DARTMOUTH COLLEGE BIOLOGICAL SAFETY PROGRAM Institutional Biosafety Committee Subcommittee for Clinical Gene Transfer

Transcription

1 INSTITUTIONAL BIOSAFETY COMMITTEE SUBCOMMITTEE FOR CLINICAL GENE TRANSFER (IBC-SCGT) CHARTER Approval Date: Version: 1 DARTMOUTH COLLEGE BIOLOGICAL SAFETY PROGRAM Institutional Biosafety Committee Subcommittee for Clinical Gene Transfer I. PURPOSE The Dartmouth College Institutional Biosafety Committee Subcommittee for Clinical Gene Transfer (IBC-SCGT) is a formal subcommittee of the Institutional Biosafety Committee (IBC) consisting of subject matter experts and overlapping members with the IBC and the Committee for the Protection of Human Subjects (CPHS, the Institutional Review Board (IRB)). The purpose of the IBC-SCGT is to review human gene transfer (HGT) studies as defined by Section III-C of the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines, 2013) conducted at Dartmouth College, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, and the Department of Veterans Affairs Research Service, on the Hanover and Lebanon, NH and White River Junction, VT campuses. Collectively, these locations will be referred to as Dartmouth College herein. II. III. IV. REGULATORY BACKGROUND Institutions that receive support from the National Institutes of Health (NIH) for recombinant or synthetic nucleic acid research are required to establish and register an IBC with the NIH Office of Biotechnology Activities (OBA) in compliance with the NIH Guidelines. The establishment of the Dartmouth IBC-SCGT complies with this federal regulation. The NIH requires all institutions receiving research funds to have all HGT research reviewed by an IBC (regardless of whether that research is directly supported by the NIH) and the Recombinant DNA Advisory Committee (RAC). If such research is conducted without approval, the NIH has the authority to withdrawal research support from that study or institution. DEFINITIONS Human gene transfer (HGT) is the deliberate transfer into human research participants of either: 1. Recombinant nucleic acid molecules, or DNA or RNA derived from recombinant nucleic acid molecules, or 2. Synthetic nucleic acid molecules, or DNA or RNA derived from synthetic nucleic acid molecules, that meet any one of the following criteria: a. Contain more than 100 nucleotides; or b. Possess biological properties that enable integration into the genome (e.g., cis elements involved in integration); or c. Have the potential to replicate in a cell; or d. Can be translated or transcribed. FUNCTION Experiments involving the use of recombinant or synthetic nucleic acids can pose potential risk to study subjects, clinical research personnel, and the environment. The function of the IBC-SCGT is to ensure that all aspects of HGT research are conducted in a safe manner according to established biosafety standards, principles, practices, and authorizations. This sub-committee

2 reports directly to the Dartmouth Institutional Biosafety Committee (IBC) and the Committee for Protection of Human Subjects (CPHS), the IRB at Dartmouth. To serve this function, the IBC-SCGT reviews: 1) the scientific principles and objectives of the clinical gene transfer protocol 2) the clinical protocol, investigator s brochure, and pharmacy manual for concerns of the safety of personnel, the community, and the environment 3) whether all appropriate requirements as stated in Appendix M of the NIH Guidelines have been fulfilled prior to initiation of the protocol 4) the Local Safety SOP 5) the consent forms for compliance with Appendix M of the NIH Guidelines The sub-committee has the authority to approve, require modifications in, or disapprove research activities that fall within its jurisdiction. Clinical gene transfer protocols and amendments to existing protocols are subject to review by the sub-committee prior to activation. V. REVIEW OF CHARTER This charter shall be reviewed and reassessed by the IBC-SCGT at least annually, and any proposed changes shall be submitted to the IBC-SCGT for approval. VI. BY-LAWS A. Membership Organization The Dartmouth College IBC-SCGT may contain no fewer than five members. Standing memberships on the IBC-SCGT include the IBC Chair, the Biological Safety Officer (BSO), and a representative from the Committee for the Protection of Human Subjects (CPHS). Based on the purview of this committee, regular IBC-SCGT membership will additionally include representatives from the following areas of expertise: Human research protocol review Clinical trials Basic and/or translational research Infectious disease Pharmacy, pharmacology Overlap members with the Dartmouth IBC The IBC-SCGT may use consulting experts or establish working groups of members or non-members to execute its responsibilities or acquire needed expertise for select tasks. Consultants or working group members may include, for example, persons knowledgeable in institutional commitments and policies, applicable law, standards of professional conduct and practice, community attitudes, the environment, or any scientific area where the IBC-SCGT members do not have expertise. Consultants or working group members are not IBC voting members unless nominated and appointed as described below. B. Procedure for Appointing Members The Dartmouth College Vice Provost for Research formally appoints all IBC members. Department Chairs are consulted prior to membership invitation of faculty. Regular and ad-hoc members will be selected by the IBC-SCGT Chair. C. Terms of Membership IBC membership is a minimum three- year period of service. Members may be appointed for subsequent three-year terms if they are willing to continue to serve. If a member does not attend three consecutive meetings, the IBC-SCGT Chair may motion that a replacement be nominated.

3 D. Conflict of Interest Policy No member of the IBC-SCGT may be involved (except to provide information requested by the IBC-SCGT) in the review or approval of a project in which he/she has been (or expects to be) engaged or in which he/she has a direct financial interest. IBC-SCGT members are also asked to withdraw from decisions where, owing to their personal relationships, there might be either real or perceived conflicts of interest. Each member is expected to notify the IBC-SCGT Chair in these circumstances and recuse him/herself when such proposals are being discussed and are up for a vote. In addition, if the IBC- SCGT Chair is the principal investigator on a project, the Biosafety Officer and the IBC Chair will sign the approval letter or any resulting correspondence. E. Quorum Meetings will proceed with no less than five members present and must contain at least the IBC-SCGT Chair, BSO, and a representative from CPHS. All IBC-SCGT members are voting members. Decisions such as approval of research projects or policies are approved when a majority of IBC-SCGT members present vote for approval. In the event that the IBC-SCGT Chair must be absent, he/she will request another committee member to serve as chair during the absence. F. Meetings The IBC-SCGT will convene on an ad-hoc basis for initial consideration of clinical gene transfer protocols and modifications to those protocols. A proposed agenda will be developed and distributed before the meeting by the Biosafety Officer (BSO) or his/her designee. Meeting minutes will be taken by the BSO or his/her designee to accurately reflect the topics of discussion. Meeting minutes will be reviewed, approved by the members, and maintained on file at Environmental Health & Safety (EHS) for at least five years. Principal Investigators are always welcome to present their work to the IBC-SCGT and are encouraged to attend. When possible and consistent with protection of privacy and proprietary interests, IBC-SCGT meetings will be made publically accessible upon request. G. Agenda, Minutes, Approval Letters, and Reports The Biosafety Officer (BSO), in collaboration with the IBC-SCGT Chair, shall be responsible for establishing the agendas for meetings. An agenda, together with relevant materials, shall be sent to committee members at least 5 days in advance of the meeting. Minutes for all meetings shall be drafted by the BSO and approved by committee members at the following meeting. Approval letters will be drafted by the BSO and co-signed by the Chair. Reports to the Vice Provost for Research and federal agencies will be drafted by the BSO in collaboration with the Chair. Dartmouth shall make available to the public all IBC-SCGT meeting minutes and any documents submitted to or received from funding agencies upon request in accordance with requirements of the NIH Guidelines. If public comments are made on IBC-SCGT actions, Dartmouth shall forward both the public comments and the IBC-SCGT s response to the Office of Biotechnology Activities, National Institutes of Health, 6705 Rockledge Drive, Suite 750, MSC 7985, Bethesda, MD (20817 for non-usps mail), , (fax). The IBC Public Attendance at IBC Meetings, Public Access to IBC Minutes, and IBC Minutes Redaction Policy shall be followed. H. Relationships to Other Committees IBC-SCGT supports transparency between the IBC, IBC-SCGT, the Committee for the

4 Protection of Human Subjects (CPHS, the Dartmouth Institutional Review Board (IRB)) and the Clinical Cancer Review Committee (CCRC). Overlap of membership between these committees will be prioritized in order maintain this collaborative oversight. VII. ROLES & RESPONSIBILITIES A. Institution (in accordance with NIH Guidelines Section IV-B-1) Dartmouth College is ultimately responsible for the effectiveness of the IBC-SCGT and may establish procedures that the IBC-SCGT shall follow in its initial and continuing review and approval of applications, proposals, and activities. Institutional responsibilities will fall under the auspices of the Vice Provost for Research. Specifically, Dartmouth College responsibilities include: i. maintaining the IBC-SCGT so that the committee meets the requirements and carries out the functions detailed in the NIH Guidelines; ii. iii. appointing the required expertise to the IBC-SCGT, including a Biosafety Officer, an expert in human gene transfer studies, and experts in the handling of recombinant or synthetic nucleic acids ensuring appropriate training for the IBC-SGT Chair and members, Biosafety Officer and other containment experts (when applicable), Principal Investigators, and laboratory or clinical staff regarding laboratory safety and implementation of the NIH Guidelines. B. Institutional Biosafety Committee (IBC) (in accordance with NIH Guidelines, Section IV-B-2) The IBC-SCGT is a subcommittee of the Dartmouth College Institutional Biosafety Committee (IBC) and reports directly to the IBC. The Dartmouth IBC reports to the Vice Provost of Research. IBC responsibilities under the NIH Guidelines are outlined in the IBC Charter. The Subcommittee s responsibilities include: i. review of all human gene transfer experiments for compliance with the NIH Guidelines as specified in Section III-C: Experiments Covered by the NIH Guidelines, and approving those research projects that are found to conform with the NIH Guidelines; ii. iii. iv. ensuring compliance with all approvals, surveillance, data reporting, and adverse event reporting requirements set forth by NIH Guidelines Sections I-E-7 through I- E-10 and Appendix M; assessment of the facilities, procedures, practices, and training and expertise of personnel involved in HGT research to determine appropriate biocontainment levels required by the NIH Guidelines for the proposed research; notifying the Principal Investigator of the results of the IBC-SCGT s review and approval; v. investigating and immediately reporting any significant problems with or violations of the NIH Guidelines and any significant research-related accidents or illnesses or serious adverse events to the appropriate institutional official and to NIH/OBA within 30 days (or immediately if warranted). Reports to NIH/OBA shall be sent to the Office of Biotechnology Activities, National Institutes of Health, 6705

5 Rockledge Drive, Suite 750, MSC 7985, Bethesda, MD (20817 for non-usps mail), , (fax). C. Biosafety Officer (BSO) (in accordance with NIH Guidelines Section IV-B-3) The Biosafety Officer s duties are outlined in the Dartmouth College Institutional Biosafety Committee (IBC) Charter. Duties and responsibilities on the IBC-SCGT additionally include: i. submit an annual report to NIH/OBA that includes a roster of IBC-SCGT members, indicating the Chair, contact person, Biosafety Officer, human gene therapy expert or ad hoc consultant (if applicable), other member roles, and biographical sketches of each member; ii. iii. iv. report to the IBC and IBC-SCGT any significant problems, violations of the NIH Guidelines, and any significant research-related accidents or illnesses or severe adverse events of which the BSO becomes aware; develop training materials for the IBC-SCGT on the NIH Guidelines provide administrative support for IBC-SCGT activities, including preparation of meeting agendas, minutes, and materials; v. provide technical advice to Principal Investigators and the IBC-SCGT on research safety procedures. D. Principal Investigator (in accordance with NIH Guidelines Section IV-B-7) On behalf of Dartmouth College, the Principal Investigator is responsible for full compliance with the NIH Guidelines in the conduct of recombinant or synthetic nucleic acid molecule research. Definition: The Principal Investigator (PI) designation is given to a Dartmouth faculty member who has primary responsibility and accountability to direct the proper conduct of a scientific research project or program. If the research is conducted by a team of researchers at a research site, the Principal Investigator is the leader responsible for that team whose name appears as Principal Investigator on the Grant Application or Award. With regard to the IBC-SCGT, the PI has overall responsibility of laboratory and/or clincal personnel working under the requirements of the NIH Guidelines. Responsibilities: To comply with the NIH Guidelines and adhere to the institutional requirements of the Dartmouth IBC, the PI shall: i. not initiate or modify any human gene transfer research prior to review and approval by the Dartmouth IBC-SCGT; ii. iii. iv. submit the initial research protocol and any subsequent changes to the IBC-SCGT for review and approval or disapproval and make an initial determination of the required levels of physical and biological containment in accordance with the NIH Guidelines; remain in communication with the IBC-SCGT throughout the conduct of the project; immediately report any significant problems, violations of the NIH Guidelines, or any significant research-related accidents and illnesses to the Biosafety Officer,

6 IBC-SCGT, NIH/OBA, and other applicable authorities; v. adhere to Dartmouth IBC approved emergency plans for handling accidental spills and personnel contamination; vi. vii. viii. ix. comply with national and international shipping requirements for infectious agents and recombinant or synthetic nucleic acid molecules; instruct and train laboratory/clinical staff in: (a) the practices and techniques required to ensure safety, (b) the procedures for dealing with accidents, and (c) the reasons and provisions for any precautionary medical practices advised or requested (e.g., vaccinations or serum collection); supervise and correct the safety performance of the laboratory/clinical staff to ensure that the required safety practices and techniques are employed; ensure the integrity of the physical containment (e.g., biological safety cabinets) and the biological containment (e.g., purity and genotypic and phenotypic characteristics). VIII. IBC-SCGT SUBMISSION AND APPROVAL PROCESS The research review process by the IBC is conducted in a step-wise fashion, starting with the submission of research information by the principal investigator (PI). A. IBC-SCGT Submission The following materials must be included in the protocol submission and must be ed to the Biosafety Officer: a. Correspondence Materials: i. Letter of approval from the National Institutes of Health Recombinant DNA Advisory Committee (RAC) ii. Documentation of Investigational New Drug status (IND) of the test agent, referencing the holder of the IND and the protocol for review iii. Letter of scientific review/merit if available (e.g., Department Approval Letter, CCRC Approval Letter) iv. Letter of IRB approval or date of expected IRB review v. Letter of assurance from the investigational/site pharmacy of ability to receive, house, and dispense study agent b. Protocols/Procedures/Manuals i. Completed Local Safety Standard Operating Procedure (SOP) template. ii. Clinical Protocol iii. Signed Investigator Protocol Signature Page iv. Investigator s Brochure (IB) v. Pharmacy and/or Laboratory Manual for study agent c. Consent Forms (please see the NIH Informed Consent Guidance for Human Gene Transfer Trials on how to include lay language about recombinant nucleic acid technology in Informed Consent forms). d. Documentation of completion of appropriate training requirements (e.g. BSL2, blood borne pathogen training) for all study personnel and pharmacy personnel who will come into contact with study agent.

7 B. IBC Approval Process All submitted documents will be distributed to committee members for their review prior to the committee meeting. Two reviewers to be appointed by the chair will review submitted information and present their findings orally to the committee. The principal investigator or his/her representative will be invited to the meeting for the purpose of briefly presenting his/her protocol and to answer questions. C. Voting Procedures All non-members, including ad-hoc members, will leave the room prior to final discussion and voting. Any committee members who are principal or co-investigators on the study protocol under discussion will leave the room prior to final discussion and voting. Any committee members with an actual or perceived conflict of interest will leave the room prior to voting. Those leaving the room will be recorded in the meeting minutes. Voting results will be reported to the IBC. Letters of correspondence regarding sub-committee decisions will be presented to the investigator, IBC, and Committee for Protection of Human Subjects (CPHS) with signatures of approval from the sub-committee chair and the Biological Safety Officer. Previously approved protocols submitting an amendment will be referred to the IBC-SCGT for review by the CCRC and CPHS dependent upon the amendment s impact on the safety and health of personnel, community, and environment. D. Vote Categories At the time of voting, sub-committee members may vote in one of the following categories: 1. Approved This vote means that the study has scientific merit, necessary regulatory requirements have been met and there are no outstanding biological safety issues. The study is approved as submitted. The investigator is not required to change any aspect of the protocol or provide any additional documentation. A letter of approval is sent to the investigator with copies to the IBC and the CPHS. 2. Conditionally Approved This vote means that the study has scientific merit; however, the subcommittee may require clarification or minor modifications of the protocol relevant to its design, conduct or biosafety issues. The committee may also require additional regulatory documentation. A letter describing the subcommittee's conditions for approval will be sent to the investigator with a copy to the CPHS. The investigator's response will be reviewed by the subcommittee chair or a designated committee member(s). This review will not be performed by a committee member who is an investigator on the study or who has actual or perceived conflict of interest. The reviewer may determine that all conditions of the committee have been adequately addressed, in which case a letter of approval will be sent as described above; that the conditions have not been adequately addressed, in which case a letter will be sent to the investigator describing the remaining conditions; or that the response should be reviewed by the full subcommittee, in which case the committee will be convened to review the response. 3. Not Approved This vote means that the concerns of the sub-committee are substantive and that the magnitude and/or number of concerns are such that conditional approval is not appropriate. A letter describing the concerns is sent to the investigator with copies to the IBC and CPHS. Full IBC-SCGT review is required if the protocol is resubmitted. 4. Voting Rules

8 In order for a study to receive "approval", "conditional approval" or "not approved" status it must obtain such a vote from the majority of the sub-committee quorum. 5. Appeal Procedures Principal investigators may appeal sub-committee decisions in writing to the Chair of the IBC-SCGGT. If the decision regarding the appeal is unsatisfactory to the investigator, a second appeal may be made to the Chair of the IBC. IX. Serious Adverse Events (SAE) A. Definitions The NIH Guidelines define serious adverse events as: any event occurring at any dose that results in any of the following outcomes: death, a life-threatening event, in-patient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization also may be considered a serious adverse event when, upon the basis of appropriate medical judgment, they may jeopardize the human gene transfer research subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition (Section I-E-8). The NIH Guidelines defines an adverse event as being associated with the use of a gene transfer product when there is a reasonable possibility that the event may have been caused by the use of that product (Section I-E-9). The NIH Guidelines defines an unexpected serious adverse event as: any serious adverse event for which the specificity or severity is not consistent with the risk information available in the current investigator s brochure (Section I-E-10). B. Safety Reporting Requirements 1. Safety Reporting (NIH Guidelines Appendix M-I-C-4) Principal Investigators must submit a written report on: (1) any serious adverse event 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); and (2) any finding from tests in laboratory animals that suggests a significant risk for human research participants including reports of mutagenicity, teratogenicity, or carcinogenicity. The report must be clearly labeled as a Safety Report and must be submitted to the NIH Office of Biotechnology Activities (NIH OBA) and to the local Institutional Biosafety Committee (IBC-SCGT) within the timeframes set forth in this Section. Principal Investigators should adhere to any other serious adverse event reporting requirements in accordance with federal regulations, state laws, and local institutional policies and procedures, as applicable. 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, telephone and fax numbers of the contact(s). The Principal Investigator is responsible for ensuring that the reporting requirements are fulfilled and will be held accountable for any reporting lapses.

9 The three alternative mechanisms for reporting serious adverse events to the NIH OBA are: by to by fax to ; or by mail to the Office of Biotechnology Activities, National Institutes of Health, MSC 7985, 6705 Rockledge Drive, Suite 750, Bethesda, Maryland Safety Reporting: Content and Format (NIH Guidelines Appendix M-I-C-4a) The serious adverse event report must include, but need not be limited to: 1. the date of the event 2. 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 3. clinical site 4. the Principal Investigator 5. NIH Protocol number 6. FDA s Investigational New Drug (IND) Application number 7. vector type, e.g., adenovirus 8. vector subtype, e.g., type 5, relevant deletions 9. gene delivery method, e.g., in vivo, ex vivo transduction 10. route of administration, e.g., intratumoral, intravenous 11. dosing schedule 12. a complete description of the event 13. relevant clinical observations 14. relevant clinical history 15. relevant tests that were or are planned to be conducted 16. date of any treatment of the event 17. the suspected cause of the event These items may be reported by using the recommended Adverse Event Reporting Template available on NIH OBA s web site at: the FDA MedWatch forms, or other means provided that all of the above elements are specifically included. Reports from laboratory animal studies as delineated in Appendix M-I-C-4 must be submitted in a narrative format. 3. Safety Reporting: Time Frames for Expedited Reports (NIH Guidelines Appendix M- I-C-4b) Any serious adverse event that is fatal or life-threatening, that is unexpected, and associated with the use of the gene transfer product must be reported to the IBC-SCGT and 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). Serious adverse events 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 IBC-SCGT and 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).

10 Changes in this schedule are permitted only where, under the FDA IND regulations [21 CFR 312(c)(3)], changes in this reporting schedule have been approved by the FDA and are reflected in the protocol. 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, then the event must be reported to the IBC-SCGT and NIH OBA within 15 days of the determination. Relevant additional clinical and laboratory data may become available following the initial serious adverse event report. Any follow-up information relevant to a serious adverse event must be reported within 15 calendar days of the sponsor s receipt of the information. If a serious adverse event occurs after the end of a clinical trial and is determined to be associated with the use of the gene transfer product, that event shall be reported to the IBC-SCGT and NIH OBA within 15 calendar days of the determination. 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). X. RESOURCES Guidelines for Research Involving Recombinant and Synthetic Nucleic Acid Molecules (NIH Guidelines), Federal Register (March 2013).