[Federal Register Volume 80, Number 200 (Friday, October 16, 2015)]
[Notices]
[Pages 62543-62550]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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 [email protected], 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 [email protected], 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: 
[email protected]. 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: 
[email protected]. 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: [email protected]. 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