposals reviewed by
                                                (3) IRB-approved informed consent                       Prerequisites for considering any specific            RAC), whether the preliminary in vitro and
                                                document; and (4) NIH grant number(s) if                human in utero gene transfer procedure                in vivo safety data were obtained in
                                                applicable.                                             include an understanding of the                       appropriate models and are sufficient, and
                                                                                                        pathophysiology of the candidate disease and          whether questions related to relevant social
                                                  To implement this new process, the                    a demonstrable advantage to the in utero              and ethical issues have been resolved. RAC
                                                NIH proposes to amend Appendix M,                       approach. Once the above criteria are met,            recommendations on a specific human gene
                                                Points to Consider in the Design and                    the RAC would be willing to consider well             transfer experiment shall be forwarded to the
                                                Submission of Protocols for the Transfer                rationalized human in utero gene transfer             NIH Director, the Principal Investigator, the
                                                of Recombinant or Synthetic Nucleic                     clinical trials.                                      sponsoring institution, and other DHHS
                                                Acid Molecules into One or More                            Research proposals involving the                   components, as appropriate. Relevant
                                                                                                        deliberate transfer of recombinant or                 documentation will be included in the
                                                Human Research Participants (Points to
                                                                                                        synthetic nucleic acid molecules, or DNA or           material for the RAC meeting at which the
                                                Consider).                                              RNA derived from such nucleic acid                    experiment is scheduled to be discussed.
                                                   Appendix M currently states:                         molecules, into human subjects (human gene            RAC meetings will be open to the public
                                                   Appendix M applies to research conducted             transfer) will be considered through a review         except where trade secrets and proprietary
                                                at or sponsored by an institution that receives         process involving both NIH/OBA and RAC.               information are reviewed (see Section IV–D–
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                                                any support for recombinant or synthetic                Investigators shall submit their relevant             5, Protection of Proprietary Data—Voluntary
                                                nucleic acid molecule research from NIH.                information on the proposed human gene                Compliance). RAC prefers that information
                                                Researchers not covered by the NIH                      transfer experiments to NIH/OBA.                      provided in response to Appendix M contain
                                                Guidelines are encouraged to use Appendix               Submission of human gene transfer protocols           no proprietary data or trade secrets, enabling
                                                M (see Section I–C, General Applicability).             to NIH will be in the format described in             all aspects of the review to be open to the
                                                   The acceptability of human somatic cell              Appendix M–I–A, Submission Requirements               public.
                                                gene transfer has been addressed in several             for Protocol Submission. Submission to NIH               Note: Any application submitted to NIH/
                                                public documents as well as in numerous                 shall be for registration purposes and will           OBA shall not be designated as ‘confidential’



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                                                62548                         Federal Register / Vol. 80, No. 200 / Friday, October 16, 2015 / Notices

                                                in its entirety. In the event that a sponsor            sciences to theology, philosophy, and law. In         protocol uses a new vector, genetic material,
                                                determines that specific responses to one or            December 1984, the Office of Technology               or delivery methodology that represents a
                                                more of the items described in Appendix M               Assessment released a background paper,               first-in-human experience, thus presenting an
                                                should be considered as proprietary or trade            Human Gene Therapy, which concluded that              unknown risk; ii) the protocol relies on
                                                secret, each item should be clearly identified          civic, religious, scientific, and medical             preclinical safety data that were obtained
                                                as such. The cover letter (attached to the              groups have all accepted, in principle, the           using a new preclinical model system of
                                                submitted material) shall: (1) Clearly indicate         appropriateness of gene transfer of somatic           unknown and unconfirmed value; or iii) the
                                                that select portions of the application contain         cells in humans for specific genetic diseases.        proposed vector, gene construct, or method
                                                information considered as proprietary or                Somatic cell gene transfer is seen as an              of delivery is associated with possible
                                                trade secret, (2) a brief explanation as to the         extension of present methods that might be            toxicities that are not widely known and that
                                                reason that each of these items is determined           preferable to other technologies. In light of         may render it difficult for oversight bodies to
                                                proprietary or trade secret.                            this public support, the NIH is prepared to           evaluate the protocol rigorously. If an
                                                   Public discussion of human gene transfer             consider proposals for somatic cell gene              oversight body requests public RAC review,
                                                experiments (and access to relevant                     transfer.                                             but the NIH determines that the protocol
                                                information) shall serve to inform the public              The NIH will not at present entertain              does not have one or more of the above
                                                about the technical aspects of the proposals,           proposals for germ line alterations but will          characteristics (listed in i, ii, or iii), then the
                                                meaning and significance of the research, and           consider proposals involving somatic cell             NIH will inform the requesting oversight
                                                significant safety, social, and ethical                 gene transfer. The purpose of somatic cell            body that public RAC review is not
                                                implications of the research. RAC discussion            gene transfer is to treat an individual patient,      warranted. (2) Public RAC review and
                                                is intended to ensure safe and ethical                  e.g., by inserting a properly functioning gene        discussion of protocols not requested for
                                                conduct of gene transfer experiments and                into the subject’s somatic cells. Germ line           review by an oversight body may be initiated
                                                facilitate public understanding of this novel           alteration involves a specific attempt to             by the NIH Director, after consultation (if
                                                area of biomedical research.                            introduce genetic changes into the germ               needed) with appropriate regulatory
                                                   In its evaluation of human gene transfer             (reproductive) cells of an individual, with the       authorities, if: (a) The protocol has one or
                                                proposals, RAC will consider whether the                aim of changing the set of genes passed on            more of the three characteristics listed above
                                                design of such experiments offers adequate              to the individual’s offspring.                        (i, ii, or iii) and public RAC review and
                                                assurance that their consequences will not go              The NIH continues to explore the issues            discussion would provide a clear and
                                                beyond their purpose, which is the same as              raised by the potential of in utero gene              obvious benefit to the scientific community
                                                the traditional purpose of clinical                     transfer clinical research. However, the NIH          or the public; or (b) the protocol otherwise
                                                investigation, namely, to protect the health            concludes that, at present, it is premature to        raises significant scientific, societal, or
                                                and well being of human subjects being                  undertake any in utero gene transfer clinical         ethical concerns.
                                                treated while at the same time gathering                trial. Significant additional preclinical and            If it is determined that a human gene
                                                generalizable knowledge. Two possible                   clinical studies addressing vector                    transfer trial will undergo RAC review, the
                                                undesirable consequences of the transfer of             transduction efficacy, biodistribution, and           NIH will immediately notify the Principal
                                                recombinant or synthetic nucleic acid                   toxicity are required before a human in utero         Investigator. RAC recommendations
                                                molecules would be unintentional: (i)                   gene transfer protocol can proceed. In                following public review on a specific human
                                                Vertical transmission of genetic changes from           addition, a more thorough understanding of            gene transfer experiment shall be forwarded
                                                an individual to his/her offspring, or (ii)             the development of human organ systems,               to the Principal Investigator, oversight
                                                horizontal transmission of viral infection to           such as the immune and nervous systems, is            bodies, and regulatory authorities, as
                                                other persons with whom the individual                  needed to better define the potential efficacy        appropriate. Relevant documentation will be
                                                comes in contact. Accordingly, Appendices               and risks of human in utero gene transfer.            included in the material for the RAC meeting
                                                M–I through M–V request information that                Prerequisites for considering any specific            at which the human gene transfer trial is
                                                will enable RAC and NIH/OBA to assess the               human in utero gene transfer procedure                scheduled to be discussed. RAC meetings
                                                possibility that the proposed experiment(s)             include an understanding of the                       will be open to the public except where trade
                                                will inadvertently affect reproductive cells or         pathophysiology of the candidate disease and          secrets and proprietary information are
                                                lead to infection of other people (e.g.,                a demonstrable advantage to the in utero              reviewed (see Section IV–D–5, Protection of
                                                medical personnel or relatives).                        approach. Once the above criteria are met,            Proprietary Data—Voluntary Compliance).
                                                   Appendix M will be considered for                    the NIH would be willing to consider well             The NIH prefers that information provided in
                                                revisions as experience in evaluating                   rationalized human in utero gene transfer             response to Appendix M contain no
                                                proposals accumulates and as new scientific             clinical trials.                                      proprietary data or trade secrets, enabling all
                                                developments occur. This review will be                    Research proposals involving the                   aspects of the review to be open to the
                                                carried out periodically as needed.                     deliberate transfer of recombinant or                 public.
                                                                                                        synthetic nucleic acid molecules, or DNA or              Some but not all sections of Appendix M–
                                                 Appendix M is proposed to be                                                                                 I Requirements for Protocol Submission,
                                                                                                        RNA derived from such nucleic acid
                                                amended as follows:                                     molecules, into one or more human subjects            Review, and Reporting—Human Gene
                                                   Appendix M applies to research conducted             (human gene transfer) will be considered              Transfer Experiments are proposed to be
                                                at or sponsored by an institution that receives         through a registration process involving the          amended to decrease the number and amount
                                                any support for recombinant or synthetic                NIH, oversight bodies, and regulatory                 of supporting documentation that must be
                                                nucleic acid molecule research from NIH.                authorities, when appropriate. Investigators          submitted upon protocol registration, and to
                                                Researchers not covered by the NIH                      shall submit the relevant information on the          modify the timing of the registration
                                                Guidelines are encouraged to use Appendix               proposed human gene transfer experiment to            processes. As proposed, Principal
                                                M (see Section I–C, General Applicability).             the oversight bodies and then to the NIH. The         Investigators must submit the material as
                                                   The acceptability of human somatic cell              format of the submission is described in              outlined below to oversight bodies at the
                                                gene transfer has been addressed in several             Appendix M–I–A, Requirements for Protocol             proposed clinical trial sites; however,
                                                public documents as well as in numerous                 Submission. Submission to the NIH OSP                 submission of responses to Appendices M–II
                                                academic studies. In November 1982, the                 shall be for registration purposes and will           through M–V or curriculum vitae will no
                                                President’s Commission for the Study of                 ensure continued public access to relevant            longer be required.
                                                Ethical Problems in Medicine and                        human gene transfer information conducted
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                                                                                                                                                                 Appendix M–I–A currently states:
                                                Biomedical and Behavioral Research                      in compliance with the NIH Guidelines.
                                                published a report, Splicing Life, which                   Public RAC review and discussion of a              Appendix M–I.A. Requirements for Protocol
                                                resulted from a two-year process of public              human gene transfer experiment may be                 Submission
                                                deliberation and hearings. Upon release of              initiated in two exceptional circumstances:              The following documentation must be
                                                that report, a U.S. House of Representatives            (1) The NIH will determine, following a               submitted (see exemption in Appendix M–
                                                subcommittee held three days of public                  request for RAC review from an oversight              III–A, Footnotes of Appendix M) in printed
                                                hearings with witnesses from a wide range of            body, whether the protocol has one or more            or electronic form to the: Office of
                                                fields from the biomedical and social                   of the following characteristics: i) The              Biotechnology Activities, National Institutes



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                                                                              Federal Register / Vol. 80, No. 200 / Friday, October 16, 2015 / Notices                                               62549

                                                of Health, 6705 Rockledge Drive, Suite 750,             viral, bacterial, or plasmid vector); and             as follows to form a consolidated
                                                Bethesda, MD 20892–7985 (20817 for non-                 modifications (e.g., deletions to attenuate or        Appendix M–1–B:
                                                USPS mail), 301–496–9838, 301–496–9839                  self-inactivate, encapsulation in any
                                                (fax), Email: rosenthg@od.nih.gov. NIH OBA              synthetic complex, changes to tropisms, etc.).        Appendix M–1–B. Selection of
                                                will confirm receipt within three working               Please reference any previous clinical                Individual Protocols for Public RAC
                                                days after receiving the submission.                    experience with this vector or similar                Review and Discussion
                                                Investigators should contact NIH OBA if they            vectors.
                                                do not receive this confirmation.                          b. Describe the genetic content of the                As part of the NIH protocol registration
                                                   1. A cover letter on institutional letterhead,       transgene or nucleic acid delivered including         process, documentation from oversight
                                                signed by the Principal Investigator(s), that:          the species source of the sequence and                bodies regarding their assessment of whether
                                                (1) Acknowledges that the documentation                 whether any modifications have been made              RAC review is warranted. If no oversight
                                                submitted to NIH OBA complies with the                  (e.g. mutations, deletions, and truncations).         body would significantly benefit from public
                                                requirements set forth in Appendix M–I–A,               What are the regulatory elements contained            RAC review and discussion, then the
                                                Requirements for Protocol Submission; (2)               in the construct?                                     Principal Investigator shall submit all of the
                                                identifies the Institutional Biosafety                     c. Describe any other material to be used          documentation required to register the
                                                Committee (IBC) and Institutional Review                in preparation of the agent (vector and               submission (see Appendix M–I–A) to the NIH
                                                Board (IRB) at the proposed clinical trial              transgene) that will be administered to the           OSP at any time but shall occur not less than
                                                site(s) responsible for local review and                human research subject (e.g., helper virus,           three working days prior to the anticipated
                                                approval of the protocol; and (3)                       packaging cell line, carrier particles).              date of enrollment of the first subject (see
                                                acknowledges that no research participant                  d. Describe the methods for replication-           definition of enrollment in Section I–E–7),
                                                will be enrolled (see definition of enrollment          competent virus testing, if applicable.               and shall be provided in electronic form to
                                                in Section I–E–7) until the RAC review                     e. Describe the intended ex vivo or in vivo        the Office of Science Policy, National
                                                process has been completed (see Appendix                target cells and transduction efficiency.             Institutes of Health, 6705 Rockledge Drive,
                                                M–I–B, RAC Review Requirements); IBC                       f. Describe the gene transfer agent delivery       Suite 750, Bethesda, MD 20892–7985 (20817
                                                approval (from the clinical trial site) has been        method.                                               for non-USPS mail), 301–496–9838, 301–
                                                obtained; IRB approval has been obtained;                  5. The proposed informed consent                   496–9839 (fax), Email: HGTprotocols@
                                                and all applicable regulatory authorizations            document.                                             mail.nih.gov. Enrollment may proceed upon
                                                have been obtained.                                        6. Specifically for submission to the NIH          acknowledgement that the submission is
                                                   2. The scientific abstract.                          OSP, the PI shall provide additional                  registered.
                                                   3. The non-technical abstract.                       documentation from oversight bodies                      If an oversight body determines that: (1) A
                                                   4. The proposed clinical protocol,                   regarding their assessment of whether RAC             protocol submission would significantly
                                                including tables, figures, and relevant                 review is warranted. In the event that review         benefit from public RAC review and
                                                manuscripts.                                            is requested, the documentation shall include         discussion and (2) that one or more of the
                                                   5. Responses to Appendices M–II through              a justification that the protocol                     following NIH RAC review criteria are met:
                                                M–V, Description of the Proposal, Informed              characteristics (see Section III–C–1) that            (i) The protocol uses a new vector, genetic
                                                Consent, Privacy, and Special Issues.                   would warrant RAC public review have been             material, or delivery methodology that
                                                Responses to Appendices M–II through M–V                met.                                                  represents a first-in-human experience, thus
                                                may be provided either as an appendix to the               Note: Any application submitted shall not          presenting an unknown risk; or (ii) the
                                                clinical protocol or incorporated in the                contain any document that is designated as            protocol relies on preclinical safety data that
                                                clinical protocol. If responses to Appendices           ’confidential’ in its entirety. In the event that     were obtained using a new preclinical model
                                                M–II through M–V are incorporated in the                a sponsor determines that a portion of a              system of unknown and unconfirmed value;
                                                clinical protocol, each response must refer to          specific document should be considered as             or (iii) the proposed vector, gene construct,
                                                the appropriate Appendix M–II through M–                                                                      or method of delivery is associated with
                                                                                                        proprietary or trade secret, each portion of
                                                V.                                                                                                            possible toxicities that are not widely known
                                                                                                        the document should be clearly identified as
                                                   6. The proposed informed consent                                                                           and that may render it difficult for local and
                                                                                                        such. In the event that a specific portion of
                                                document.                                                                                                     federal regulatory bodies to evaluate the
                                                                                                        the submission does contain information that
                                                   7. Curriculum vitae of the Principal                                                                       protocol rigorously, and is therefore
                                                                                                        a sponsor considers to be proprietary or trade
                                                Investigator(s) (no more than two pages in                                                                    requesting RAC review and public
                                                                                                        secret, the submission to the NIH OSP must
                                                biographical sketch format).                                                                                  discussion, the Principal Investigator shall
                                                                                                        contain a letter from the sponsor that: (1)
                                                   Note: A human gene transfer experiment                                                                     submit the documentation as outlined in
                                                                                                        Clearly indicates what select portions of the
                                                submitted to NIH OBA should not contain                                                                       Appendix M–I–A at least 8 weeks prior to the
                                                                                                        application contain information considered
                                                confidential commercial information or trade                                                                  next scheduled meeting in order to be
                                                secrets, enabling all aspects of the review to          as proprietary or trade secret, (2) provides an
                                                                                                        adequate and convincing justification as to           reviewed at that RAC meeting. The
                                                be open to the public.                                                                                        submission shall include documentation
                                                                                                        the reason that this information is considered
                                                 Appendix M–I–A is proposed to be                       to be proprietary or trade secret. The                from oversight bodies regarding their
                                                amended as follows:                                     justification must be able to demonstrate with        assessment of whether RAC review is
                                                                                                        specificity how release of that information           warranted and that one or both have justified
                                                                                                        will reveal a trade secret or will result in          their request according the NIH RAC review
                                                Appendix M–I–A. Requirements for                                                                              criteria listed above. The submission shall be
                                                Protocol Submission                                     substantial competitive harm.
                                                                                                           Appendix M–I–B, RAC Review                         provided to the NIH in electronic form to the
                                                   The following documentation must be                  Requirements is proposed to be amended to             Office of Science Policy, National Institutes
                                                submitted according to institutional policy,            change the process and timing of initial and          of Health, 6705 Rockledge Drive, Suite 750,
                                                to the appropriate oversight bodies and                 RAC review. Currently, investigators are              Bethesda, MD 20892–7985 (20817 for non-
                                                subsequently in electronic form to the NIH              informed within 15 working days whether or            USPS mail), 301–496–9838, 301–496–9839
                                                OSP:                                                    not the protocol requires public RAC review.          (fax), Email: HGTprotocols@mail.nih.gov. If
                                                   1. A scientific abstract.                            Public discussion of selected protocols then          NIH determines that any of the criteria listed
                                                   2. The proposed clinical protocol,                   occurs at the next quarterly RAC meeting,             in subsections (i), (ii), or (iii) above is met,
                                                including tables, figures, and any relevant             which occurs, at a minimum of, eight weeks            the protocol will undergo public RAC review
                                                publications.                                                                                                 and discussion.
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                                                                                                        after receipt of a complete protocol
                                                   3. Summary of preclinical studies                    submission. Under the proposal, individual               If an oversight body requests that the RAC
                                                conducted in support of the proposed                    RAC members will no longer make a                     review a protocol and the NIH determines
                                                clinical trial or reference to the specific             recommendation regarding whether a                    that the protocol does not satisfy one or more
                                                section of the protocol providing this                  protocol should be selected for review at a           of the above NIH RAC review criteria, the
                                                information.                                            public meeting.                                       NIH OSP will inform the Principal
                                                   4. A description of the product:                                                                           Investigator, oversight bodies, and regulatory
                                                   a. Describe the derivation of the delivery            Therefore, Appendix M–1–B–1 and                      authorities, as appropriate, that RAC review
                                                vector system including the source (e.g.,               Appendix M–1–B–2 are being amended                    is not warranted.



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                                                62550                         Federal Register / Vol. 80, No. 200 / Friday, October 16, 2015 / Notices

                                                   Even if an oversight body does not request              The current appendices Appendix M–II,              reasonable accommodations, should
                                                that a particular protocol be reviewed by the           Description of the Proposal; Appendix M–III,          notify the Contact Person listed below
                                                RAC, the NIH Director, after consultation (if           Informed Consent; Appendix M–IV, Privacy;             in advance of the meeting.
                                                needed) with appropriate regulatory                     and Appendix M–V, Special Issues are
                                                authorities, may initiate RAC review if (a) the         proposed to be deleted in their entirety,               The meeting will be closed to the
                                                protocol has one or more of the                         except for Appendix M–III–B–2-b, Long Term            public as indicated below in accordance
                                                characteristics listed above (i, ii, or iii) and        Follow-Up which will be updated to include            with the provisions set forth in section
                                                public RAC review and discussion would                  a reference to FDA’s current guidance on this         552b(c)(6), Title 5 U.S.C., as amended
                                                provide a clear and obvious benefit to the              issue and will become Appendix M–II.                  for the review, discussion, and
                                                scientific community or public; or (b) the                Appendix M–II is proposed to be                     evaluation of individual intramural
                                                protocol otherwise raises significant
                                                scientific, societal, or ethical concerns.
                                                                                                        amended as follows:                                   programs and projects conducted by the
                                                   Completion of the registration process is            Appendix M–II. Long Term Follow-Up                    National Institute of Environmental
                                                defined as: (1) Receipt by the Principal                                                                      Health Sciences, including
                                                Investigator of a letter from the NIH OSP                  To permit evaluation of long-term safety           consideration of personnel
                                                indicating that protocol registration process           and efficacy of gene transfer, prospective            qualifications and performance, and the
                                                is complete and that enrollment may                     subjects should be informed that they are             competence of individual investigators,
                                                proceed; or (2) receipt by the Principal                expected to cooperate in long-term follow-up
                                                                                                        that extends beyond the active phase of the           the disclosure of which would
                                                Investigator of a letter from the NIH after                                                                   constitute a clearly unwarranted
                                                public RAC review that summarizes the                   study. A list of persons who can be contacted
                                                committee’s key comments and                            in the event that questions arise during the          invasion of personal privacy.
                                                recommendations (if any).                               follow-up period should be provided to the              Name of Committee: Board of Scientific
                                                   A complete human gene transfer protocol              investigator. In addition, the investigator           Counselors, NIEHS.
                                                package must be submitted at least eight                should request that subjects continue to                Date: November 15–17, 2015.
                                                weeks before a scheduled RAC meeting to be              provide a current address and telephone                 Closed: November 15, 2015, 7 p.m. to 10
                                                reviewed at that upcoming meeting.                      number.                                               p.m.
                                                   After a human gene transfer experiment is               The subjects should be informed that any             Agenda: To review and evaluate
                                                publicly reviewed by the full RAC at a                  significant findings resulting from the study         programmatic and personnel issues.
                                                regularly scheduled meeting, the NIH OSP                will be made known in a timely manner to                Place: Doubletree Guest Suites, 2515
                                                will send a letter summarizing the RAC’s key            them and/or their parent or guardian                  Meridian Parkway, Research Triangle Park,
                                                comments and recommendations (if any)                   including new information about the                   NC 27713.
                                                regarding the protocol to the Principal                 experimental procedure, the harms and                   Open: November 16, 2015, 8:30 a.m. to
                                                Investigator(s), oversight bodies, and                  benefits experienced by other individuals             11:50 a.m.
                                                regulatory authorities as appropriate.                  involved in the study, and any long-term                Agenda: Scientific Presentations.
                                                Completion of RAC review is defined as                  effects that have been observed.                        Place: Nat. Inst. of Environmental Health
                                                receipt by the Principal Investigator(s) of a              Additional guidance is available in the            Sciences, Building 101, Rodbell Auditorium,
                                                letter from the NIH OSP summarizing the                 FDA Guidance for Industry: Gene Therapy               Rooms 101 ABC, 111 T. W. Alexander Drive,
                                                                                                        Clinical Trials—Observing Subjects for
                                                committee’s findings. Unless the NIH                                                                          Research Triangle Park, NC 27709.
                                                                                                        Delayed Adverse Events (available at the
                                                determines that there are exceptional                                                                           Closed: November 16, 2015, 11:50 a.m. to
                                                                                                        following URL: http://www.fda.gov/
                                                circumstances, the letter containing                                                                          1:30 p.m.
                                                                                                        BiologicsBloodVaccines/
                                                recommendations and comments made                                                                               Agenda: To review and evaluate
                                                                                                        GuidanceComplianceRegulatoryInformation/
                                                following public review will be sent within                                                                   programmatic and personnel issues.
                                                                                                        Guidances/CellularandGeneTherapy/
                                                10 working days after the completion of the                                                                     Place: Nat. Inst. of Environmental Health
                                                                                                        default.htm).
                                                RAC meeting at which the protocol was                                                                         Sciences, Building 101, Rodbell Auditorium,
                                                                                                           Appendix M–VI Footnotes of Appendix M
                                                reviewed.                                                                                                     Rooms 101 ABC, 111 T. W. Alexander Drive,
                                                                                                        will be renumbered to Appendix M–III.
                                                   RAC meetings will be open to the public                                                                    Research Triangle Park, NC 27709.
                                                                                                        Footnotes of Appendix M. There will be no
                                                except where trade secrets or confidential              amendment to the language.                              Open: November 16, 2015, 1:30 p.m. to 3
                                                commercial information are reviewed. To                                                                       p.m.
                                                enable all aspects of the protocol review                 Dated: October 9, 2015.                               Agenda: Poster Session.
                                                process to be open to the public, information           Francis S. Collins,                                     Place: Nat. Inst. of Environmental Health
                                                provided in response to Appendix M–I–A                                                                        Sciences, Building 101, Rodbell Auditorium,
                                                                                                        Director, National Institutes of Health.
                                                should not contain trade secrets or                                                                           Rooms 101 ABC, 111 T. W. Alexander Drive,
                                                confidential commercial or financial                    [FR Doc. 2015–26388 Filed 10–15–15; 8:45 am]          Research Triangle Park, NC 27709.
                                                information. An application submitted to the            BILLING CODE 4140–01–P                                  Closed: November 16, 2015, 3 p.m. to 3:30
                                                NIH OSP shall not contain any document                                                                        p.m.
                                                that is designated as ‘confidential’ in its                                                                     Agenda: To review and evaluate
                                                entirety. In the event that a determination has         DEPARTMENT OF HEALTH AND                              programmatic and personnel issues.
                                                been made that a specific portion of a                  HUMAN SERVICES                                          Place: Nat. Inst. of Environmental Health
                                                document submitted as one of the items                                                                        Sciences, Building 101, Rodbell Auditorium,
                                                described in Appendix M should be                       National Institutes of Health                         Rooms 101 ABC, 111 T. W. Alexander Drive,
                                                considered as confidential commercial or                                                                      Research Triangle Park, NC 27709.
                                                financial information or a trade secret, each           National Institute of Environmental                     Open: November 16, 2015, 3:45 p.m. to
                                                item must be clearly identified as such. The            Health Sciences; Notice of Meeting                    5:25 p.m.
                                                cover letter (attached to the submitted                                                                         Agenda: Scientific Presentations.
                                                material) shall: (1) Clearly designate the                 Pursuant to section 10(d) of the                     Place: Nat. Inst. of Environmental Health
                                                information that is considered as confidential          Federal Advisory Committee Act, as                    Sciences, Building 101, Rodbell Auditorium,
                                                commercial or financial information or a                amended (5 U.S.C. App.), notice is                    Rooms 101 ABC, 111 T. W. Alexander Drive,
                                                trade secret; and (2) explain and justify each          hereby given of a meeting of the Board                Research Triangle Park, NC 27709.
srobinson on DSK5SPTVN1PROD with NOTICES




                                                designation to demonstrate with specificity             of Scientific Counselors, NIEHS.                        Closed: November 16, 2015, 5:25 p.m. to
                                                how release of that information will reveal a                                                                 5:55 p.m.
                                                                                                           The meeting will be open to the
                                                trade secret or will result in substantial                                                                      Agenda: To review and evaluate
                                                competitive harm.                                       public as indicated below, with                       programmatic and personnel issues.
                                                   There are no proposed amendments to                  attendance limited to space available.                  Place: Nat. Inst. of Environmental Health
                                                Appendix M–I–C, Reporting Requirements                  Individuals who plan to attend and                    Sciences, Building 101, Rodbell Auditorium,
                                                and Appendix M–I–D, Safety Assessments in               need special assistance, such as sign                 Rooms 101 ABC, 111 T. W. Alexander Drive,
                                                Human Gene Transfer Research.                           language interpretation or other                      Research Triangle Park, NC 27709.



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Document Created: 2015-12-14 15:23:31
Document Modified: 2015-12-14 15:23:31
CategoryRegulatory Information
CollectionFederal Register
sudoc ClassAE 2.7:
GS 4.107:
AE 2.106:
PublisherOffice of the Federal Register, National Archives and Records Administration
SectionNotices
ActionNotice of proposed changes to the NIH Guidelines.
DatesTo ensure consideration, comments must be submitted in writing by November 30, 2015.
ContactIf 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.
FR Citation80 FR 62543 

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