Human Gene Therapy Application Procedures

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Human Gene Therapy Application Procedures

• Robert J. Hashimoto
• The University of Louisville
• April 5, 2001

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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.

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BEFORE IBC REVIEW OF GENE THERAPY RESEARCH

• APPLICATIONS MUST BE FORWARDED TO THE NIH

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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.)

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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.

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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

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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.

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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

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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

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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)

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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

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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.

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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.

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APPENDIX M, new requirements

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

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IRB CONSIDERATIONS

• FACTORS FOR IRB REVIEW OF GENE THERAPY PROTOCOLS

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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

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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)

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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

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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

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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.

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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?

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Summary Slide

• IRB CONSIDERATIONSSelection and Exclusion of
  Subjects

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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.

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IRB CONSIDERATIONSInformed Consent

• The 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.

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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.

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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,

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INFORMED CONSENTMore Required Elements

• Other elements of Informed Consent include but
  are not limited to the information in the
  following slides...

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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.

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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.

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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.

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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.

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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).

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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.

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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

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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.

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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.

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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

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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.

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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.

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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?

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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?

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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.

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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

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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.

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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.

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IBC CONSIDERATIONS

• FACTORS FOR IBC REVIEW

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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.

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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.

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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

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FACTORS TO EVALUATE FOR GENE THERAPY

• Source 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)

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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

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IBC CONSIDERATIONSCONTAINMENT 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

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IBC CONSIDERATIONSRISK/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

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IBC CONSIDERATIONSADVERSE 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

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IBC CONSIDERATIONSCONSTRUCT

• 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

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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.

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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.

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IBC CONSIDERATIONSPREVIOUS 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.

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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.

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IBC CONSIDERATIONSNON-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).

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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.

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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.

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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.

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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.

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IBC CONSIDERATIONSPatient 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.

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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.

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AFTER IBC APPROVALDELIBERATIONS 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).

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AFTER INSTITUTIONAL IRB AND IBC APPROVAL

• WHAT NEXT?

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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.

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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.

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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

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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

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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.

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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.

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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.