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Human Gene Transfer Research

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Overview of Human Gene Transfer Research

The following explanations are provided to assist investigators in determining whether their proposed research may constitute human gene transfer and, therefore, require additional oversight.

What is DNA?

Deoxyribonucleic acid (DNA) is the building block of life. This molecule encodes different characteristics in all living things. With the exception of identical twins, all individuals have different DNA molecules. In some individuals, the DNA contain mutations that encode aberrant messages. These mutations can cause abnormalities that may result in disease.

What is not Human Gene Transfer Research?

When DNA is manipulated outside of the body but is not integrated into a person's genome, it is an example of recombinant DNA (rDNA) research but is not gene transfer. Likewise, if protein or RNA products of the rDNA are injected into a person, no gene transfer has occurred.*

Experiments involving rDNA require review and approval by the UCI Institutional Biosafety Committee (IBC). Institutional Review Board (IRB) review and approval is required if human subjects are involved. Institutional Animal Care and Use Committee (IACUC) review and approval is required if vertebrate animals are used.

*Note: use of retroviral vectors constitutes human gene transfer.

What is Human Gene Transfer (a.k.a. "Gene Therapy")?

Human gene transfer is the process of transferring genetic material (DNA or RNA) into a person. DNA may be transferred as "naked" DNA, encapsulated DNA, or DNA within another organism, such as a virus. Use of retroviral vectors in humans also constitutes human gene transfer when the virus contains enzymes that result in a DNA copy of the RNA genome.

Human gene transfer 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 triggering the immune system to fight disease. 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, hemophilia, and cystic fibrosis). 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.

Scientists are attempting to determine whether human gene transfer can be safe and effective as a treatment for disease. Some experimental gene transfer procedures involve the introduction of DNA into cells, which then are injected into a person with disease. All such human gene transfer research studies require approval by the UCI Institutional Review Board (IRB), the UCI Institutional Biosafety Committee (IBC), and possibly the NIH Recombinant DNA Advisory Committee (RAC).

All human gene transfer protocols subject to the NIH Guidelines must be registered with the NIH and be reviewed and approved by institutional oversight bodies such as the IBCs and IRBs.

Federal Oversight and Review Requirements

Human Gene Transfer Research is defined by federal regulations as, "Any deliberate transfer of recombinant DNA, or DNA or RNA derived from recombinant DNA (technology), into human research participants."

The NIH Office of Biotechnology Activities (OBA) exists because 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.

The NIH OBA 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:

  • 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.
  • 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 enterprise.

For information regarding the Registration and Review Process for Human Gene Transfer Protocols, please refer to the NIH FAQ page.

The Recombinant DNA Advisory Committee (RAC)

The RAC is a panel of up to 21 national experts in various fields 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 NIH locus of oversight for recombinant DNA research. In this capacity, the RAC recommends changes to the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines), which outline responsible research practices in basic and clinical recombinant DNA research.

Another important RAC function is to review research proposals involving human gene transfer research, or "gene therapy" as it is often called. RAC review of individual human gene transfer protocols are limited to cases in which an oversight body ( i.e., UCI IBC) determines that a protocol would significantly benefit from RAC review, and has been determined to meet one or more of the following criteria:

  1. The protocol uses a new vector, genetic material, or delivery methodology that represents a first-in-human experience, thus presenting an unknown risk; or
  2. The protocol relies on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value; or
  3. 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 to evaluate the protocol rigorously.

NOTE:  Even if the protocol does not meet the proposed criteria 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.

To learn more about the RAC, please visit the OBA website.

Who is Responsible for the RAC Submission?

  • For Sponsor initiated studies (i.e., the production of vectors for human application is not performed by the UCI investigator) the Sponsor must complete the RAC submission process and provide the UCI investigator with the required Appendix M information for the IBC review. All documents required for NIH protocol registration and confirmation of NIH protocol registration must be submitted as part of the IBC application submission.
  • For UCI investigator initiated studies (i.e., the production of vectors for human application is performed by the UCI investigator), the IBC, with additional expertise obtained from the IRB, will assess whether the protocol would also benefit from RAC review.  To make this assessment, the UCI investigator must submit an IBC application, the RAC Review Assessment Form, and all documents required for NIH protocol registration to the IBC. The IBC will inform the UCI investigator whether the protocol meets the criteria for RAC review. 

The UCI investigator is responsible for the submission of the relevant information on the proposed human gene transfer experiments to NIH Office of Biotechnology Activities (OBA) in accordance with Appendix M of the NIH Guidelines.  NIH protocol registration confirmation must be submitted to the IBC prior to IBC approval.

UCI Oversight and Review Requirements

Human Gene Transfer studies must be reviewed by the UCI Institutional Biosafety Committee (IBC) and the UCI Institutional Review Board (IRB). IBC review is concurrent with IRB review of new protocols. IRB approval will be granted upon receipt of the IBC approval letter. If, however, substantive changes to the IRB protocol are required based on IBC determination or RAC review, additional IRB review will be required to confirm that changes meet requirements for IRB approval under 45 CFR 46.111 and 21 CFR 56.111.

IBC Review and Submission

Environmental Health & Safety assumes all administrative support responsibilities for the Recombinant and Synthetic Nucleic Acid Activities Program and the UCI IBC. All issues related to this program should be addressed to the Campus Biosafety Officer at (949) 824-9888.

More information is available on the UCI IBC website.

IRB Review and Submission

Human gene transfer research requires review by the IRB. The IRB protocol submission requirements for human gene transfer studies are the same as with other human research protocols. See How to Submit Electronic IRB Applications for Review for detailed information.

IRB Submission Requirements

Provide the following information with your submission to the IRB:

  • UCI IRB application
  • Informed consent document
    • Additional consent elements unique to human gene transfer research should be included in the IRB informed consent document, such as reproductive considerations; long term follow-up (FDA requires 15 years or until death); autopsy to study pathology of disorder/illness; risk of media interest in the study.
    • Note: Investigators should review the NIH Guidance on Informed Consent For Gene Transfer Research for useful information about preparing the informed consent document and performing the informed consent process.
  • The FDA Investigational New Drug (IND) number
  • Sponsor's Master Protocol

Other UCI Reviews

The hospital (UCIMC) also reviews human gene transfer studies to assure adequate facilities are available to perform the study. See the Gene Medicine Advisory Committee website for more information. Note: you must have HSIS Intranet access to view this link.

The campus Biosafety Officer will review the Clinical safety standard operating procedures (SOPs) for the conduct of human gene transfer studies. Contact Sheila Hedayati at 949-824-9888 or shedayat@uci.edu, or visit the EH&S Biosafety website for more information.

Notification to NIH-OBA of UCI Approvals

Evidence of UCI approvals should be provided by the UCI investigator to the NIH-OBA unless the study is sponsor initiated. In the latter case, the UCI investigator should provide this information to the sponsor of the study for submission to NIH-OBA.

After receiving approval from both the UCI IBC and UCI IRB, participants may be enrolled at the UCI site. The UCI investigator has 30 days after the enrollment of the first participant to submit the following documentation to NIH-OBA:

  • UCI IBC approval letter
  • UCI IRB approval letter and (IRB stamped) informed consent document
  • Curriculum vitae of the Lead Researcher and any Co-investigators
  • NIH grant number(s), if applicable

Serious Adverse Event Reporting Requirements for Human Gene Transfer Research

All unanticipated problems must be submitted to the UCI IRB. See the Unanticipated Problems webpage for detailed information.

Human gene transfer (a.k.a. "gene therapy") protocols have additional adverse event reporting responsibilities. The NIH Guidelines require that any significant problems, violations, or any significant research-related accidents and illnesses” be reported to the NIH Office of Biotechnology Activities' (OBA) within 30 days.  If the gene transfer study is supported by an external sponsor, this reporting should be coordinated with the sponsor. In addition to submitting a serious adverse event (SAE) to the OBA, LR must submit SAEs to the UCI Institutional Biosafety Committee (IBC), and any unanticipated problems to the UCI IRB. 

Failure to report gene transfer SAEs to the federal oversight bodies (FDA, NIH-OBA) may result in sanctions for the LR and for the institution. For more information regarding the additional reporting responsibilities for human gene transfer research, please refer to the OBA main webpage, the OBA FAQ page on incident reporting, or contact the UCI IBC.

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