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THE COMMITTEE ON HUMAN RESEARCH

UCSF GUIDANCE ON RESEARCH TOPICS AND ISSUES

HUMAN GENE TRANSFER/RECOMBINANT DNA RESEARCH
(revised January 2006)

• Brief Overview


• National Institutes of Health (NIH) Guidelines


• Application at the Federal Level
  • Recombinant DNA Advisory Committee (RAC) Review
  
  
  • Food and Drug Administration (FDA) Review
• Application at the Local (UCSF) Level
  • Biological Safety Committee (BSC) Review
  • Committee on Human Research (CHR) Review
• Coordination of Approvals


• Reporting Adverse Events

Brief Overview

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.” Special provisions are necessary for conducting human gene transfer research at UCSF. Principal investigators (PIs) must complete a process of multiple reviews and approvals at both federal and local/institutional levels, as explained below.

Application to the following will be required:

• RAC – Recombinant DNA Advisory Committee (NIH)



• FDA – Food and Drug Administration (DHHS)



• BSC – Biological Safety Committee (UCSF)



• CHR – Committee on Human Research (UCSF)

This guidance is meant to assist the investigator in obtaining all reviews needed as efficiently as possible.

National Institutes of Health (NIH)

National Institutes of Health (NIH) Guidelines: In undertaking any gene transfer study, PIs should first consult Appendix M of the NIH Guidelines, “Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA Molecules into One or More Human Research Participants.”

IMPORTANT NOTE: These NIH guidelines apply to any research to be conducted at or sponsored by an institution receiving support for recombinant DNA research from NIH. Thus, they apply to all UCSF PIs involved in such research.

Application at the Federal Level

Recombinant DNA Advisory Committee (RAC) Review

The NIH Guidelines, Appendix M, outlines the scope of acceptable gene transfer proposals as well as specific review requirements and procedures of the Recombinant DNA Advisory Committee (RAC), within the NIH Office of Biotechnology Activities (OBA).

RAC is a public advisory committee to the Director of NIH; its members include physicians, scientists, medical ethicists, consumer activists, and private citizens, as well as ex officio members of the federal government such as the FDA and the Office of Human Research Protection (OHRP).

The initial RAC review process will include a determination as to whether the study presents characteristics that warrant public RAC review and discussion. RAC may decide that the protocol does not need further in-depth review at a public meeting. However, FDA and local review will still be needed (see below).

Protocols and consent forms should be prepared in accord with NIH Guidelines, Appendix M, sections II-V. (Also see http://www4.od.nih.gov/oba/rdna.htm regarding informed consent and RAC Frequently Asked Questions (FAQs) for more information).

IMPORTANT NOTE: RAC review must precede local/ institutional review. Any recommendations resulting from the RAC review must be included in the applications to the UCSF Biological Safety Committee (BSC) and Committee on Human Research (CHR) (see below).

Who is responsible for the RAC/OBA submission?

For UCSF Investigator-initiated (investigator-sponsor) studies (e.g., production of vectors for human application is performed by the UCSF investigator), the UCSF PI is responsible for the submission of the relevant information on the proposed human gene transfer research to OBA (see directly above).

For Sponsor-initiated studies (e.g., the production of vectors for human application is not performed by the UCSF investigator), the Sponsor must complete the RAC submission process and provide the UCSF PI with the required Appendix M information for the UCSF BSC and CHR reviews.

IMPORTANT NOTE: In both Investigator-initiated and Sponsor-initiated studies, no participants may be enrolled at an individual site until the OBA has received the following information from the site PI:

1. Approval from the Institutional Biosafety Committee (IBC)—BSC at UCSF;
2. Approval from the Institutional Review Board (IRB)—CHR at UCSF;
3. CHR-approved informed consent document.
4. Curriculum vitae of the PI(s) (no more than two pages in biographical sketch format); and
5. NIH grant number(s) if appropriate.

Food and Drug Administration (FDA) Review

The study sponsor or investigator-sponsor will also need to submit an Investigational New Drug (IND) application to the FDA (see UCSF Guidance on Investigational New Drugs and Biologics). The IND number will be required for final CHR approval.

Application at the Local (UCSF) Level

After the study sponsor or investigator-sponsor has sought initial RAC review and IND approval from the FDA, the UCSF PI must apply for institutional review of the gene transfer research.

Biological Safety Committee (BSC): The PI will need to obtain a Biological Use Authorization (BUA).

Committee on Human Research (CHR): The PI must also obtain approval from the CHR and submit the Human Gene Transfer / Recombinant DNA Research Application Supplement.

Applications may be submitted simultaneously to the BSC and CHR for parallel review (see BSC review deadlines and CHR meeting dates for schedules).

Coordination of Approvals

CHR and BSC: The CHR and BSC will coordinate resolution of any concerns raised by either committee before issuing final authorization and approval. A link will be maintained between the approved CHR application and the BUA for the life of the study.

CHR and FDA: The CHR must receive the IND approval number (obtained from the FDA) before final CHR approval is issued.

CHR, BSC and RAC: A copy of final RAC approval or exemption from review letter should be provided by the PI to the CHR and BSC with the initial application. The CHR will not review the application without this letter.

Copies of UCSF CHR and BSC approvals should be provided by the investigator to OBA unless the study is sponsor-initiated, in which case the PI should provide this information to the sponsor for submission to OBA.

Reporting Adverse Events for Human Gene Transfer Studies

Should an adverse event occur within a gene transfer study, the following applies:

• The UCSF PI must consult and follow policies and procedures for reporting adverse events to the CHR and the BSC (see UCSF Adverse Event Reporting Guidelines for information and forms).



• PIs at all sites must report qualifying serious adverse events (SAEs) to the OBA according to the guidance provided in Appendix M-I-C-3 and M-I-C-4 of the NIH Guidelines. PIs may delegate this task to another party (e.g., the sponsor), provided a letter of delegation signed by the PI is on file with the OBA. In either case, any OBA reports concerning UCSF-enrolled participants should also be submitted to the CHR and BSC.



• If the study IND is held by a UCSF investigator (investigator-sponsor), the PI must also report qualifying SAEs directly to the FDA (see 21 CFR 312.32); if the study IND is held by an outside sponsor (sponsor-initiated), this responsibility falls to the sponsor.