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PDF version of FAQ
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1. The NIH and Human Gene Transfer Trials |
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1.1 What is human gene transfer research?
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1.2 Why are human gene transfer trials reviewed by the NIH?
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1.3 What is the RAC?
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1.4 What characteristics distinguish the NIH review process from others that my protocol may have to undergo?
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1.5 What are the
NIH Guidelines
and how do they address human gene transfer trials?
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2. Review of Human Gene Transfer Trials |
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2.1 I am an investigator whose projects are funded entirely by private industry. Must I submit my protocol to NIH for review?
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2.2 Are there any clinical trials involving the administration of recombinant DNA to a human that are exempt from Appendix M-I?
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2.3 Are all clinical studies that involve the generation of an immune response to a microbial immunogen exempt from Appendix M-I?
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2.4 Are clinical trials that fulfill all of the criteria as outlined in Appendix M-VI-A exempt from all other requirements specified in the
NIH Guidelines
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2.5 I am an investigator developing a protocol for a gene transfer clinical trial. What are some of the first things I need to do to prepare for a review of my trial?
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3. Submitting your protocol |
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3.1 To whom do I send my protocol?
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3.2 Should I submit the very same information that I send to the Food and Drug Administration (FDA)?
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3.3 What happens to my protocol when the NIH Office of Biotechnology Activites (OBA) receives it?
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4. Your Protocol and the Public RAC Meeting |
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4.1 What happens if my protocol is selected for public RAC review?
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4.2 What is the outcome of the RAC review?
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4.3 What is the relationship of the RAC review to review by the Institutional Review Board (IRB), the Institutional Biosafety Committee (IBC),
and the FDA?
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5. After the RAC Meeting |
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5.1 When may I start enrolling subjects in my protocol?
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5.2 After I finish the RAC review of my protocol and begin to enroll patients, do I need to
report additional information to NIH OBA?
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5.3 Am I required to submit any amendments to my protocol?
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5.4 Am I able to report information to NIH OBA electronically?
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What is human gene transfer research?
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Human gene transfer research involves the deliberate transfer of recombinant DNA, or DNA or
RNA derived from recombinant DNA, into a person. At present, human gene transfer research is
experimental and is being studied to see whether it could treat certain health problems by
compensating for defective genes, producing a potentially therapeutic substance, or manipulating
the immune system to fight disease better. Human gene transfer may help improve genetic
disorders, particularly those conditions that result from inborn errors in a single gene (for example
sickle cell anemia, and hemophilia). It may also hold promise for diseases with more complex
origins, like cancer and heart disease. Gene transfer is also being studied as a possible treatment
for certain infectious diseases, such as AIDS. This type of experimentation is sometimes called
"gene therapy" research.
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Why are human gene transfer trials reviewed by the NIH?
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Human gene transfer research raises scientific, medical, ethical, and social considerations worthy
of special attention and public discussion. Some of these issues arise from the fact that the
techniques being used are relatively new and their risks and benefits are not well characterized.
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The NIH review process allows for an in-depth examination of the issues associated with this
technology in a setting where public input and comment is encouraged. This open discussion has
two important benefits. First, it disseminates this information to scientists who can then
incorporate new scientific findings and ethical considerations into the design of trials they may be
conducting or planning. The efficiency of the research system is improved by allowing scientists
to build on a common foundation of new knowledge emanating from this ongoing process of
analysis and assessment. Second, it creates enhanced public awareness and allows for a public
voice in the review of the safety and ethics of gene transfer research. This helps assure the public
that scientists are attending to these important matters and sustains confidence in the research.
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Finally, as the major funder of human gene transfer research and the basic science that underpins
it, the NIH has an important responsibility for the appropriate stewardship of this area of scientific
activity. This stewardship role is both an ethical obligation and a public mandate associated with
the tax-derived research funds appropriated to the agency by Congress.
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What is the Recombinant DNA Advisory Committee?
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The Recombinant DNA Advisory Committee is a panel of up to 21 national experts representing
various fields of science, medicine, genetics, ethics, and patient perspectives that considers the
current state of knowledge and technology regarding recombinant DNA research. A key role of
the RAC is to advise the NIH Director and the NIH Office of Biotechnology Activities (OBA),
which is the locus of NIH oversight for recombinant DNA research. An important RAC function
is to review research proposals involving human gene transfer research, or "gene therapy" as it is
often called. All human gene transfer clinical trials occurring at or sponsored by institutions
receiving NIH funds for recombinant DNA research must be submitted to OBA for review by the
RAC.
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What characteristics distinguish the NIH review process from others that a protocol may undergo?
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The NIH review process was established in response to concern about the special scientific, safety,
and ethical dimensions of gene transfer research. A notable and unique feature of the NIH review
process is public discussion during meetings of the RAC. The RAC is composed of experts with
diverse backgrounds, expertise, and points of view. The RAC is thereby constituted to provide
full, in-depth review of the many dimensions of human gene transfer research.
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Another special characteristic of the NIH process is open access to information, since materials
submitted to the NIH, through OBA, are generally considered to be in the public domain and are
made freely available. Information regarding human gene transfer trials registered with NIH is
accessible electronically from OBA's Genetic Modification Clinical Research Information System
(GeMCRIS). Openness and public
participation contribute toward a better scientific understanding of this field of research and
provide the public a voice in deliberations about the various dimensions of gene transfer research.
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What are the
NIH Guidelines
and how do they address human gene transfer trials?
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The
NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines)
set
forth the principles for NIH and institutional oversight of recombinant DNA research, including
human gene transfer trials. The NIH Guidelines were first published in 1976 as an outcome of a
public process by which scientists developed standards to address the potential risks associated
with recombinant DNA research. The NIH Guidelines articulate standards for investigators and
institutions to follow to ensure the safe handling and containment of recombinant DNA and
products derived therefrom. They outline requirements for institutional oversight, including
Institutional Biosafety Committees (IBCs), and describe the procedures of the RAC.
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The
NIH Guidelines
are a dynamic document that changes with the science and understanding of
recombinant DNA research. In 1990, a new section to the
NIH Guidelines
was added, Appendix
M, which describes points to consider in the design and submission of human gene transfer trials,
including the standards and procedures to which investigators must adhere. Appendix M is
described in greater detail below.
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To facilitate navigation of the
NIH Guidelines,
the full text electronic version posted on OBA's
website is indexed and hyperlinked to allow immediate access to any section, appendix, or
referenced resource of particular interest. A copy of the
NIH Guidelines
can be found here.
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I am an investigator whose projects are funded entirely by private industry. Must I submit
my protocol to NIH for RAC review?
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Even if your project is funded entirely by private sources, you must submit your protocol to the
NIH if the sponsor of your research or the institution where you will conduct your project receives
any NIH money for recombinant DNA research. Also, research involving the testing in humans of
materials containing recombinant DNA developed with NIH funds must be reviewed by the RAC,
if the institution that developed those materials sponsors or participates in those projects.
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If the conditions above do not apply to your research you may nontheless submit your protocol
voluntarily. Following the
NIH Guidelines
will allow you to conduct your research safely and
ethically. Undergoing RAC review allows you to obtain feedback on the conduct and design of
your protocol from a panel of experts that helps improve the science and safety of the study.
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Are there any clinical trials involving the administration of recombinant DNA to a human
that are specifically exempted from the RAC review process?
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Yes. Appendix M-VI-A of the
NIH Guidelines for Research Involving Recombinant DNA
Molecules (NIH Guidelines)
exempts certain types of trials for infectious diseases from the
requirements for submission of the protocol to NIH OBA, RAC review, and subsequent reporting
(Appendix M-I). Specifically, this exemption applies to clinical studies involving the
administration of recombinant DNA in which "induction or enhancement of an immune response
to a vector-encoded microbial immunogen is the major goal, such an immune response has been
demonstrated in model systems, and the persistence of the vector-encoded immunogen is not
expected." These trials, however, require IBC review and approval (see question 2.4). These trials
can be submitted on a voluntary basis, particularly if the investigator believes that a clinical trial
involving the administration of recombinant DNA presents scientific, safety, or ethical issues that
would benefit from RAC review. Investigators who submit trials voluntarily will be expected to
comply with all aspects of the protocol review and reporting requirements. Investigators and
institutional review bodies are encouraged to contact OBA for assistance in
determining whether this exemption applies to their specific trial.
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Are all clinical studies that involve the generation of an immune response to a microbial
immunogen exempt from Appendix M-I?
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No. This is just one of the three criteria that must be met for a trial to be exempted. The exemption
found in Appendix M-I was intended to streamline the development of new vaccines against
infectious diseases. Some studies that involve generating an immune response to a microbial
immunogen are targeting viruses that cause cancer. If the principal goal of the study is to treat a
precancerous or cancerous lesion for example, the study does not fall under this exemption.
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In addition, some human studies involve the administration of a microbial immunogen in
combination with recombinant DNA that encodes for a cytokine or other immune stimulant, for
example recombinant interleukin-2. Such trials are also not exempt under Appendix M-VI-A since
the recombinant DNA encoding the cytokine is not of microbial origin.
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Are clinical trials that fulfill all of the criteria as outlined in Appendix M-VI-A exempt from
all other requirements specified in the
NIH Guidelines
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No. Vaccine trials that meet the exemption criteria set forth in Appendix M-VI-A are exempt only
from the requirements of Appendix M-I (Requirements for Protocol Submission, Review and
Reporting) and are expected to follow all other requirements of the
NIH Guidelines.
This includes
having the vaccine trial reviewed and approved by an IBC before research participants are
enrolled. More information regarding the IBC's role in reviewing and overseeing trials involving
the administration of recombinant DNA can be found on the IBC page of the OBA website.
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I am an investigator developing a protocol for a gene transfer clinical trial. What are the
first things I need to do to prepare for a review of my trial by the RAC?
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First, you should read Appendix M of the
NIH Guidelines,
which outlines points to consider in the
design and conduct of these trials. It also includes details about submitting your protocol for
review by the RAC.
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You can find information about protocol submission deadlines for the quarterly RAC meetings on
the OBA website.
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As part of the packet of materials that you will send to the NIH, you will need to submit responses
to Appendices M-II through M-V of the NIH Guidelines, which pose questions concerning the
objective and rationale of the proposed research. It is acceptable to reference sections of the
protocol in response to specific questions of Appendix M. These sections also explore how you
will handle informed consent issues and privacy for research participants and their families. In
addition to these responses, your packet must contain:
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A cover letter on institutional letterhead signed by the Principal Investigator(s). The
letter should (1) acknowledge that the documentation submitted to NIH OBA complies
with the requirements set forth in Appendix M-I-A, "Requirements for Protocol
Submission"; (2) identify the IBC and Institutional Review Board (IRB) at the proposed
clinical trial site(s) responsible for local review and approval of the protocol; and (3)
acknowledge that no research participant will be enrolled (see definition of enrollment in
Section I-E-7 of the
NIH Guidelines
) until the RAC review process has been completed
(see Appendix M-I-B, "RAC Review Requirements"), IBC approval (from the clinical
trial site), IRB approval, and all applicable regulatory authorizations have been obtained;
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A scientific abstract;
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A non-technical abstract;
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The proposed clinical protocol, including tables, figures, and relevant manuscripts;
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The proposed informed consent document; and
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Curriculum vitae
or biosketch of key study personnel.
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To whom do I send my protocol?
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You may submit your completed Appendix M submission by mail, by overnight express, or by email.
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By U.S. mail, send it to:
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Attn: Biotechnology Program Advisor
NIH Office of Biotechnology Activities
National Institutes of Health,
6705 Rockledge Drive, Suite 750,
Bethesda, Maryland 20892-7985
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By overnight express, send it to:
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Attn: Biotechnology Program Advisor
NIH Office of Biotechnology Activities
National Institutes of Health,
6705 Rockledge Drive, Suite 750
Bethesda, Maryland 20817-1814
Telephone: 301-496-9838
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By email, send it to: rosenthg@od.nih.gov
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Should I submit the very same information that I send to the Food and Drug Administration (FDA)?
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Investigators should submit all the material specified in Appendix M of the NIH Guidelines. This
includes information that may not normally be part of an FDA investigational new drug
application, since the scope and purpose of RAC review is different from that of the FDA.
Furthermore, unlike FDA review, the RAC process is open to the public. Any member of the
public may observe the discussion of your protocol at a RAC meeting or request the materials that
you submit to this office. This allows all interested parties to consider this field of research in all
its dimensions. Because of this characteristic, you generally should not submit trade secrets or
confidential commercial information in your Appendix M submission to the NIH. If for some
reason you find it necessary to include trade secrets or confidential commercial information in
your submission, it should be clearly labeled as such. It is never acceptable to label the entirety of
your Appendix M submission as confidential. Submission deadlines are eight weeks prior to each
RAC meeting. Specific deadline information is available on the OBA website.
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What happens to my protocol when OBA receives it?
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NIH OBA will confirm receipt of your protocol within three working days. If it appears that any
portion of the necessary submission is missing, OBA staff will contact you immediately to request
those materials.
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Once your submission is complete, a summary of the submission is sent to members of the RAC
for an initial review. During the preliminary protocol review process, individual RAC members
may request additional information or clarification about your submission and sometimes make
specific comments or suggestions about the protocol design, informed consent document, or other
matters. Any individual RAC comments of this nature are then conveyed to you. All such
correspondence is part of the public record of this protocol, and is available to the investigators,
sponsor, the IRB, IBC, FDA, and the Office for Human Research Protections (OHRP).
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As an outcome of this initial review, RAC members make a recommendation as to whether the
protocol raises important scientific, safety, medical, ethical, or social issues that warrant in-depth
discussion at the RAC's quarterly public meetings. Factors that may warrant public discussion
include unique applications of gene transfer research, the use of new or otherwise notable vector
or gene delivery systems, special clinical concerns, or important social or ethical issues raised by
the proposed research.
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Fifteen business days after submission of all the information required under Appendix M, you will
be notified of the outcome of this initial review process and whether your protocol has been
selected for public RAC review. The in-depth, public review of a protocol occurs when (1) the
OBA Director initiates that review following a recommendation for review by at least three RAC
members, the FDA or a federal agency other than NIH; or (2) the NIH Director initiates that
review.
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What happens if my protocol is selected for public RAC review?
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If your protocol has been selected for public review, and your complete submission was received
at least eight weeks before the next RAC meeting, your protocol will be reviewed at the next
meeting. If the next RAC meeting is less than eight weeks away, public discussion of your
protocol will be deferred until the following RAC meeting to allow sufficient time for the review
process.
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Several RAC members are assigned to conduct an in-depth written review of your protocol and
will pose a series of questions about the trial. A written response to this review is required to be
submitted prior to the RAC meeting. Other experts in the field (ad hoc reviewers) may be asked to
provide a review of your protocol, as well. As the person responsible for the design and conduct
of the trial, you will be asked to make a 15-20 minute presentation about your protocol at the RAC
meeting. You are welcome to bring colleagues to the meeting to help with your presentation and
to answer questions. This face-to-face interaction greatly improves the quality of the discussion
and permits immediate and in-depth exploration of issues that your protocol may raise.
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What is the outcome of the RAC review?
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The outcome of RAC review is a series of recommendations and advice from the RAC. RAC
review does not constitute a formal approval of your proposed protocol. Investigators and
sponsors should carefully consider these recommendations as part of optimizing the safe and
ethical conduct of the trial. These recommendations will be captured in a summary letter prepared
by OBA staff, which will be sent to you within 10 business days after completion of the RAC
meeting. The summary letter also will be sent to the IRB and IBC reviewing your protocol, as
well as the FDA and OHRP.
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What is the relationship of RAC review to review by the IRB, the IBC, and the FDA?
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Unlike the RAC, these other entities will be reviewing your protocol as part of a formal approval
process, either for conduct at your institution (in the case of local review bodies) or for authorizing
your Investigational New Drug (IND) application (in the case of the FDA). A benefit of the RAC
process is that it informs the discussions that these other bodies will undertake in making certain
determinations about your protocol.
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RAC review occurs before final IBC approval in order to inform that committee of the RAC's
recommendations before the IBC makes its final determination. Your IRB and the FDA may
review your protocol before or after RAC review, but both will nonetheless be notified of the RAC
recommendations.
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When may I start enrolling patients in my protocol?
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Under the NIH Guidelines, patient enrollment is considered to begin with the process of obtaining
informed consent from prospective participants. This process cannot begin until: (1) you receive a
letter from OBA indicating that the RAC review process has been completed; and (2) IBC
approval as well as all other applicable regulatory authorization(s) have been obtained.
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After I finish the RAC review of my protocol and begin to enroll patients, do I need to
report additional information to NIH OBA?
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Yes. Within 20 working days of consenting the first research participant, you must submit the
following documentation to NIH OBA:
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A copy of the informed consent document approved by the IRB;
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A copy of the protocol approved by the IBC and IRB;
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A copy of the final IBC approval from the clinical trial site;
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A copy of the final IRB approval;
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A brief written report that includes the following information: (1) how the investigator(s)
responded to each of the RAC's recommendations on the protocol (if applicable); and (2)
any modifications to the protocol as required by FDA;
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Applicable NIH grant number(s);
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The FDA IND number; and
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The date of the initiation of the trial.
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Investigators also have an ongoing responsibility to monitor the trial and to keep OBA, as well as
IRBs, IBCs, the FDA, and any sponsoring NIH institutes or centers, informed of any adverse
events on the trial. Serious adverse events that are unexpected and possibly associated with the
gene transfer product must be submitted to OBA within 15 calendar days of sponsor notification,
unless they are fatal or life threatening, in which case they must be reported within 7 calendar
days. Investigators are encouraged to report serious adverse events electronically to NIH by using
GeMCRIS. Investigators can contact OBA (oba@nih.gov) to become registered to file
electronically as discussed below.
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In addition, investigators must file an annual report with OBA, providing specific information
about the trials. The format of this report can be found in Appendix M-I-C-3 of the
NIH Guidelines.
Investigators should also notify OBA of any additional sites that are conducting the
trial, and submit for the new site:
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IBC approval (from the clinical trial site);
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IRB approval;
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The IRB-approved informed consent form;
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Curriculum vitae
of the investigator(s); and
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NIH grant number(s), if applicable.
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Am I required to submit any amendments to my protocol?
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You are required to file any updated versions of the protocol with NIH OBA with the annual
report as required under Appendix M-I-C-3. However, if there is a significant amendment to the
original protocol that was reviewed by the RAC, OBA may request you file a new protocol rather
than an amendment. Changes that might warrant an entire new submission include significant
alterations to the study design (for example target populations or route of delivery of vector.) We
encourage investigators to consult with OBA regarding whether significant changes in the
protocol constitute a new protocol or an amendment to an existing protocol.
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Am I able to report information to NIH OBA electronically?
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Information on adverse events occurring on human gene transfer trials may be reported to OBA
using GeMCRIS. In order to become authorized to use GeMCRIS for adverse event reporting,
investigators, study coordinators, and sponsors first will need to obtain a User ID and password.
Principal Investigators should verify the information for their trials on the GeMCRIS public
information site. Principal Investigators should then send a signed, written request on institutional letterhead to OBA. This
request should indicate the Principal Investigators email address and the OBA number(s) for the
human gene transfer protocol(s) with which he or she is associated. For more information please
visit Using GeMCRIS for Adverse Event Reporting.
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