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Human Gene Therapy Application Procedures

Human Gene Therapy Application Procedures. Robert J. Hashimoto The University of Louisville April 5, 2001. INTRODUCTION.

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Human Gene Therapy Application Procedures

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  1. Human Gene Therapy Application Procedures Robert J. Hashimoto The University of Louisville April 5, 2001

  2. INTRODUCTION Human Gene Therapy protocols must be adequately reviewed at the institutional level after subsequent review by the National Institutes of Health(NIH). After NIH review, all protocols must be jointly reviewed by the Institutional Review Board and the Institutional Biosafety Committee.

  3. BEFORE IBC REVIEW OF GENE THERAPY RESEARCH APPLICATIONS MUST BE FORWARDED TO THE NIH

  4. WHAT IS THE RAC?ROLE OF THE RAC • The RAC is the acronym for Recombinant DNA Activities Committee. • The purpose of the RAC is to: • examine clinical trials that involve the transfer of recombinant DNA to humans. (Currently, all human gene transfer trials in which NIH funding is involved (either directly or indirectly) are registered with the RAC and OBA.)

  5. WHAT IS THE RAC? ROLE OF THE RAC Factors that may contribute to public discussion of a protocol by the RAC include: (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.

  6. NIH REQUIREMENTSSection III-C(amended as of 10/10/00) • Section III-C. Experiments that Require Institutional Biosafety Committee and Institutional Review Board Approvals and RAC Review Before Research Participation • Section III-C-1. Experiments Involving the Deliberate Transfer of Recombinant DNA or DNA or RNA Derived from Recombinant DNA into One or More Human Subject Participants

  7. SECTION III-C-1, CONTINUED • Submission of human gene transfer protocols by the PI/Protocol Director shall be directly to NIH/OBA prior to institutional review and approval. • The IRB may review the gene transfer protocol simultaneously with RAC Review; however, participants may not be enrolled.

  8. INITIAL SUBMISSION TO THE NIH Submission of a gene therapy experiment to the NIH requires the following: A cover letter on institutional letterhead signed by the Protocol Director that: acknowledges that the documentation submitted to NIH/OBA complies with the requirements described in Appendix M-I-A. This cover letter also must:

  9. INITIAL SUBMISSION TO THE NIH • Identify the IBC and IRB at the proposed clinical trial site responsible for local review and approval of the protocol • acknowledges that no research participant will be enrolled until the RAC process is complete, IBC and IRB approval have been obtained and that all regulatory authorizations have been obtained. • Other documents to be submitted include:

  10. INITIAL SUBMISSION TO THE NIH • Scientific abstract -1 page • Non-technical abstract -1 page • the proposed clinical protocol • Responses to Appendix M-II through M-V, Description of the Proposal, Informed Consent, Privacy and Confidentiality, and Special Issues(which may be incorporated into the clinical protocol or provided as an appendix to the clinical protocol)

  11. INITIAL SUBMISSION TO THE NIH • The Proposed Informed Consent document with any appendices • curricula vitae -2 pages for each key professional person in biographical sketch format

  12. FULL RAC REVIEW? • Full RAC review of an individual human gene transfer experiment can be initiated by the NIH Director or recommended to the NIH Director by: (i) three or more RAC members, or (ii) other Federal agencies. • An individual human gene transfer experiment that is recommended for full RAC review should represent novel characteristics deserving of public discussion.

  13. NIH REQUIREMENTSAPPENDIX M • Appendix M is titled, Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA Molecules into One or More Research Participants, and is an outline that must be completed prior to review by the NIH RAC.

  14. APPENDIX M, new requirements • Once the PI/Protocol Director has received RAC written comments, then the IBC can proceed with its review and approval.

  15. IRB CONSIDERATIONS FACTORS FOR IRB REVIEW OF GENE THERAPY PROTOCOLS

  16. Documents Submitted for IRB Gene Therapy Review • IBC Application Form • IBC Approval Letter and Comments for IRB • Human Subjects IRB Application Form • Human Subjects IRB Consent Form • Clinical Protocol • Investigational Brochure • Appendix M of the NIH Guidelines

  17. OTHER IRB DOCUMENTSINVESTIGATIONAL BROCHURE The Investigational Brochure: • Is a document produced by the sponsor that summarizes previous findings and data • May include information about previous animal experiments and clinical trials • Describes previous adverse events (if applicable)

  18. OTHER DOCUMENTSCLINICAL PROTOCOL The Clinical Protocol: • Is the description of the therapy and will include all participants in a multi-center clinical trial • Describes the scope of the work • Details the procedures to be performed during the therapy

  19. IRB CONSIDERATIONS The IRB will deliberate on: • the risks to subjects • the anticipated benefits to subjects • the importance of the knowledge that may reasonably be expected to result • the informed consent process to be employed

  20. IRB CONSIDERATIONSAlternative Therapy The IRB will: • investigate current alternative therapies. • determine in what groups of patients are these alternative therapies effective. • enumerate the relative advantages and disadvantages of alternate therapy as compared with the proposed gene therapy.

  21. IRB CONSIDERATIONSExtent of Therapy • The IRB will review the protocol to determine the following extent of therapy. Is it designed to: • prevent all manifestations of the disease or to halt the progression of the disease after symptoms have begun to appear? • reverse manifestations of the disease in seriously ill victims?

  22. Summary Slide • IRB CONSIDERATIONSSelection and Exclusion of Subjects

  23. IRB CONSIDERATIONSSelection and Exclusion of Subjects • The IRB shall determine what selection criteria will be employed by the protocol director/PI. It will verify the human subject exclusion and inclusion criteria for the gene therapy study.

  24. IRB CONSIDERATIONSInformed Consent • The Experimental Subject’s Bill of Rights must be included in the consent form when performing a medical treatment. The Consent Form must be clearly written in lay language, provide full disclosure and risk information and be submitted with the protocol for review by institutional committees.

  25. IRB CONSIDERATIONSInformed Consent, Previous Adverse Events • There should be clear itemization in the Informed Consent document of types of adverse experiences related to the gene therapy intervention, their relative severity, and their expected frequencies. • Animal data should also be reviewed at this time.

  26. INFORMED CONSENTRequired Elements, Description of Research The Consent Form must state that: • the procedure involves research and identification of any procedures which are experimental; • an explanation of the purposes of the gene therapy research • the expected duration of the subject's participation • a description of the procedures to be followed,

  27. INFORMED CONSENTMore Required Elements Other elements of Informed Consent include but are not limited to the information in the following slides...:

  28. INFORMED CONSENTRequired Elements, Risks and Discomforts • A description of any reasonably foreseeable risks or discomforts to the subject; • It is necessary to warn potential subjects that, for genetic materials previously used in relatively few or no humans, unforeseen risks are possible, including ones that could be severe.

  29. INFORMED CONSENTRequired Elements, Disclosure of Alternate Therapy • A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject in lieu of the gene therapy procedure.

  30. INFORMED CONSENTRequired Elements, Compensation and Treatment • For research involving more than minimal risk, an explanation as to whether any compensation, and an explanation as to whether any medical treatments are available, if injury occurs and, if so, what they consist of, or where further information may be obtained.

  31. INFORMED CONSENTRequired Elements-Voluntary Participation • A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits, to which the subject is otherwise entitled.

  32. INFORMED CONSENTOther Elements, Unforeseeable Risks • A statement that the particular gene treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant), which are currently unforeseeable(this is especially important with vaccinia vector based gene therapy).

  33. INFORMED CONSENTOther Elements of a Consent Form-Withdrawal • The Informed Consent document should indicate any possible adverse medical consequences that may occur if the subjects withdraw from the study once the study has started. • These procedures for orderly termination of subject participation must be available prior to the initiation of the gene therapy clinical trial.

  34. INFORMED CONSENTOther Elements, Number of Subjects • The approximate number of subjects involved in the study. • The Informed Consent document should also provide information regarding the approximate number of people who have previously received the genetic material under study

  35. IRB CONSIDERATIONSInformed Consent-Minors If an experimental gene therapy procedure will be administered to a minor who is seven years of age or older, consent must be obtained from the minor as well as the parent or guardian.

  36. IRB CONSIDERATIONSBenefits • The subjects should be provided with an accurate description of the possible benefits, if any, of participating in the proposed study. For studies that are not reasonably expected to provide a therapeutic benefit to subjects, the Informed Consent document should clearly state that no direct clinical benefit to subjects is expected to occur as a result of participation in the study, although knowledge may be gained that may benefit others.

  37. IRB CONSIDERATIONSReproductive Hazards • To avoid the possibility that any of the reagents employed in the gene transfer research could cause harm to a fetus/child, subjects should be given information concerning possible risks and the need for contraception by males and females during the active phase of the study

  38. IRB CONSIDERATIONSLong Term Follow Up • To permit evaluation of long-term safety and efficacy of gene transfer, the prospective subjects should be informed that they are expected to cooperate in long-term follow-up that extends beyond the active phase of the study.

  39. IRB CONSIDERATIONSReport Adverse Events • Investigators who have received approval from the FDA to initiate a human gene transfer protocol (whether or not it has been reviewed by the RAC) must report any serious adverse event immediately to the local IRB, IBC, NIH Office for Human Research Protections, NIH/OBA, and FDA, followed by the submission of a written report filed with each group.

  40. IRB CONSIDERATIONSConflict of Interest Questions to Ask • Conflict of Interest Questions to Ask: • Does the investigator(s) or co-investigator(s) have a separate consulting agreement with the sponsoring company? • Does the investigator(s) or co-investigator(s) have stock and/or stock options with a sponsoring company?

  41. IRB CONSIDERATIONSConflict of Interest Questions to Ask • Is the investigator(s) or co-investigator(s) a member of an advisory board with a sponsoring company? • Is the study driven by commercial interests as opposed to academic or patient care concerns?

  42. IRB CONSIDERATIONSLength of Gene Therapy Study • Probable Duration: The Protocol Director/PI should include an estimate of the probable duration of the entire gene therapy study, as well as an estimate of the total time each subject is to be involved.

  43. IRB CONSIDERATIONS Tissue Sampling or Banking for Research. • The IRB must ask if the Protocol Director/PI is taking samples of tissues, cells, blood or body fluids and if yes, will they be stored for research? • If yes, then the consent form must be modified with appropriate language in the consent form

  44. IRB CONSIDERATIONSObligations of PI • Any change in the research protocol that alters the procedures or risks must be submitted to the IRB for review prior to the implementation of such change. • Any observed complications in subjects or evidence of increase in the original estimate of risk should be reported at once to the IRB before continuing with the project.

  45. IRB CONSIDERATIONSObligations of PI-annual IRB review • The investigators must inform the participants of any significant new knowledge obtained during the course of the gene therapy research. • All continuing projects and activities must be reviewed and re-approved at least annually by the IRB.

  46. IBC CONSIDERATIONS FACTORS FOR IBC REVIEW

  47. Documents Submitted for IBC Gene Therapy Review • RAC Comments, if any • IBC Application Form • Human Subjects IRB Application Form • Human Subjects Consent Form • Clinical Protocol • Investigational Brochure • Appendix M of the NIH Guidelines • The PI may have to obtain additional proprietary information as needed.

  48. THE IBC APPLICATION REVIEW PROCESS • The IBC shall review its application form to assess the containment of the vector and potential for environmental release. • As in laboratory research, clinical use of viral vectors must factor in adequate containment of the vector as well as appropriate work precautions for the clinical staff.

  49. THE IBC APPLICATION FORM-GENE THERAPY ISSUES The IBC application form should include the following information when completed: • the vector usage • the scope of the work, including the rationale for using gene therapy • the dose • the vector • the target area for therapy • the potential for environmental shedding

  50. FACTORS TO EVALUATE FOR GENE THERAPY • Source of Vectors used (e.g., sponsor’s name) • Proprietary Name of Recombinant DNA Molecule (if applicable, e.g., VacEaze) • Biohazardous Agent(s) Used (e.g., Adenovirus) • Biosafety Level of Biohazardous Agent(s) (per CDC)

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