0. Human Gene Therapy Institutional Review Procedures
September 1, 2017
Institutional Biosafety Committee (IBC)&
Institutional Review Board (IRB)

1. Introduction
Review and proper registration of Human Gene Transfer protocols is very complex. A protocol goes through rigorous review by multiple Committees both internally and externally. Due to this complexity, we have developed this guidance to assist researchers navigate the process.
FDA
Hospital Service Lines
Institutional Biosafety Committee (IBC)
Recombinant DNA Advisory Committee (RAC)
Committees on Human Research (IRB)
NIH Office of Science Policy (OSP)

2. Investigator-Initiated vs Industry Sponsored
Investigator-Initiated - If this is an investigator-initiated gene transfer project, then all of the requirements as outlined in this power point are the local investigator’s responsibility.
Industry-Sponsored - Some of the requirements as outlined in this power point are to be completed by the local investigator while some are to be completed by the sponsor. We will address where there are differences.

3. Step 1: Obtain FDA Approval
FDA approval is required prior to submission for institutional review. This will be the responsibility of the local investigator for investigator-initiated protocols and the sponsor for industry-sponsored projects.

4. Step 2: Obtain Approval from the Following Hospital Services
Local Investigator is responsible to obtain feasibility approvals from the following hospital services, regardless of sponsorship:
UVMMC Investigational Drug Pharmacy
UVMMC Environmental Health and Safety Dept
UVMMC Infectious Disease
UVMMC Infection Prevention

5. Materials Required for Each Service Review
Each service will require the following materials for review:
Clinical Trial Protocol
Investigational Drug Brochure
Standard Operating Procedures for Drug Preparation
Standard Operating Procedures for Transport of Drug
Standard Operating Procedures for Handling of Drug by Clinical Staff

6. Step 3: Institutional Biosafety Review

7. IBC REVIEW
Local investigator is responsible for submission to the IBC.
Gene transfer protocols will require a full Committee review.
All Service Line reviews must be complete prior to submission to the IBC.
A site risk assessment must be completed prior to submission to the IBC. This would typically be done by the UVMMC Environmental Health and Safety staff, UVM Biosafety, the UVMMC Research Pharmacy Manager and the PI for the project.
IBC Committee will make the final determination regarding RAC Review for the institution. This determination is separate and distinct from an industry-sponsored determination.

8. Documents Required for IBC Review
IBC Protocol Form including
Standard Operating Procedures for Drug Preparation, Transport, and Handling as approved by the Service Lines
Complete Human Subjects IRB Cover Form
Draft of Human Subjects IRB Consent Form
Clinical Protocol
Investigational Drug Brochure
*Review of these materials satisfies the requirement to meet the Points to Consider Section, M-I-A, of the NIH Guidelines.

9. Step 4: Recombinant DNA Advisory Committee (RAC) Review
The Recombinant DNA Advisory Committee is a federal advisory committee that provides recommendations to the NIH Director related to basic and clinical research involving recombinant or synthetic nucleic acid molecules. 
RAC review is not required for all gene transfer protocols. Effective April 27, 2016, a protocol will be selected for RAC review if (1) a local oversight body (IBC or IRB) determines that the protocol would significantly benefit from RAC review and
(2) the protocol satisfies one or more of the following criteria:
(i) new vectors/new gene delivery systems,
(ii) new diseases,
(iii) unique applications of gene transfer, and
(iv) other issues considered to require further public discussion.

10. Who Decides if RAC Review Is Required?
Investigator-Initiated Single-Site
UVM’s IBC will determine if a protocol requires RAC review based on the criteria presented in previous slide.
Industry-Sponsored Multiple Sites
Often times, sponsors will make a study level decision and approach RAC if they feel it meets criteria. The local site, however still makes its own determination of the need for RAC review. The various sites’ determinations are provided back to NIH for consideration.

11. Step 5: IRB REVIEW

12. IRB Review
Local investigator is responsible for submission to the IRB.
Gene transfer protocols will require a full Committee review.
Initial IBC review has to be completed with an approved- type status.
IRB formally cedes the decision as to whether RAC review will be required to the IBC Committee.

13. Documents for IRB Review
Completed Human Subjects IRB Cover Form
Draft of Human Subjects IRB Consent Form (revised after IBC changes)
Clinical Protocol
Investigational Drug Brochure
IBC Materials
Approval
Copy of Clarification Memo and PI Response
Documentation of RAC Review Determination, if applicable
*Review of these materials satisfies the requirement to meet the Points to Consider Section, M-I-A, of the NIH Guidelines.

14. Step 6: Register Protocol with NIH Office of Science Policy (OSP)
All human gene transfer studies must be registered with the NIH before enrollment may begin. OSP maintains a database of all registered/approved experiments.

15. Documentation of Registration with NIH OSP must occur prior to release of Committee Approvals
The following documents must be submitted to NIH Office of Science Policy: (if investigator-initiated this responsibility falls to the researcher, if industry-sponsored this responsibility falls to the sponsor)
A scientific abstract
Proposed clinical trial
Summary of preclinical studies
Description of the product
Proposed Informed Consent
Documentation from the IBC/IRB regarding their assessment of whether public RAC review is warranted.
Documents are ed to

16. Step 7: AFTER NIH OSP REGISTRATION IS RECEIVED

17. Once Registration is Received the Following will Occur
When NIH registration has been confirmed, the investigator provides notification to the IBC and IRB.
IBC will issue approval upon completion of IBC review.
IRB approval is issued upon completion of IRB review.
Recruitment of Subjects May Begin

18. Post Approval Reporting Requirements
Within 30 days of the first patient enrollment, the PI, if investigator-initiated, or the Sponsor, if industry- sponsored, must submit the following documents to OSP:
IBC approval
IRB approval
IRB-approved consent form
NIH grant number (if applicable)
And Curriculum Vitae of the PI
Documents are ed to

19. Serious Adverse Event Reporting Requirements for Human Gene Therapy Research
Human gene transfer 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 Science Policy (OSP) 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 OSP, researcher must submit SAEs to the IBC and the IRB. 

20. CONCLUSION
This presentation was designed to inform the audience on the local and national requirements for review of gene therapy experiments.