1. Human Gene Therapy Application Procedures Robert J. Hashimoto The University of Kentucky November 22, 2002

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 REQUIREMENTS Section III-C (amended as of April 2002) 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 REQUIREMENTS APPENDIX 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 Pre-Institutional Review 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 DOCUMENTS INVESTIGATIONAL 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 DOCUMENTS CLINICAL 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 Alternative 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.

20. IRB CONSIDERATIONS Extent 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?

21. IRB CONSIDERATIONS Selection and Exclusion of Research Participants and the Importance of Informed Consent

22. IRB CONSIDERATIONS Selection and Exclusion of Subjects The IRB shall determine what selection criteria that will be employed by the protocol director/PI. The IRB will verify the human subject exclusion and inclusion criteria for the gene therapy study.

23. IRB CONSIDERATIONS Informed 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.

24. IRB CONSIDERATIONS Informed 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.

25. INFORMED CONSENT Required 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,

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

27. INFORMED CONSENT Required 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.

28. INFORMED CONSENT Required 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.

29. INFORMED CONSENT Other 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).

30. INFORMED CONSENT Other 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.

31. IRB CONSIDERATIONS Informed 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.

32. IRB CONSIDERATIONS Informed Consent-Benefits 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.

33. IRB CONSIDERATIONS Report 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.

34. IRB CONSIDERATIONS Conflict 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?

35. IRB CONSIDERATIONS Conflict 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?

36. IRB CONSIDERATIONS Obligations of PI Any modification or 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.

37. IBC CONSIDERATIONS FACTORS FOR IBC REVIEW

38. 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.

39. 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.

40. 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

41. 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)

42. SERVICE SUPPORT -hospital The IBC and Biosafety Officer may at one time or another need to work with the following hospital organizations. Environmental Services Pharmacy Infection Control Security Facilities Management

43. IBC CONSIDERATIONS CONTAINMENT ISSUES The IBC should evaluate the following issues, similar to laboratory safety: medical waste disposal personal protective equipment disinfection/sterilization hand washing and other good work practices training of health care workers

44. IBC CONSIDERATIONS RISK/BENEFIT TO PATIENT In addition, the IBC shall evaluate: the potential of risk of the vector to patients (subjects), family members or the environment the efficacy or potential benefits of the therapy versus the biohazard or other toxicity risk with regard to alternative therapy

45. IBC CONSIDERATIONS ADVERSE EVENTS, SHEDDING The IBC shall evaluate: adverse events in previous clinical trials and animal studies to predict the potential of similar events in future trials the appropriate level of monitoring for potential microbial shedding

46. IBC CONSIDERATIONS CONSTRUCT The IBC will review Appendix M and evaluate the molecular structure of the vector. It is essential to determine what part of the wild type virus has been deleted and what genetic material has been added. For example, the E1 and E3 regions of adenovrius code for replication

47. IBC CONSIDERATIONS THE VECTOR The IBC application should include: a description of the gene (genomic or cDNA), the bacterial plasmid or phage vector, the delivery vector (if any) a complete nucleotide sequence analysis or a detailed restriction enzyme map of the total construct.

48. IBC CONSIDERATIONS TARGET AREA The Protocol Director must: indicate what cells/organs are the intended target cells of recombinant DNA. be able to characterize the cells before and after treatment, if the treatment is ex vivo and returned to the patient.

49. IBC CONSIDERATIONS PREVIOUS CELL CULTURE/ANIMAL STUDIES The Protocol Director must: indicate which animal and cultured cell models were used in laboratory studies to assess the in vivo efficacy of the gene transfer system describe the ways that these models are similar to and different from the proposed human treatment.

50. IBC CONSIDERATIONS GENE EXPRESSION The Protocol Director must indicate if the gene is expressed in cells other than the target cells. If yes, the extent of this expression must be described.

51. IBC CONSIDERATIONS NON-RETROVIRAL DELIVERY SYSTEMS The Protocol Director must: state what animal studies have been conducted to determine if there are pathological or other undesirable consequences of the protocol (including insertion of DNA into cells other than those treated, particularly germ-line cells).

52. IBC CONSIDERATIONS TOXICITY The Protocol Director must describe : the laboratory evidence that is available concerning potential harmful effects of the transfer (e.g., development of neoplasia, harmful mutations, regeneration of infectious particles, or immune responses) the steps will be taken in designing the vector to immunize pathogenicity. the laboratory studies have been performed to check for pathogenicity, and what is the sensitivity of the analyses.

53. IBC CONSIDERATIONS TOXICITY AND THE ENVIRONMENT The Protocol Director must: describe any potential benefits and hazards of the proposed therapy to persons other than the patients being treated. Indicate if there is a significant possibility that the added DNA will spread from the patient to other persons or to the environment.

54. IBC CONSIDERATIONS THE ENVIRONMENT The Protocol Director must state: the precautions that will be taken to prevent a spread of virus/vector(e.g., patients sharing a room, health-care workers, or family members). the measures that will be undertaken to mitigate the risks, if any, to public health.

55. IBC CONSIDERATIONS VECTOR DOSE The Protocol Director must: indicate the concentrations of virus that shall will be administered to the patients. provide the description of dose, the volume, actual dosage and number of doses that will be administered to the patients.

56. IBC CONSIDERATIONS Patient Conditions That Amplify Risks of Shedding The Protocol Director must indicate if there are any pre-existing patient medical conditions amongst the recruited subjects that may somehow amplify the risks of using this vector.

57. AFTER IBC REVIEW/APPROVAL If the IBC reviews first, ensure that the IRB: receives a copy of the IBC approval letter and any deliberations. receives a modified Human Subjects Consent Form after IBC changes are implemented. mentions in the consent form of risks associated with the vectors.

58. AFTER IBC APPROVAL DELIBERATIONS FORWARDED TO THE IRB The IRB deliberations should include: any physiological considerations noted by the IBC of vector based complications associated with the gene therapy intervention (this may affect the assessment of risk/benefit to the patient).

59. AFTER INSTITUTIONAL IRB AND IBC APPROVAL WHAT NEXT?

60. NIH SUBMISSIONS Once both committees have approved the protocol, then the Protocol Director must obtain both committee approval letters since those will need to be forwarded to the NIH.

61. NIH/OBA REVIEW Regardless if a gene therapy protocol is novel (needs full RAC review) or previously found to be exempt from RAC review, verification of IBC and IRB approval must be submitted to the NIH, Office of Biotechnology Affairs(OBA). OBA registers all human gene therapy experiments and maintains a database of registered/approved experiments.

62. OTHER REQUIRED DOCUMENTS (after IRB, IBC approval) Within 20 days from enrolling the first participant, the Protocol Director must submit the following documents to NIH/ OBA: a copy of the Consent Form approved by the IRB a copy of the protocol approved by the IBC and IRB

63. OTHER REQUIRED DOCUMENTS (after IRB, IBC approval) Verification letter from the IBC Clinical Trial Site A brief written report that elaborates on: a) on the RAC Recommendations; b) modifications of the protocol based on FDA requirements the FDA IND number the date of trial initiation

64. TRAINING REQUIREMENTS The NIH Recombinant DNA Guidelines require both the IRB and IBC to receive training on gene therapy and the principles of the gene therapy so that members can make informed decisions on applications brought forward for review.

65. ADVERSE EVENT REPORTING Note that all serious adverse events involving enrolled study patients, occurring here and at other institutions, must be reported to both the IRB and IBC regardless of whether or not the events are thought to be related to the gene transfer intervention.

66. CONCLUSION This presentation was designed to inform the audience on the requirements of the IBC review of a gene therapy experiment. It is not all inclusive as each institution may have State or Local requirements that may need to be followed in addition to the items described in this lecture.