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No research participant may be enrolled in a human gene transfer clinical study until IBC and IRB approvals and applicable regulatory authorizations are obtained AND the RAC registration process is completed.
Furthermore, investigators are required to submit specific additional materials to NIH OBA either prior to the enrollment of any research participant (for additional clinical trial sites being added to multi-center trials) OR no later than 20 working days after the enrollment of the first research participant (for the primary site identified with a clinical trial).
Human gene transfer experiments involve the "deliberate transfer of recombinant or synthetic nucleic acid molecules, or DNA or RNA derived from recombinant or synthetic nucleic acid molecules, into human research participants."
Because it is a type of human subjects research, proposals for Human Gene Transfer (HGT) clinical trials at U-M are submitted via an IRB Application instead of an IBC registration. However, IBC guidelines and processes apply as recombinant DNA (rDNA) is involved. At U-M, the IBC participates as part of the broader IRBMED review process.
Review and Reporting Process
Human Gene Transfer (HGT) research projects require a special review and reporting process:
- NIH OBA Recombinant DNA Advisory Committee (RAC) Process
- IBC Review: Ancillary to IRB
- IRBMED Review
- Reporting Adverse Events (AEs)
In addition to this special review process, PIs must be familiar with the special reporting requirements, outlined in Appendix M-I-C of the NIH Guidelines, for before, during, and after these experiments.
In April 2016, NIH OBA issued revisions to the NIH Guidelines, including changes to the RAC review process. These changes apply to human gene transfer trials that were not reviewed by the RAC prior to April 2016. The revised process requires oversight bodies (IBC and IRB) at the initiating site to determine whether RAC review is needed. For complete information about these changes, see the RAC Review Factsheet.
The IBC will review your human gene transfer proposal through the IRB application, which you will start in the eResearch Regulatory Management (eRRM) system. In section 7, indicate that your project involves human gene transfer. eRRM will then prompt you to complete the section of the IRB application specific to human gene transfer.
The IBC will need to review the following documents, which you should upload to your IRB application (relevant sections noted in parentheses below):
- Scientific abstract (Section 23-2.8)
- Non-technical abstract (Section 23-2.8)
- Clinical protocol including tables, figures and relevant manuscripts (Section 5)
- Summary of preclinical studies conducted in support of the proposed clinical trial OR reference to the specific seciton of the protocol providing this information (Section 23-2.7).
- A description of the product as a stand-alone document (Section 23-2.7):
- 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.
- 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?
- 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).
- The methods for replication-competent virus testing, if applicable.
- The intended ex vivo or in vivo target cells and transduction efficiency.
- The gene transfer agent delivery method.
- Investigator's brochure (Section 15)
- Proposed informed consent document(s) (Section 10)
- NIH OSP registration number, if available (Section 23.1.1)
- Other documentation; e.g., outcome letter from initiating site or from NIH OSP (Section 23-2.7)
The IBC may request additional documentation in the course of its review. Also be sure to refer to Appendix M for detailed information about the documentation and reporting requirements for these projects, as well as for information about ensuring informed consent for human gene transfer research.
Submission of the IRB Application informs both the IBC and the IRB of the need to review the proposal and allows the IBC staff access to the uploaded documentation. In this case, the IBC functions as an "Ancillary Committee" in the IRB review process, with an IBC determination being required prior to final review and approval by the IRBMED. IBC review is subject to the committee’s meeting schedule. Allow four weeks prior to an IBC meeting for the preliminary staff review of your human gene transfer proposal.
After all required ancillary committee(s) approve the proposal, the IRBMED reviews the application and issues its determination. For more information, contact the IRBMED at 734-763-4768.
This information is for Principal Investigators (and their study teams) who are conducting human gene transfer clinical trials at U-M:
There are special reporting requirements for adverse events that occur on human gene transfer clinical trials at U-M. These requirements differ from those described in the Standard IRBMED Adverse Event Reporting Timetable. Principal Investigators at U-M involved in this type of clinical trial must follow the U-M IBC Adverse Event Reporting Requirements for Human Gene Transfer Clinical Trials, which explains the criteria, the timing, and the process for reporting human gene transfer AEs to the U-M IBC and, when required, to the NIH Office of Biotechnology Activities (NIH OBA).
- Adverse events meeting certain criteria on human gene transfer clinical trials at U-M must be reported to the U-M IBC.
- Reporting adverse events to the U-M IBC occurs through the IRB AE/ORIO reporting function.
- In some instances these adverse events must also be reported by the Principal Investigator to the NIH Office of Biotechnology Activities (NIH OBA) within specific timeframes.
- These requirements are in addition to any reporting requirements imposed by the study sponsor or other regulatory bodies.
- Your IRB application should indicate at Section 32-1 that you will be following a Study-Specific AE Reporting Plan (U-M IBC Adverse Event Reporting Requirements for Human Gene Transfer Clinical Trials).
Full information on NIH OBA reporting requirements is at Appendix M-I-C-4 of the NIH Guidelines for Research Involving Recombinant and Synthetic Nucleic Acid Molecules. Questions about the U-M IBC Adverse Event Reporting Requirements for Human Gene Transfer Clinical Trials, or other matters regarding IBC oversight of human gene transfer clinical trials, can be directed to the IBC at 734-615-3960 or IBCstaff@umich.edu.