Transcript Human Gene Therapy Clinical Trial Procedures

Human Gene Therapy
Application Procedures
Robert J. Hashimoto
The University of
Kentucky
November 22, 2002
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.
BEFORE IBC REVIEW OF
GENE THERAPY
RESEARCH
APPLICATIONS MUST BE
FORWARDED TO THE NIH
WHAT IS THE RAC?
ROLE OF THE RAC
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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.)
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.
NIH REQUIREMENTS
Section III-C(amended as of April 2002)
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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
SECTION III-C-1,
CONTINUED
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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.
INITIAL SUBMISSION TO THE
NIH
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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:
INITIAL SUBMISSION TO THE
NIH
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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:
INITIAL SUBMISSION TO THE
NIH
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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)
INITIAL SUBMISSION TO THE
NIH
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The Proposed Informed Consent document with
any appendices
curricula vitae -2 pages for each key
professional person in biographical sketch
format
FULL RAC REVIEW?
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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 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.
APPENDIX M
Pre-Institutional Review
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Once 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 Review
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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
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)
OTHER DOCUMENTS
CLINICAL PROTOCOL
The Clinical Protocol:
 Is the description of the therapy and will
include all participants in a multi-center
clinical trial
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Describes the scope of the work
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Details the procedures to be performed
during the therapy
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.
IRB CONSIDERATIONS
Extent of Therapy
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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?
IRB CONSIDERATIONS
Selection and Exclusion of
Research Participants and the
Importance of Informed Consent
IRB CONSIDERATIONS
Selection and Exclusion of Subjects
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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.
IRB CONSIDERATIONS
Informed Consent
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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.
IRB CONSIDERATIONS
Informed Consent, Previous Adverse Events
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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.
INFORMED CONSENT
Required Elements, Description of Research
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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,
INFORMED CONSENT
More Required Elements
Other elements of Informed Consent
include but are not limited to the
information in the following slides...:
INFORMED CONSENT
Required Elements, Risks and Discomforts
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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.
INFORMED CONSENT
Required Elements, Disclosure of Alternate Therapy
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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.
INFORMED CONSENT
Other Elements, Unforeseeable Risks
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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).
INFORMED CONSENT
Other Elements of a Consent Form-Withdrawal
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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.
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.
IRB CONSIDERATIONS
Informed Consent-Benefits
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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.
IRB CONSIDERATIONS
Report Adverse Events
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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.
IRB CONSIDERATIONS
Conflict of Interest Questions to Ask
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Conflict of Interest Questions to Ask:
Does the investigator(s) or coinvestigator(s) have a separate consulting
agreement with the sponsoring company?
Does the investigator(s) or coinvestigator(s) have stock and/or stock
options with a sponsoring company?
IRB CONSIDERATIONS
Conflict of Interest Questions to Ask
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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?
IRB CONSIDERATIONS
Obligations of PI
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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.
IBC CONSIDERATIONS
FACTORS FOR IBC REVIEW
Documents Submitted for IBC
Gene Therapy Review
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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.
THE IBC APPLICATION REVIEW
PROCESS
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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.
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
FACTORS TO EVALUATE FOR
GENE THERAPY
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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)
SERVICE SUPPORT-hospital
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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
IBC CONSIDERATIONS
CONTAINMENT ISSUES
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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
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
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
IBC CONSIDERATIONS
CONSTRUCT
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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
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.
IBC CONSIDERATIONS
TARGET AREA
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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 CONSIDERATIONS
PREVIOUS CELL CULTURE/ANIMAL STUDIES
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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.
IBC CONSIDERATIONS
GENE EXPRESSION
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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.
IBC CONSIDERATIONS
NON-RETROVIRAL DELIVERY SYSTEMS
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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).
IBC CONSIDERATIONS
TOXICITY
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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)
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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 ENVIRONMENT
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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.
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.
IBC CONSIDERATIONS
VECTOR DOSE
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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 CONSIDERATIONS
Patient Conditions That Amplify Risks of Shedding
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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.
AFTER IBC REVIEW/APPROVAL
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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.
AFTER IBC APPROVAL
DELIBERATIONS FORWARDED TO THE IRB
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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).
AFTER INSTITUTIONAL IRB
AND IBC APPROVAL
WHAT NEXT?
NIH SUBMISSIONS
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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.
NIH/OBA REVIEW
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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.
OTHER REQUIRED
DOCUMENTS (after IRB, IBC approval)
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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
OTHER REQUIRED
DOCUMENTS (after IRB, IBC approval)
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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
TRAINING REQUIREMENTS
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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.
ADVERSE EVENT REPORTING
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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.
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.