The transfer of recombinant or synthetic nucleic acid molecules into human subjects (human gene transfer) must be reviewed by the University of Utah Institutional Biosafety Committee (IBC) and Institutional Review Board (IRB), as well as the NIH Office of Science Policy (OSP). Some projects will also require review by the Recombinant DNA Advisory Committee (RAC).
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.
The April 2016 iteration of the NIH guidelines for research involving recombinant or synthetic nucleic acid molecules incorporated significant changes related to the necessity for RAC review. RAC review of individual human gene transfer protocols will be performed only in exceptional cases that meet both of the following specified criteria:
1. The University of Utah IBC or 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
As described in Appendix M-1-A of the Guidelines, the following documentation must be submitted, according to institutional policy, to the IBC at an initial site and subsequently in electronic form to the NIH OSP:
- A scientific abstract.
- The proposed clinical protocol, including tables, figures, and any relevant publications.
- Summary of preclinical studies conducted in support of the proposed clinical trial or reference to the specific section of the protocol providing this information.
- A description of the product:
- 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.
- 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?
- 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).
- Describe the methods for replication-competent virus testing, if applicable.
- Describe the intended ex vivo or in vivo target cells and transduction efficiency.
- Describe the gene transfer agent delivery method.
5. The proposed informed consent document(s).
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 one or more of the NIH RAC review criteria (see Section III-C-1) are met shall be included.
The information described in bullets 1-5 will need to be submitted for IBC review: a link to the IBC registration form is included at the bottom of this page. In addition, the University of Utah IBC requires Caregiver Information Sheets when agents requiring BSL2 containment are used (such as recombinant viral vectors). These Information Sheets should be given to individuals who may potentially be exposed to the recombinant agent, such as family members who may help change wound dressings. These should include, in lay terms, descriptions of the agent, how to care for wounds, how to clean up spills of bodily fluids, the signs and symptoms of exposure to the agent, and who to contact if they are concerned they have been exposed to the agent.
The IBC will make a determination as to whether the research requires RAC review. Once the IBC has reviewed the protocol it will provide the PI with documentation stating its findings regarding RAC review and the PI is responsible for providing this to NIH OSP as part of their submission to NIH (bullet 6). Note the IRB can also make a determination that public RAC review is required.
NIH is then tasked to review the IBC recommendations. However, if the IBC or IRB requests public RAC review, but the NIH does not concur that (a) the individual protocol would significantly benefit from RAC review and (b) that the submission meets one or more of the RAC review criteria (listed above), then the NIH OSP will inform, within 10 working days, the University of Utah IBC and IRB that public RAC review is not warranted. In addition, if the IBC or IRB do not recommend RAC review but 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 above) 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, then a public RAC review will be conducted.
No research participant shall be enrolled (see definition of enrollment inSection I-E-7of the NIH Guidelines) until the NIH protocol registration process has been completed (see Appendix M-I-B,Selection of Individual Protocols for Public RAC Review and Discussion of the NIH Guidelines).
For review by the University of Utah IBC, the investigator must submit the following;
1) A completed and signed copy of the Human Gene Transfer registration form (a link can be found at the bottom of this page).
2) A complete packet of documentation to be submitted to NIH OSP as described in Appendix M-I-A of the NIH Guidelines. If the University of Utah is not the lead/initial site please include copies of documentation from the lead site on the determination for the requirement for RAC review.
3) Copies of correspondence from the NIH OSP and/or RAC.
4) Training records for personnel involved in the study
5) If the University of Utah is the lead/initial site, detailed responses to the questions; (i) Does the protocol use a new vector, genetic material, or delivery methodology that represents a first-in-human experience, thus presenting an unknown risk? (ii) Does the protocol rely on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value? and (iii) Is the proposed vector, gene construct, or method of delivery associated with possible toxicities that are not widely known and that may render it difficult for oversight bodies to evaluate the protocol rigorously?
6) Vector Maps.
7) Copies of the Informed Consent Documents.
8) Copies of Caregiver Information Sheets (BSL2 protocols).
9) One copy of any portions of FDA, IND correspondence that discussed safety issues and/or agent description information attached.
10) Investigator’s brochure.
Send a copy of completed forms to the following individual:
Biosafety Specialist / IBC Administrator
Environmental Health & Safety
University of Utah
125 S. Fort Douglas Blvd., Building 605
Salt Lake City, Utah 84113
Office (801) 581-6590
Fax (801 585-7240
biosafety@oehs.utah.edu
Adverse Events
Principal Investigators must submit a written report on: (1) any serious adverse event that is both unexpected and associated with the use of the gene transfer product (i.e., there is reasonable possibility that the event may have been caused by the use of the product; investigators should not await definitive proof of association before reporting such events); and (2) any finding from tests in laboratory animals that suggests a significant risk for human research participants including reports of mutagenicity, teratogenicity, or carcinogenicity. The report must be clearly labeled as a “Safety Report” and must be submitted to the NIH Office of Science Policy (NIH OSP) and to the Institutional Biosafety Committee within the following timeframes:
Any serious adverse event that is fatal or life-threatening, that is unexpected, and associated with the use of the gene transfer product must be reported as soon as possible, but not later than 7 calendar days after the sponsor’s initial receipt of the information (i.e., at the same time the event must be reported to the FDA).
Serious adverse events that are unexpected and associated with the use of the gene transfer product, but are not fatal or life-threatening, must be reported as soon as possible, but not later than 15 calendar days after the sponsor’s initial receipt of the information (i.e., at the same time the event must be reported to the FDA).