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Clinical Trials with rDNA: Instructions for Submission to the IBC

Principal investigators, follow these instructions for gene transfer clinical trial submission to UC San Diego's Institutional Biosafety Committee.

National Institutes of Health (NIH) Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules is the definitive reference for rDNA research in the United States and has been adopted by UC San Diego.

Procedures below help UCSD investigators comply with NIH Guidelines. Although the information below is extensive, PIs should not consider this a complete list of all requirements.

It is the principal investigator's responsibility to ensure ALL regulations and requirements are met.

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1. Plan your submittal times.

Consider how you want to sequence the various reviews and approvals. Normally, it is advisable to start with the RAC* review and then follow with Food & Drug Administration, Institutional Biosafety Committee, and finally the Institutional Review Board.

Consult with the various reviewers when planning a strategy.

For example:

  • UCSD's IBC will not approve a study without the RAC’s recommendations, and the IRB will not approve a study involving rDNA without IBC approval.

* Recombinant DNA Advisory Committee, or RAC, reviews protocol, scientific and safety related dimensions of the gene transfer intervention, and issues pertinent to the informed consent.

2. Read this trial submission overview.

Submission procedures depend on if the clinical trial study will be initiated at UC San Diego, or if UCSD will be an additional site for a trial initiated elsewhere.


If initiated at UCSD, the submission process is:

  1. Submit required documents to NIH Office of Biotechnology Activities (OBA).
  2. Following responses from NIH regarding public RAC review:
    • If public review is NOT warranted: complete and submit a Biohazard Use Authorization (BUA) application for IBC approval. (See Section 4 for details)
    • If public review IS warranted: after public review and completion of necessary documentation in response to RAC’s comments, complete and submit a BUA application for IBC approval. (See Section 4 for details)
  3. After BUA and IRB approvals are granted, send a 20-day initiation report to NIH and EH&S Biosafety after enrollment of the first trial participant. (See Section 6 for details)
    Note: BUA and IRB applications may be done in parallel, but the IRB will not give approval until after the BUA is approved.

If initiated elsewhere:

  1. Complete and submit a BUA application for IBC approval. (See Section 4 for details) The BUA and IRB applications may be done in parallel.
  2. After BUA and IRB approvals are granted, send additional clinical site package to NIH. (See Section 6 for details)
  3. After enrollment of the first trial participant at UCSD, do the following:
    • Work with the sponsor to ensure that the 20-day initiation report is sent to the NIH.
    • Notify EH&S Biosafety within 20 working days of first enrollment.

3. Prepare the initial protocol for submission to NIH.

Follow these steps to prepare and submit the initial protocol to NIH:

1. Assemble the following documents into a package:

  • Cover letter on UC San Diego letterhead signed by the PI that:
    • Acknowledges the documentation submitted to the NIH/OBA complies with requirements in Appendix M-1-A of the NIH Recombinant DNA Guidelines
    • Identifies the UCSD Institutional Biosafety Committee and UCSD Institutional Review Board as the proposed clinical trial site that will be responsible for local review and approval of the protocol
    • Acknowledges that no research participant will be enrolled until the NIH RAC review process has been completed
  • Scientific abstract (%7e 1 page)
  • Non-technical abstract (%7e 1 page)
  • Proposed clinical protocol including tables, figures, and relevant manuscripts
  • Proposed informed consent document
  • Curriculum vitae of the principal investigator (no more than 2 pages)

2. E-mail the package to EH&S Biosafety at ehsbio@ucsd.edu for review.

3. Submit the package to the NIH.

Note: When applicable, refer to drug as investigational new drug.

Exception

Human studies in which induction or enhancement of an immune response to a vector-encoded microbial immunogen is the major goal, such an immune response has been demonstrated in model systems, and the persistence of the vector-encoded immunogen is not expected, are exempt from Appendix M-I.

4. Submit a BUA application for IBC approval.

Every clinical trial protocol involving gene transfer must have an IBC-approved BUA before work can begin.

Submission dates: BUA applications are reviewed at the IBC's monthly meeting. See the 2017 IBC Important Dates Schedule (PDF) for due dates.

Follow these steps to create and submit a BUA for IBC approval:

1. Create a Biohazard Use Authorization (BUA):

PI contacts with editing rights can prepare the BUA for submittal; however, only the PI can press the "BUA Submittal" button when the protocol is ready for IBC review.

2. Upload the following documents to the BUA:

Upload the following documents in the BUA application’s Section 10 – Attachments:

A. Responses to Appendix M-II

    • Provide the information requested in NIH Recombinant DNA Guidelines, Appendix M-II. Ensure that the PI or the sponsor has completed Appendix M-II. Responses must correspond with UCSD being the study and treatment site. Please change any buildings and room numbers or policies to be consistent with those sites at UC San Diego.

B. RAC Correspondence

    • Include a copy of RAC letter addressing whether or not a RAC review was warranted.
    • If review of the protocol did not warrant a public discussion and RAC review, please attach this letter.
    • If it was determined that RAC review and public discussion was warranted, please attach the letter from the RAC and the PI response letter addressing each of their concerns.

C. FDA IND Review Correspondence

    • Include all documents related to the FDA IND effective date.

D. Investigator’s Brochure

E. Previous Human or Animal Data for this IND

F. Clinical Protocol

G. IRB-approved Informed Consent Form (Appendix M-III) (a draft copy is acceptable)

Informed consent documents should be in compliance with NIH Guidelines Appendix M-III and Protection of Human Subjects (45 CFR Part 46). If the research involves children special attention should be paid to Subpart D, Additional Protections for Children Involved as Subjects in Research.

The following should be included in the Informed Consent Form

    • Description/Purpose of the study in non-technical language and include other available therapies or interventions.
    • Accurate description of possible benefits of participation. If none, state clearly that no direct clinical benefit to subjects is expected.
    • Itemization of types of adverse experiences, severity, and the expected frequency.
    • Indicate the number of subjects who have previously received the genetic material under the study.
    • Provide specific information regarding financial cost to the subject in participation to the protocol or long-term follow-up that is not covered by the investigator.

The following should be in addition to the above requirements in the Informed Consent Form of Gene Transfer Research:

    • Provide information concerning possible risks to a fetus/child, need for contraception by males and females and a specified time.
    • Details on long-term follow-up that extends beyond the active phase of the study and include who to contact during the follow-up period.
    • Inform subjects that at time of death, no matter what the cause, permission for an autopsy will be requested of their families.
    • Subjects should be made aware that the institution and the investigator will make every effort to provide protection from the media for privacy protection. Medical records may be shared with representatives of applicable Federal agencies (e.g., NIH, FDA), representative of collaborating institutions, vector suppliers, etc.

H. Delegation letter, if applicable

    • Delegation of NIH reporting responsibility (optional). Principal investigators may delegate to another party, such as a corporate sponsor, the reporting functions set forth in Appendix M, with written notification to the NIH/OBA of the delegation and of the name(s), address, and telephone and fax numbers of the contact. The PI is responsible for ensuring that the reporting requirements are fulfilled and will be held accountable for any reporting lapses.

I. Site-specific rDNA SOP

    • Where are you getting your vector? Please include gene maps of the vector.
    • How will the material be transported from the GMP facility to the preparation site?
    • How will the material be transported from the preparation site (pharmacy or equivalent) to the patient delivery site?
    • How will the material be stored and prepared for patient use?
    • Where will the material be prepared?
    • How will waste products be handled and disposed of both in preparation and in patient delivery?
    • What are the disinfection SOPs?
    • What is the training for the personnel involved with the project?
    • What is the titer used and in what concentrations? What is the diluent?
    • What will be used for personal protective equipment?
    • Is the administration room positively or negatively pressured with respect to adjacent space?
    • Outline procedures for accidental spills or exposure.
    • What precautions will immediate family members be apprised of regarding how to handle patient body fluids?

3. Submit BUA for IBC review.

5. IBC Review Process

UC San Diego IBC has partnered with WIRB Copernicus Group (WCG) to review all clinical trials requiring a BUA. Under this partnership, there is a cost associated with the review of clinical protocols, payment of which is the responsibility of the sponsor.

Review Process for IBC Review of Clinical Protocols:

  1. PI submits Clinical BUA.
  2. BUA is routed to WCG for review.
  3. WCG contacts the Clinical Coordinator for completion of the WCG form (PDF). (Please right click on form and save to desktop in order to fill out and complete.)
  4. Upon receipt of the WCG form, a review is conducted and presented at an IBC meeting for review and approval by the committee.
  5. If requested by IBC, a site visit may be conducted.

6. Comply with these post-approval reporting requirements.

If the clinical trial is initiated at UCSD:

Within 20 business days after enrollment of the first trial participant, submit the following documentation to the NIH/OBA (see the "Contacts" section below for NIH/OBA reporting methods) and to UCSD's IBC via e-mail at ehsbio@ucsd.edu:

  • Copies of the:
    • Informed consent document approved by the Institutional Review Board (IRB)
    • Clinical protocol approved by the IBC and IRB
    • Final IBC approval letter from the clinical trial site
    • Final IRB approval letter
  • A brief written report that includes the following information:
    • How the investigator(s) responded to each of the RAC’s recommendations on the protocol (if applicable)
    • Any modifications to the protocol required by FDA
  • Applicable NIH grant number(s)
  • FDA Investigational New Drug Application (IND) number
  • Initiation date of the trial

If the clinical trial is initiated elsewhere (additional clinical trial sites):

  1. Notify the NIH/OBA that UCSD is an additional trial site BEFORE the first trial participant is enrolled by submitting the following documentation:
    • IBC approval letter from the clinical trial site
    • IRB approval letter
    • IRB-approved informed consent document
    • Curriculum vitae of the PI(s) (no more than 2 pages in biographical sketch format)
    • NIH grant number(s) if applicable
  2. After enrollment of the first trial participant at UCSD, confirm with the sponsor that the 20-day initiation report has been sent.

7. Submit an annual report to the NIH and UCSD's IBC.

Requirement

Within 60 days after the 1 year anniversary of the date on which the investigational new drug (IND) application went into effect, and after each subsequent anniversary until the trial is completed, the PI (or delegate) must submit an annual report to the NIH/OBA and IBC.

Note: If your trial is exempt from Appendix M (see Appendix M-VI-A), the NIH annual report is not required. UCSD's IBC, however, requires an annual report without exception. In the case of exempt protocols, the most current summary update submitted to the IRB may be submitted to the IBC to fulfill the annual report requirement.


How to Submit the Annual Report

NIH/OBA

  • Submit the report (for non-exempt protocols) separately to the NIH/OBA. See the "Contacts" section below for NIH/OBA reporting methods. Please note that failure to submit the annual report to the NIH by the due date will require EH&S Biosafety to send a notification of non-compliance to NIH.
  • Delegation of NIH reporting responsibility (optional): Principal investigators may delegate to another party, such as a corporate sponsor, the reporting functions set forth in Appendix M, with written notification to the NIH/OBA of the delegation and of the name(s), address, and telephone and fax numbers of the contact. The PI is responsible for ensuring that the reporting requirements are fulfilled and will be held accountable for any reporting lapses. Attach a copy of the delegation letter in the BUA.

UCSD's IBC

  • Submit your annual report to UCSD's IBC online as part of the BUA Clinical Trial Annual Verification (Renewal) process. Follow the steps below to submit an annual report during the BUA renewal process.

BUA Clinical Trial Annual Verification (Renewal) Procedures

The BUA for the clinical trial does not expire but is subject to annual verification, or renewal. EH&S Biosafety initiates the BUA renewal process by sending the PI a BUA Clinical Trial Annual Verification (Renewal) notice.

To submit the annual report to UCSD's IBC during the renewal process, follow these steps:

  • Log on to the BIO application from My Research Safety at myresearchsafety.ucsd.edu.
  • Select your BUA from the My BUAs tab and press the Renew button at the bottom of the screen.
  • Review all aspects of your BUA for accuracy and update information as necessary.
    • Important: Consult EH&S Biosafety, before making changes to an approved BUA. Significant changes to a protocol may require an amendment or a new BUA.
  • In the Renewal Summary, describe this action as “Annual Report” and provide a brief, non-technical summary of the annual report.
  • Upload your annual report document, including documentation of submittal date to NIH. The report must include all of the information listed below:
    • Clinical trial information – A brief summary of the status of each trial in progress and each trial completed during the previous year. The summary must include the following information for each trial:
      • Title and purpose of the trial
      • Clinical site
      • The principal investigator(s)
      • Clinical protocol identifiers, including the NIH OBA protocol number, NIH grant number(s), if applicable, and the FDA IND application number
      • Participant population such as disease indication and general age group (i.e., adult or pediatric)
      • Total number of participants planned for inclusion in the trial; the number entered into the trial to date; the number whose participation in the trial was completed; and the number who dropped out of the trial with a brief description of the reasons
      • Status of the trial (i.e., open to accrual of subjects, closed but data collection ongoing, or fully completed)
      • If the trial has been completed, a brief description of any study results
    • Progress report and data analysis – Information obtained during the previous year's clinical and nonclinical investigations, including:
      • A narrative or tabular summary showing the most frequent and most serious adverse experiences by body system
      • A summary of all serious adverse events submitted during the past year
      • A summary of serious adverse events that were expected or considered to have causes not associated with the use of the gene transfer product such as disease progression or concurrent medications
      • If any deaths have occurred, the number of participants who died during participation in the investigation and causes of death
      • Brief description of any information obtained that is pertinent to an understanding of the gene transfer product’s actions, including (for example) information about dose-response, information from controlled trials, and information about bioavailability
    • Updated clinical protocol – A copy of the updated clinical protocol including a technical and non-technical abstract
    • Informed consent – Attach the most recent copy of the informed consent form.
  • Upload your Bloodborne Pathogens Exposure Control Plan, if applicable.
  • Upload the attachments below only if changes have been made (submit in “Track Changes” view):
    • Current Investigators Brochure
    • Current protocol
    • Current informed consent form
  • Update your Authorized Personnel, PI Contacts, and their training records.
    • Important: Training records must be current to complete the BUA annual verification.
  • Click the Renew button to submit your BUA verification (renewal) to the IBC.

8. Provide safety reports as required.

Requirements

A clearly written report must be submitted to the NIH/OBA (see Incident Reporting template, Word File), FDA (See Serious Adverse Events form), and the UC San Diego IBC (in the form of a BUA Amendment/Renewal) if the following instances occur:

  • Any serious adverse event (SAE) that is both unexpected and associated with the use of the gene transfer product (i.e., there is reasonable possibility that the event may have been caused by the use of the product; investigators should not await definitive proof of association before reporting such events).
  • Any SAE that is fatal or life-threatening, that is unexpected, and associated with the use of the gene transfer product must be reported to the NIH/OBA as soon as possible, but not later than 7 calendar days after the sponsor’s initial receipt of the information (i.e., at the same time the event must be reported to the FDA).
  • SAEs that are unexpected and associated with the use of the gene transfer product, but are not fatal or life-threatening, must be reported to the NIH/OBA as soon as possible, but not later than 15 calendar days after the sponsor’s initial receipt of the information (i.e., at the same time the event must be reported to the FDA).
  • Any finding from tests in laboratory animals that suggests a significant risk for human research participants including reports of mutagenicity, teratogenicity, or carcinogenicity must be reported as soon as possible, but not later than 15 calendar days after the sponsor’s initial receipt of the information (i.e., at the same time the event must be reported to the FDA).

Report Content and Format

The SAE report must include (but is not limited to):

  • Date of the event
  • Designation of the report as an initial report or a follow-up report, identification of all safety reports previously filed for the clinical protocol concerning a similar adverse event, and an analysis of the significance of the adverse event in light of previous similar reports
  • Clinical site
  • Principal investigator
  • NIH protocol number
  • FDA’s Investigational New Drug (IND) application number
  • Vector type (i.e., adenovirus)
  • Vector subtype (i.e., type 5, relevant deletions)
  • Gene delivery method (i.e., in vivo, ex vivo transduction)
  • Route of administration (i.e., intratumoral, intravenous)
  • Dosing schedule
  • A complete description of the event
  • Relevant clinical observations
  • Relevant clinical history
  • Relevant tests that were or are planned to be conducted
  • Date of any treatment of the event
  • Suspected cause of the event

Note: Reports from laboratory animal studies as delineated in Appendix M-I-C-4 must be submitted in a narrative format.


How to Report

  • NIH/OBA - Submit safety reports using the recommended Adverse Event Reporting Template (PDF) available on NIH/OBA’s website, the FDA MedWatch forms, or other means provided that all of the above elements are specifically included.
    • Delegation of NIH reporting responsibility (optional): Principal investigators may delegate to another party, such as a corporate sponsor, the reporting functions set forth in Appendix M, with written notification to the NIH/OBA of the delegation and of the name(s), address, and telephone and fax numbers of the contact. The PI is responsible for ensuring that the reporting requirements are fulfilled and will be held accountable for any reporting lapses. Attach a copy of the delegation letter in the BUA.
  • UCSD's IBC - Report serious adverse events to UCSD's IBC by amending the BUA. To amend your BUA:
    • Log on to the BUA application from My Research Safety at myresearchsafety.ucsd.edu.
    • Click the Authorizations tab and select Biohazard Use Authorization to open the BUA application.
    • Select your BUA from the My BUAs tab and press the Renew or Amend button at the bottom of the screen to proceed.

If you change the protocol ...

Important

Significant changes to an approved protocol may require submission of update to the NIH/OBA, and/or an amendment. All changes cannot be addressed here. Consult EH&S Biosafety, before making changes to an approved BUA.

Typical occasions when an amendment or a new BUA are required are listed below.

Amendments are required for:

  • Serious adverse event (SAE) reporting (see Section 9 for details)
  • Changes in location
  • Title changes that do not change study parameters
  • Changes to the investigational drug (at a minimum this requires an amendment, but might it require a new BUA)

New BUA’s may be required for the following (contact EH&S Biosafety):

  • Changes to the investigational drug
  • Changes in the study population
  • Changes in administration of the investigational drug
  • New phase (i.e., going from phase 1 to phase 2)
  • Changes to the IRB number

Contacts

National Institutes of Health, Office of Biotechnology Activities

There are 3 mechanisms for reporting information to the NIH/OBA:

Mail E-mail Fax

Office of Biotechnology Activities
Attn: Biotechnology Program Advisor
National Institutes of Health, MSC 7985
6705 Rockledge Drive, Suite 750
Bethesda, Maryland 20892-7985

oba@od.nih.gov (301) 496-9839

You may phone the NIH at (301) 496-9838.

UC San Diego, EH&S Biosafety staff

Seth Mullen Susan Mayo Sheryl Major Le’Kneitah Smith
Biosafety Officer Associate Biosafety Officer High Containment Officer Associate Biosafety Officer
(858) 534-0353 (858) 534-5366 (858) 822-2493 (858) 534-8854
smullen@ucsd.edu
sgardner@ucsd.edu smajor@ucsd.edu lpsmith@ucsd.edu

References

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