81 FR 15315 - Final 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 81, Issue 55 (March 22, 2016)

This notice sets forth final changes to the National Institutes of Health 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 protocols, as initially outlined by the NIH Office of Science Policy (OSP) in a Federal Register notice issued on October 16, 2015 (80 FR 62543). Following the solicitation of public comment on its original proposal, the NIH is amending the NIH Guidelines in the following areas: (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 submission requirements under Appendix M-I-A of the NIH Guidelines. In a continuing effort to harmonize with the Food and Drug Administration (FDA) regulations, a change is being made to the reporting requirement for additional clinical trial sites allowing for a delay of 30 days to submit appropriate documentation. The changes set forth in this notice do not affect the responsibility of the Principal Investigator to submit documentation to his or her local oversight bodies and to the NIH, nor do they affect the requirement to submit appropriate documentation to the NIH when new clinical trial sites are registered. The changes also do not affect the responsibility of a Principal Investigator (or a delegated clinical trial sponsor) to submit appropriate and timely follow up information to the NIH as outlined in the NIH Guidelines (e.g., protocol amendments, serious adverse events, annual reports with cumulative safety data).

[Federal Register Volume 81, Number 55 (Tuesday, March 22, 2016)]
[Notices]
[Pages 15315-15322]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2016-06448]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


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

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

ACTION: Notice of changes to the NIH Guidelines.

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[[Page 15316]]

SUMMARY: This notice sets forth final changes to the National 
Institutes of Health 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 protocols, as initially outlined by the NIH Office of Science 
Policy (OSP) in a Federal Register notice issued on October 16, 2015 
(80 FR 62543). Following the solicitation of public comment on its 
original proposal, the NIH is amending the NIH Guidelines in the 
following areas: (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 submission requirements under Appendix M-I-A of the 
NIH Guidelines. In a continuing effort to harmonize with the Food and 
Drug Administration (FDA) regulations, a change is being made to the 
reporting requirement for additional clinical trial sites allowing for 
a delay of 30 days to submit appropriate documentation.
    The changes set forth in this notice do not affect the 
responsibility of the Principal Investigator to submit documentation to 
his or her local oversight bodies and to the NIH, nor do they affect 
the requirement to submit appropriate documentation to the NIH when new 
clinical trial sites are registered. The changes also do not affect the 
responsibility of a Principal Investigator (or a delegated clinical 
trial sponsor) to submit appropriate and timely follow up information 
to the NIH as outlined in the NIH Guidelines (e.g., protocol 
amendments, serious adverse events, annual reports with cumulative 
safety data).

DATES: Changes outlined in this notice will be effective April 27, 
2016, to coincide with the RAC review cycle and to allow institutions 
and investigators to establish processes for implementing the new 
review procedures.

FOR FURTHER INFORMATION CONTACT: If you have questions, or require 
additional background information about these changes, please contact 
the NIH by email at [email protected], by telephone at 301-496-
9838, 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.

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 and public 
consultation, the NIH is amending 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 being implemented 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 
Principal Investigator. Requests for RAC review must originate from 
oversight bodies involved in the initial site(s) review. 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 within 10 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 will:
    a. Inform the requestor that RAC review is not warranted, and
    b. indicate that information regarding human gene transfer trials 
is available in the Genetic Modification Clinical Research Information 
System (GeMCRIS[supreg]), which may be found at https://www.gemcris.od.nih.gov.
    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 implemented:
    1. The Principal Investigator will continue to be responsible for 
submitting documentation regarding a proposed human gene transfer 
protocol to his or her local oversight bodies. The Principal 
Investigator 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, documentation shall also include written 
assessments originating from all oversight bodies involved in the 
review at an initial site(s) as to whether or not RAC review is 
warranted.
    2. Completion of the protocol registration process:
    a. If no oversight body involved in the review at an initial 
site(s) requests public RAC review, the IBC(s) may proceed with its 
approval process upon receipt of documentation from the NIH indicating 
that the initial protocol registration process is complete. This 
documentation will be provided by the NIH to the Principal Investigator 
within 10 working days.
    b. If one or more oversight bodies involved in the review at an 
initial site(s) requests public RAC review and

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the NIH agrees that the submission has met the above criteria in (A), 
the protocol will undergo RAC review and public discussion. The IBC(s) 
may not approve a protocol until the RAC has completed its review. The 
IBC(s) may proceed with the approval process upon receipt of a letter 
from the NIH summarizing the RAC's comments and recommendations (if 
any) regarding the protocol. Unless the NIH determines that there are 
exceptional circumstances, the NIH will send notification to the 
Principal Investigator within 10 working days after the completion of 
the RAC meeting at which the experiment was reviewed. Receipt of this 
letter concludes the protocol registration process.
    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 is 
reducing 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 
GeMCRIS[supreg], which facilitates safety data reporting and enables 
public access to information about human gene transfer protocols 
registered with the NIH.
    The changes to the RAC review process, outlined above, will require 
amendment of multiple portions of the NIH Guidelines (see section below 
on ``Amendments to the NIH Guidelines'').

Overview of Comments Received in Response to the October 16, 2015 
Notice

    In response to its October 16, 2015, Federal Register notice, the 
NIH received 11 letters of comment from academic institutions, private 
companies, and trade organizations representing the biosafety and 
biomedical research communities. The majority of letters endorsed the 
proposed changes to the review process; however commenters suggested 
that some revisions would be helpful to clarify the proposal. All 
comments, regardless of position, were reviewed and considered by the 
NIH. These comments, along with the NIH responses, are summarized 
below:
    Submission requirements for human gene transfer protocols. Several 
comments focused on the appropriate amount of documentation needed for 
the registration of human gene transfer protocols, especially in light 
of other federal reporting requirements. In its report, the IOM 
recognized the value of ongoing registration of all protocols, the 
dissemination of that information on these protocols through GeMCRIS, 
the ongoing reporting and analysis of safety data, and their public 
discussion at scientific workshops and symposia for the benefit of this 
field. Thus, to continue the NIH's role in fostering a public 
discussion of human gene transfer research, no further changes to the 
material required under Appendix M-I-A are being made.
    Criteria by which human gene transfer protocols will be selected. 
Some entities raised concerns about the difficulty in applying the IOM 
criteria to human gene transfer protocols, specifically in terms of 
defining ``novelty.'' Given the evolving field of human gene transfer 
research, it is important that the RAC review criteria maintain a 
degree of flexibility. Thus, the NIH intends to implement the IOM 
criteria as outlined in its report. Of relevance, the IOM did elaborate 
that ``[n]ovelty indicates an untested area of science, one that brings 
an additional layer of uncertainty as compared to research in areas of 
greater experience and one for which institutional review bodies 
typically do not have the requisite expertise.'' This may include a 
novel approach, application of a new technology, or a new route of 
administration of a gene transfer product to target a disease.
    Process by which human gene transfer protocols will be selected. 
Several comments requested clarification regarding the process by which 
a RAC public discussion would occur, whether entities other than 
oversight bodies (e.g. investigational new drug sponsors or Principal 
Investigators) could request review, or in the case of trials being 
conducted at more than one site, whether a clinical trial site added 
after completion of the protocol registration process for the initial 
site(s) could request RAC review. The ability to request RAC review 
lies initially and solely within the purview of the local oversight 
bodies (i.e., IBC and IRB), although the NIH Director in consultation 
(as needed) with the appropriate regulatory authorities may also 
require it. Since both the expertise that these oversight bodies (IBCs 
and IRBs) have regarding the review of human gene transfer trials and 
their rationale for requesting public review are potentially very 
different, a recommendation for public review from either oversight 
body will be sufficient to trigger a determination from the NIH as to 
whether the IOM criteria are met. To clarify the process for requesting 
RAC review, the NIH Guidelines will be amended to specify that a 
request for RAC review must be made by oversight bodies involved in the 
review at an initial site(s) registering the protocol with the NIH.
    RAC expertise and review. Several comments discussed the value of 
RAC review in terms of scientific expertise, and expressed concerns 
about removing this resource for local oversight bodies. The NIH 
recognizes the value of the RAC and intends to continue to support its 
review of those protocols that would benefit from additional expertise 
and public discussion. Historically, only a fraction of all protocols 
registered with the NIH are publicly reviewed and it is expected that 
oversight bodies will continue to review and approve protocols in the 
same manner they always have. In cases where an oversight body feels 
additional expertise is needed, it is encouraged to augment its 
membership with ad hoc experts.
    Proprietary confidential information. Comments were raised 
regarding the confidentiality of information submitted to the NIH, 
especially in cases where the submitter considers the information to be 
confidential or proprietary. The NIH Guidelines state that documents 
submitted to the NIH should not contain information considered 
``confidential'' and that the amended NIH Guidelines will further 
indicate that an entire document such as a clinical protocol cannot be 
classified as ``confidential'' in its entirety. Should a submitter 
choose to provide information that is considered to be trade secret, 
confidential commercial, or financial in nature, it is incumbent on the 
submitter to identify clearly these specific portions, outlining how 
the release of this information would cause financial or competitive 
harm. All records submitted to the NIH, including human gene transfer 
clinical trial information, are subject to the Freedom of Information 
Act (FOIA--5 U.S.C. 552) and the Department of Health and Human 
Services FOIA regulations (45 CFR part 5). Details about the FOIA and 
the regulations can be found on the NIH Web site at this address: 
http://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/freedom-information-act-office.

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

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deleted (except for the requirements under the membership provisions of 
IBCs, Section IV-B-2-a).
    Section I-E will 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'' in the context of human gene 
transfer research is a federal entity that by statute has oversight 
over research involving human subjects.
    Section III-C-1 will 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 determination, following a request from one or more oversight 
bodies involved in the review at an initial site(s), whether a proposed 
human gene transfer experiment 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 will be initiated in two exceptional circumstances: (1) 
Following a request for public RAC review from one or more oversight 
bodies involved in the review at an initial site(s), the NIH concurs 
that the submission meets one or more of the following NIH RAC review 
criteria: (i) The protocol uses a new vector, genetic material, or 
delivery methodology that represents a first-in-human experience, thus 
presenting an unknown risk; (ii) the protocol relies on preclinical 
safety data that were obtained using a new preclinical model system of 
unknown and unconfirmed value; or (iii) the proposed vector, gene 
construct, or method of delivery is associated with possible toxicities 
that are not widely known and that may render it difficult for 
oversight bodies involved in the review at an initial site(s) to 
evaluate the protocol rigorously. However, if one or more oversight 
bodies involved in the review at an initial site(s) requests public RAC 
review, but the NIH does not concur that the submission meets one or 
more of the RAC review criteria (listed in i, ii, or iii), then the NIH 
OSP will inform, within 10 working days, the requesting and other 
oversight bodies involved in the review at an initial site(s) that 
public RAC review is not warranted. (2) The NIH Director, in 
consultation (if needed) with appropriate regulatory authorities, 
determines that the submission: (a) Meets one or more of the NIH RAC 
review criteria (listed in i, ii, or iii) and that public RAC review 
and discussion would provide a clear and obvious benefit to the 
scientific community or the public; or (b) raises significant 
scientific, societal, or ethical concerns.
    For a clinical trial site that is added after 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 will 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 to be amended.
    Section IV-B-2-a-(1) will be amended as follows:
    Section IV-B-2-a-(1). The Institutional Biosafety Committee must be 
composed 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

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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 to be amended.
    Section IV-B-2-b-(1) will be amended as follows:
    Section IV-B-2-b-(1). Reviewing recombinant or synthetic nucleic 
acid molecule research conducted at or sponsored by the institution for 
compliance with the NIH Guidelines as specified in Section III, 
Experiments Covered by the NIH Guidelines, and approving those research 
projects that are found to conform to 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 to be amended.
    Section IV-B-6 will 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) will 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 will 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 will 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

[[Page 15320]]

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 involved in the review at an initial site(s), 
and regulatory authorities, when appropriate. Investigators shall 
submit the relevant information on the proposed human gene transfer 
experiment to the oversight bodies involved in the review at an initial 
site(s) 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 will be initiated in two exceptional circumstances: (1) 
Following a request for public RAC review from one or more oversight 
bodies involved in the review at an initial site(s), the NIH concurs 
that the submission meets one or more of the following NIH RAC review 
criteria: (i) The protocol uses a new vector, genetic material, or 
delivery methodology that represents a first-in-human experience, thus 
presenting an unknown risk; (ii) the protocol relies on preclinical 
safety data that were obtained using a new preclinical model system of 
unknown and unconfirmed value; or (iii) the proposed vector, gene 
construct, or method of delivery is associated with possible toxicities 
that are not widely known and that may render it difficult for 
oversight bodies involved in the review at an initial site(s) to 
evaluate the protocol rigorously. However, if one or more oversight 
bodies involved in the review at an initial site(s) requests public RAC 
review, but the NIH does not concur that the submission meets one or 
more of the RAC review criteria (listed in i, ii, or iii), then the NIH 
OSP will inform, within 10 working days, the requesting and other 
oversight bodies involved in the review at an initial site(s) that 
public RAC review is not warranted. (2) The NIH Director, in 
consultation (if needed) with appropriate regulatory authorities, 
determines that the submission: (a) Meets one or more of the NIH RAC 
review criteria (listed in i, ii, or iii) and that public RAC review 
and discussion would provide a clear and obvious benefit to the 
scientific community or the public; or (b) raises significant 
scientific, societal, or ethical concerns.
    If it is determined that a human gene transfer trial will undergo 
public 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 involved in the review at an initial 
site(s), 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). Information provided in 
response to Appendix M should not contain any 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 will 
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. 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 will 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 involved in 
the review at an initial site(s) 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?

[[Page 15321]]

    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 Principal 
Investigator shall provide additional documentation originating from 
oversight bodies involved in the review at an initial site(s) regarding 
their assessment of whether public RAC review is warranted. In the 
event that review is requested, a justification that the NIH RAC review 
criteria (see Section III-C-1) are met shall be included.
    Note: Any application submitted 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 
should be considered proprietary or trade secret, each specific portion 
should be clearly identified as such. In the event that a specific 
portion of the submission is identified to be proprietary or trade 
secret, the submission to the NIH OSP must contain a letter that: (1) 
Clearly indicates what select portions of the application contain 
information considered as proprietary or trade secret, and (2) provides 
justification as to why 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 will be amended to change 
the process and timing of public 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. 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 
originating from all oversight bodies involved in the review at an 
initial site(s) regarding their assessment of whether public RAC review 
is warranted must accompany the Principal Investigator's submission to 
the NIH. If no oversight body involved in the review at an initial 
site(s) requests public RAC review, then the required documentation to 
register the protocol (see Appendix M-I-A) shall be submitted to the 
NIH OSP at any time, but not less than 10 working days prior to the 
anticipated date of enrollment of the first subject (see definition of 
enrollment in Section I-E-7). This information 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]. An acknowledgement that the protocol 
registration process is complete will occur within the 10 working days 
period prior to the anticipated date of enrollment. Final IBC approval 
may then be granted.
    If one or more oversight bodies involved in the review at an 
initial site(s) requests public RAC review, but the NIH does not concur 
that the submission meets one or more of the RAC review criteria, the 
NIH OSP will notify the Principal Investigator, oversight bodies 
involved in the review at an initial site(s), and regulatory 
authorities, as appropriate, that public RAC review is not warranted. 
An acknowledgement that the protocol registration process is complete 
will accompany this decision. Final IBC approval may then be granted.
    If an oversight body involved in the review at an initial site(s) 
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 originating from 
oversight bodies involved in the review at an initial site(s) regarding 
their assessment of whether public 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 the NIH concurs that the submission meets 
one or more of the following NIH RAC review criteria above, the 
protocol will undergo public RAC review and discussion.
    Even if an oversight body involved in the review at an initial 
site(s) does not request public RAC review, the NIH Director, after 
consultation (if needed) with appropriate regulatory authorities, may 
initiate public 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. If a protocol is to undergo 
RAC public discussion a complete human gene transfer protocol package 
must be submitted at least 8 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 comments and recommendations (if any) 
regarding the protocol to the Principal Investigator(s), oversight 
bodies involved in the review at an initial site(s), and regulatory 
authorities as appropriate. Unless the NIH determines that there are 
exceptional circumstances, the NIH will send this letter to the 
Principal Investigator within 10 working days after the completion of 
the RAC meeting at which the experiment was reviewed. Receipt of this 
letter concludes the

[[Page 15322]]

protocol registration process. Final IBC approval may then be granted.
    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. 
Documentation submitted to the NIH OSP shall not be designated as 
`confidential' in its entirety. In the event that a determination has 
been made that a specific portion of a document submitted should be 
considered as proprietary or trade secret, each specific portion should 
be clearly identified as such. The cover letter (attached to the 
submitted material) shall: (1) Clearly indicate what select portions 
contain information considered as proprietary or a trade secret; and 
(2) provide justification as to why this information is considered to 
be proprietary or trade secret. This 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-C-2 currently states:

Appendix M-I-C-2. Additional Clinical Trial Sites

    No research participant shall be enrolled (see definition of 
enrollment in Section I-E-7) at a 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.

Appendix M-1-C-2 will be amended as follows:

Appendix M-I-C-2. Additional Clinical Trial Sites

    Within 30 days of enrollment (see definition of enrollment in 
Section I-E-7) at a clinical trial site, the following documentation 
shall be submitted to NIH OSP: (1) Institutional Biosafety Committee 
approval (from the clinical trial site); (2) Institutional Review 
Board approval; (3) Institutional Review Board-approved informed 
consent document; and (4) NIH grant number(s) if applicable.

There are no amendments to 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 will 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 will 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 of 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: March 15, 2016.
Francis S. Collins,
Director, National Institutes of Health.
[FR Doc. 2016-06448 Filed 3-21-16; 8:45 am]
 BILLING CODE 4140-01-P