Human Gene Therapy Application ProceduresRobert J. HashimotoThe University of Louisville April 5, 2001

INTRODUCTIONHuman 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.

BEFORE IBC REVIEW OF GENE THERAPY RESEARCHAPPLICATIONS MUST BE FORWARDED TO THE NIH

WHAT IS THE RAC?ROLE OF THE RACThe 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.)

WHAT IS THE RAC? ROLE OF THE RACFactors 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.

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 ParticipationSection 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

SECTION III-C-1, CONTINUEDSubmission 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.

INITIAL SUBMISSION TO THE NIHSubmission 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:

INITIAL SUBMISSION TO THE NIHIdentify the IBC and IRB at the proposed clinical trial site responsible for local review and approval of the protocolacknowledges 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:

INITIAL SUBMISSION TO THE NIHScientific abstract -1 pageNon-technical abstract -1 pagethe proposed clinical protocolResponses 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)

INITIAL SUBMISSION TO THE NIHThe Proposed Informed Consent document with any appendicescurricula vitae -2 pages for each key professional person in biographical sketch format

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.

NIH REQUIREMENTSAPPENDIX MAppendix 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.

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

IRB CONSIDERATIONS FACTORS FOR IRB REVIEW OF GENE THERAPY PROTOCOLS

Documents Submitted for IRB Gene Therapy ReviewIBC Application FormIBC Approval Letter and Comments for IRBHuman Subjects IRB Application FormHuman Subjects IRB Consent FormClinical ProtocolInvestigational BrochureAppendix M of the NIH Guidelines

OTHER IRB DOCUMENTSINVESTIGATIONAL BROCHUREThe Investigational Brochure:Is a document produced by the sponsor that summarizes previous findings and dataMay include information about previous animal experiments and clinical trialsDescribes previous adverse events (if applicable)

OTHER DOCUMENTSCLINICAL PROTOCOLThe Clinical Protocol:Is the description of the therapy and will include all participants in a multi-center clinical trialDescribes the scope of the work Details the procedures to be performed during the therapy

IRB CONSIDERATIONS The IRB will deliberate on:the risks to subjectsthe anticipated benefits to subjectsthe importance of the knowledge that may reasonably be expected to resultthe informed consent process to be employed

IRB CONSIDERATIONSAlternative TherapyThe 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.

IRB CONSIDERATIONSExtent of TherapyThe 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?

Summary SlideIRB CONSIDERATIONS Selection and Exclusion of Subjects

IRB CONSIDERATIONSSelection and Exclusion of SubjectsThe 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.

IRB CONSIDERATIONSInformed ConsentThe Experimental Subjects 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.

IRB CONSIDERATIONSInformed Consent, Previous Adverse EventsThere 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.

INFORMED CONSENTRequired Elements, Description of ResearchThe 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 researchthe expected duration of the subject's participationa description of the procedures to be followed,

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

INFORMED CONSENTRequired Elements, Risks and DiscomfortsA 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.

INFORMED CONSENTRequired Elements, Disclosure of Alternate TherapyA 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.

INFORMED CONSENTRequired Elements, Compensation and TreatmentFor 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.

INFORMED CONSENTRequired Elements-Voluntary ParticipationA 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.

INFORMED CONSENTOther Elements, Unforeseeable RisksA 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).

INFORMED CONSENTOther Elements of a Consent Form-WithdrawalThe 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.

INFORMED CONSENTOther Elements, Number of SubjectsThe 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

IRB CONSIDERATIONSInformed Consent-MinorsIf 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.

IRB CONSIDERATIONSBenefitsThe 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.

IRB CONSIDERATIONSReproductive HazardsTo 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

IRB CONSIDERATIONSLong Term Follow UpTo 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.

IRB CONSIDERATIONSReport Adverse EventsInvestigators 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.

IRB CONSIDERATIONSConflict of Interest Questions to AskConflict 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?

IRB CONSIDERATIONSConflict of Interest Questions to AskIs 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?

IRB CONSIDERATIONSLength of Gene Therapy StudyProbable 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.

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

IRB CONSIDERATIONSObligations of PIAny 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.

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.

IBC CONSIDERATIONSFACTORS FOR IBC REVIEW

Documents Submitted for IBC Gene Therapy ReviewRAC Comments, if any IBC Application FormHuman Subjects IRB Application FormHuman Subjects Consent FormClinical ProtocolInvestigational BrochureAppendix M of the NIH GuidelinesThe PI may have to obtain additional proprietary information as needed.

THE IBC APPLICATION REVIEW PROCESSThe 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.

THE IBC APPLICATION FORM-GENE THERAPY ISSUESThe IBC application form should includethe following information when completed: the vector usagethe scope of the work, including the rationale for using gene therapythe dosethe vectorthe target area for therapythe potential for environmental shedding

FACTORS TO EVALUATE FOR GENE THERAPYSource of Vectors used (e.g., sponsors 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)

SERVICE SUPPORT-hospital The IBC and Biosafety Officer may at one time or another need to work with the following hospital organizations.Environmental ServicesPharmacyInfection ControlSecurityFacilities Management

IBC CONSIDERATIONSCONTAINMENT ISSUESThe IBC should evaluate the following issues, similar to laboratory safety:medical waste disposalpersonal protective equipmentdisinfection/sterilizationhand washing and other good work practicestraining of health care workers

IBC CONSIDERATIONSRISK/BENEFIT TO PATIENTIn addition, the IBC shall evaluate:the potential of risk of the vector to patients (subjects), family members or the environmentthe efficacy or potential benefits of the therapy versus the biohazard or other toxicity risk with regard to alternative therapy

IBC CONSIDERATIONSADVERSE EVENTS, SHEDDINGThe IBC shall evaluate:adverse events in previous clinical trials and animal studies to predict the potential of similar events in future trialsthe appropriate level of monitoring for potential microbial shedding

IBC CONSIDERATIONSCONSTRUCTThe 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

IBC CONSIDERATIONSTHE 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.

IBC CONSIDERATIONSTARGET 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.

IBC CONSIDERATIONSPREVIOUS CELL CULTURE/ANIMAL STUDIESThe 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 systemdescribe the ways that these models are similar to and different from the proposed human treatment.

IBC CONSIDERATIONS GENE EXPRESSIONThe 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.

IBC CONSIDERATIONSNON-RETROVIRAL DELIVERY SYSTEMSThe 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).

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.

IBC CONSIDERATIONS TOXICITY AND THE ENVIRONMENTThe 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.

IBC CONSIDERATIONS THE ENVIRONMENTThe 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.

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.

IBC CONSIDERATIONSPatient Conditions That Amplify Risks of SheddingThe 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.

AFTER IBC REVIEW/APPROVALIf 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.

AFTER IBC APPROVALDELIBERATIONS FORWARDED TO THE IRBThe 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).

AFTER INSTITUTIONAL IRB AND IBC APPROVALWHAT NEXT?

NIH SUBMISSIONSOnce 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.

NIH/OBA REVIEWRegardless 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.

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 IRBa copy of the protocol approved by the IBC and IRB

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

TRAINING REQUIREMENTSThe 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.

ADVERSE EVENT REPORTINGNote 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.

CONCLUSIONThis 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.

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