Office of Human Research
Page Title

SOP No.: 203     NIH REQUIREMENTS FOR OBA-REVIEWED RESEARCH

Author:    Office of Human Research

Effective Date:  October 1, 2007

Supercedes document dated:              N/A

Last Reviewed on:     N/A                                 

Results of Review:               N/A

This SOP pertains to:  All FDA-regulated human subject research subject to investigational new drug (IND) regulations, that also is subject to OBA requirements for gene transfer research, and which is conducted within the Thomas Jefferson University.

Responsibility for executing this SOP:  Investigator and Designated Research Personnel

Approved By:

 

J. Bruce Smith, MD

 

Associate Vice President for Research

 

(signature on file at OHR)

Approved By:

 

Steven E. McKenzie, MD, Ph.D.

 

Vice President for Research

 

(signature on file at OHR)

 

1. PURPOSE

This procedure serves as a companion to SOP 201, Contacts and Submissions for the FDA and SOP 202, Reporting Requirements for the FDA. It describes additional regulatory submission and reporting requirements associated with The (OBA)-reviewed research that must be provided to the OBA Recombinant DNA Advisory Committee (RAC) before such research can begin in human participants, and while such studies are underway.

2. OBA/RECOMBINANT DNA ADVISORY COMMITTEE (RAC) REVIEW OF RESEARCH GENERAL INSTRUCTIONS

  1. The Investigator and all other participating Investigators are responsible for full compliance with the NIH Guidelines in the conduct of recombinant DNA research.
  2. The Investigator must notify the OHR of their intention to submit to the OBA prior to submission development.
  3. The Investigator and all other participating Investigators are responsible for ensuring that all aspects of Appendix M of the NIH Guideline have been appropriately addressed prior to the submission of a human gene transfer experiment to the OBA, and providing a letter signed by the Investigators on institutional letterhead acknowledging that the documentation being submitted to the NIH OBA complies with the requirements set forth in Appendix M.
  4. The Investigator and all other participating Investigators are responsible for ensuring that appropriate NIH OBA staff members are contacted early and as often as necessary to conduct effective and timely meetings and develop complete and accurate submissions.
  5. The Investigator is responsible for assuring that the OHR is involved in the development of the formal OBA submission.
  6. The Investigator and all other participating Investigators may delegate to another party, such as a corporate Sponsor, the reporting functions set forth in Appendix M with written notification to OBA of the delegation and how the individual so delegated may be contacted.
  7. The Investigator and all other participating Investigators and their designees are responsible for recognizing and reporting serious adverse events (SAE), which require immediate reporting to the NIH OBA.
  8. The Investigator, all other participating Investigators or their designees are responsible for documenting all adverse events on the appropriate case report form (CRF) and other regulatory reporting forms (See SOP 203 Attachment B, the OBA Template for Reporting Adverse Events in Human Gene Transfer Trials).
  9. For experiments involving the deliberate transfer of recombinant DNA, or DNA or RNA derived from recombinant DNA, into human research participants (human gene transfer), no research participant may be enrolled until the RAC review process has been completed, the site's Institutional Biosafety Committee (IBC) approval has been obtained, Institutional Review Board (IRB) approval has been obtained, and all applicable regulatory authorization(s) have been obtained, e.g., the FDA.
  10. Enrollment is defined as the process of obtaining informed consent from a potential research participant, or a designated legally authorized representative (legal guardian) of the participant, to undergo any test or procedure associated with the gene transfer experiment.
  11. The information provided in response to Appendix M should not contain any confidential commercial information or trade secrets, enabling all aspects of RAC review to be open to the public.
  12. No adverse event (AE) report is confidential so no trade secret or confidential commercial information should be in the AE report, nor should any research subject facial or direct identifiers be included in the report. Facial and direct identifiers include:
    • name
    • street address (renamed postal address information, other than city, State and zip code)
    • telephone and fax numbers
    • e-mail address
    • social security number
    • certificate/license numbers
    • vehicle identifiers and serial numbers
    • URLs and IP addresses
    • full face photos and any other comparable images
    • medical record numbers (prescription numbers), health plan beneficiary numbers, and other account numbers
    • device identifiers and serial numbers
    • biometric identifiers, including finger and voice prints.
  13. The RAC will consider whether a proposed human gene transfer study presents characteristics that warrant public RAC review and discussion.
  14. Protocols may be submitted for RAC review prior to local IRB approval.
  15. Protocols must be submitted for RAC review and the RAC review process completed prior to local IBC approval.
  16. The documentation must be submitted in printed or electronic form to the: NIH Office of Biotechnology Activities, National Institutes of Health/MSC 7985, 6705 Rockledge Drive, Suite 750, Bethesda, Maryland 20892 (20817 for non-Postal Service delivery). Verify the address before sending submission.
  17. The Investigator should retain documents confirming OBA receipt of the submission. (OBA normally issues this within three (3) working days after receiving the submission).

3. SPECIFIC PROCEDURES

3.1 Preparing the OBA/RAC Submission

The submission consists of the following:

  1. A cover letter on institutional letterhead, signed by the Principal Investigator(s) must be submitted that:
    • Acknowledges that the documentation submitted to OBA complies with the requirements set forth in Appendix M-I-A, Requirements for Protocol Submission
    • Identifies the IBC and IRB at the proposed clinical study site(s) responsible for local review and approval of the protocol
    • Acknowledges that no research participant will be enrolled until the RAC review process has been completed, IBC approval (from the clinical study site) has been obtained; IRB approval has been obtained; and all applicable regulatory authorizations have been obtained
  2. The scientific abstract.
  3. The non-technical abstract.
  4. The proposed clinical protocol, including tables, figures, and relevant manuscripts.
  5. Responses to Appendices M-II through M-V, Description of the Proposal, Informed Consent, Privacy and Confidentiality, and Special Issues.
  6. The aforementioned responses to Appendices M-II through M-V may be provided either as an appendix to the clinical protocol or incorporated in the clinical protocol.
  7. If responses to Appendices M-II through M-V are incorporated in the clinical protocol, each response must refer to the appropriate Appendix M-II through M-V.
  8. The proposed informed consent form.
  9. Curricula vitae of the PIs, no more than two pages in biographical sketch format.

3.2 Review and Follow-up

  1. During the RAC's initial review, individual committee members may request additional information relevant to the protocol.
  2. The OBA will notify the PIs in a timely manner of the RAC requests for additional information.
  3. Once the local IBC is in receipt of the RAC recommendations, the IBC may proceed with its protocol approval process.
  4. No later than 20 working days after enrollment of the first research participant, the PI must have provided to the OBA:
    • The final protocol, as approved by the local IRB and IBC and as authorized by the FDA along with the IND number
    • The NIH grant number(s), if applicable
    • A copy of the IRB and IBC approvals
    • As applicable, a written response addressing each of the RAC recommendations resulting from public review and discussion of the protocol
    • The date of the initiation of the study
    • For a clinical study site that is added after the RAC review process, no research participant shall be enrolled at the new site until the following documentation has been submitted to the OBA:
    • IBC approval letter (from the new site)
    • IRB approval letter
    • IRB-approved informed consent form
    • Curriculum vita of the PI, no more than two pages in biographical sketch format
    • NIH grant number(s) if applicable.

3.3 Reporting Requirements

3.3.1 Additional Clinical Trial Sites

The Investigator will ensure that no participant is enrolled at a clinical trial site until the following documentation has been submitted to the NIH OBA:

  • IBC approval for the clinical site
  • IRB approval
  • IRB approved Informed Consent Form
  • CV of Principal Investigator (no more than 2 pages in Biographical sketch format)
  • NIH Grant number
  • FDA Form 1572 submitted to FDA by Investigator
  • IND Number

 

3.3.2 Annual Reports

  1. The Investigator will ensure that within 60 days after the one-year anniversary date on which the IND went into effect and after each subsequent anniversary until the trial is completed, the Principal Investigator (or delegate) shall submit the information noted in the bulleted list below.

    When multiple studies are conducted under one IND, the Investigator may choose to submit a single annual report covering all studies, provided that each study is identified by its OBA protocol number.

    Clinical Trial Information including a brief summary of the status of each trial in progress and each trial completed during the previous year. It should include:

      1. The title and purpose of the protocol
      2. Clinical Site
      3. The principal investigator
      4. Clinical Protocol identifiers [NIH OBA]
      5. FDA IND number
      6. Subject population
      7. Total number of participants planned and number entered to date
      8. Number of participants whose participation was completed and the number who dropped out with brief description of the reasons
      9. Status of the trial (open to accrual, closed but data collection continued, etc)
      10. If trial has been completed, brief description of results
  2. Progress Report and Data Analysis
The progress report and data analysis includes information obtained during the previous year's clinical and non-clinical investigations, including;
    • Narrative tabular summary showing most frequent and most serious adverse events by body system
    • 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 [i.e., disease progression]
    • Any deaths that have occurred, the number of participants who died during participation and causes of death
    • A 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
    • A copy of the updated clinical protocol including a technical and non-technical abstract

3.3.3 Safety Reporting

  1. The Investigator must ensure that written reports are provided to the OBA for all Serious Adverse Events (SAEs) for all participating investigators. The investigator may use the recommended Adverse Event Reporting Template at http://www4.od.nih.gov/oba/RAC/Adverse_Event_Template.doc, or the FDA Medwatch Form 3500 A at http://www.fda.gov/medwatch/safety/3500A.pdf.
  2. The Investigator and participating investigators may also report adverse events electronically directly to the NIH using the Genetic Modification Clinical Research Information System (GeMCRIS). To gain access to the system the investigator must contact the GeMCRIS Systems Administrator at NIH Office of Biotechnology Activities, 6705 Rockledge Drive, Suite 750, Bethesda, MD 20892; fax: 301-496-9839.
  3. The Investigator and participating investigators may save a copy of the electronic GeMCRIS report on their computer, print and mail to the FDA with a FDA form 1571

    Serious Adverse Events may be reported to the NIH OBA via

    • The GeMCRIS Electronic Reporting System
    • E-Mail to oba@od.nih.gov
    • Fax: 301-469-9839
    • Mail to the Office of Biotechnology Activities
      National Institutes of Health, MSC 7985
      6705 Rockledge Drive, Suite 750
      Bethesda, MD 20892-7985
  4. Any SAEs that are both unexpected and associated with the use of the transfer product (i.e., that there is a reasonable possibility that the event may have been caused by the use of the product) must be reported regardless of whether there is proof of the relationship to the transfer product
  5. The report must be clearly labeled "SAFETY REPORT" and must be submitted to the NIH OBA, the FDA, the Institutional Biosafety Committee and the IRB within the required time frames:
  6. The SAE report MUST INCLUDE but need not be limited to:
    • The date of the event
    • Designation of the report as initial or follow up report, identification of all safety reports previously filed for the clinical protocol concerning a similar event and an analysis of the significance of the adverse event in light of previous similar reports.
    • Clinical Site
    • The Principal Investigator
    • NIH Protocol Number
    • IND Number
    • Vector Type
    • Gene Delivery Method, e.g., in-vivo, ex-vivo, transduction
    • Route of Administration
    • Dosing Schedule
    • A complete description of the event
    • Relevant clinical observations and history
    • Relevant tests that were or are planned to be conducted
    • Date of any treatment of the event; and
    • The suspected cause of the event
  7. If a gene therapy vector used for dosing was manufactured using federal funds, the Investigator will notify all other applicable federal offices of an SAE within 24 hours via telephone or other appropriate alternative.

3.3.4 Reporting Timeframes

The Investigator must assure that all adverse events are reported in accordance with required regulatory time frames.

  1. Any SAEs that are fatal or life threatening, unexpected and associated with the use of the gene transfer product:
    • Report to the NIH OBA and the FDA as soon as possible, but no later than 7 calendar days after the Investigator's initial receipt of the information.
    • Report to the Thomas Jefferson University IRB immediately (see DHSP policy GA 111)
    • Report to participating sites as soon as possible but no later than 7 calendar days
  2. For SAE's that are unexpected and associated with the use of the transfer product but are not fatal or life threatening:
    • Report to the NIH OBA and the FDA within 15 days of this determination
    • Report to the Thomas Jefferson University IRB as per DHSP policy GA 111.
    • Report to participating sites as soon as possible but no later than 15 calendar days
  3. If after further evaluation, an adverse event initially considered not to be associated with the use of the gene transfer product is subsequently determined to be associated:
    • Report to the NIH OBA and the FDA within 15 days of this determination
    • Report to the IRB immediately
    • Report to participating sites as soon as possible but no later than 15 calendar days
  4. Any follow up information to an initial safety report must be submitted to the FDA as soon as relevant information becomes available
  5. Any relevant additional clinical and laboratory data that becomes available following the initial SAE report must be reported to the OBA NIH and the FDA within 15 calendar days of the sponsor's receipt of the information.
  6. If an SAE occurs after the end of a clinical trial and is determined to be associated with the gene transfer product, that event shall be reported to the NIH OBA and the FDA within 15 calendar days of the determination.
  7. 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, to the NIH OBA and the FDA but no later than 15 calendar days after the sponsor's initial receipt of the information.

4. ATTACHMENTS

A.          OBA Review Process

B.           OBA Template for Reporting Adverse Events in Human Gene Transfer Trials

 

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