Human Gene Transfer Clinical Trials

Human Gene Transfer (HGT) is a type of human subjects research that is subject to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules. Human gene transfer studies involve the deliberate transfer into human subjects of either recombinant or synthetic nucleic acid (DNA or RNA) molecules that meet any one of the following criteria:

• Contain more than 100 nucleotides
• Possess biological properties that enable introduction of stable genetic modifications into the genome
• Have the potential to replicate in a cell
• Can be translated or transcribed

Examples of studies that likely involve human gene transfer include:

• Administration of a recombinant viral vector, regardless of its ability to replicate
• Administration of mRNAs that encode proteins, e.g., mRNA vaccines for cancer or infectious agents
• Administration of CRISPR components to participants for gene editing
• Ex vivo genetic modification of patient-derived cells (e.g., CAR-T cells) that are then reintroduced into humans

FDA-approved human gene transfer products require IBC approval if the product is being used in a clinical trial for a different disease/condition than that for which FDA granted approval. 

IBC Submission and Review Process for HGT Clinical Trials

Submission Process

Proposals for HGT clinical trials at U-M are submitted to the IBC via an IRB application (HUM).  The IBC functions as an "Ancillary Committee" in the IRB review process, with an IBC determination occurring prior to final review and approval by the IRBMED.  The timetable for IBC review is subject to the committee’s meeting schedule and associated deadlines. 

In section 7, indicate that your project involves human gene transfer.  You will then be prompted to complete section 23 of the IRB application specific to human gene transfer. Submission of the IRB application (if properly identified as HGT) automatically informs the IBC of the proposal and allows IBC staff and reviewers access to the application and uploaded documents.

Review Process

The IBC will review the answers to section 23 of the IRB application as well as the following documents and aspects of the proposal. The IBC may request additional information and documentation during its review.

• Scientific abstract
• Clinical protocol including tables, figures and relevant manuscripts
• Summary of preclinical studies conducted in support of the proposed clinical trial
• Investigator’s brochure, for a description of the product, including:
  • 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.);
  • 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);
  • 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);
  • Methods for replication-competent virus testing, if applicable;
  • Intended ex vivo or in vivo target cells and transduction efficiency; and
  • Gene transfer agent delivery method.
• Proposed informed consent document(s)

Reporting Adverse Events (AEs) on HGT Clinical Trials

The reporting requirements for adverse events that occur on human gene transfer clinical trials are outline on the U-M IBC Adverse Event Reporting Requirements for Human Gene Transfer Clinical Trials. Reporting adverse events to the IBC occurs through the IRB AE/ORIO reporting function. If the IBC served as an ancillary committee for the original review, then the IBC is alerted automatically to the submission of an AE/ORIO. IBC reviewers are looking at AEs for unexpected potential relatedness to the study agent.

Amendments on HGT Clinical Trials

The IBC has a review and approval role for amendments to approved human gene transfer clinical trials. If the IBC served as an ancillary committee for the original review, then the IBC is alerted automatically to the submission of an amendment. For amendments, the IBC reviewers are looking at whether the changes have an impact on the biosafety profile of the study.

For IBC review of an amendment, study teams must upload a tracked-changes version of amended documents or supply a complete and clear page-by-page index to the changes made.