IBC Requirements for Human Gene Transfer (HGT) Studies
I.
INTRODUCTION
Per NIH Guidelines Section III-C, 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.
Human gene transfer studies require approval from the Institutional Biosafety Committee (IBC)
and the Institutional Review Board (IRB), registration with the NIH Office of Science Policy (NIH
OSP), and potentially other institutional approvals. Certain studies may also require review by
the NIH Recombinant DNA Advisory Committee (NIH RAC) prior to research participant
enrollment.
II. STUDY INITIATION
a. Enrollment: Per NIH Guidelines Section I-E-7 , “enrollment” is the process of obtaining
informed consent from a potential research participant, or a designated legal guardian of
the participant, to undergo a test or procedure associated with the gene transfer
experiment.
If UCLA is the initial or only site for the study, no research participant shall be enrolled in
the study until:
• An assessment has been performed by the Institutional Biosafety Committee (IBC)
and Institutional Review Board (IRB) to determine whether NIH RAC review is
needed, when applicable;
• NIH RAC review has been completed, when applicable;
• IBC approval (from the clinical trial site) has been obtained;
• IRB approval has been obtained;
• NIH protocol registration process has been completed; and
• All applicable regulatory authorization(s) have been obtained.
For multi-site studies, if UCLA is added as a clinical trial site after the NIH protocol
registration process, no research participant shall be enrolled at UCLA until approval
from the UCLA IBC and IRB are in place. Within 30 days of enrollment at UCLA, the
following documentation shall be submitted to NIH OSP: (1) IBC approval; (2) IRB
approval; (3) IRB-approved informed consent document(s); and (4) NIH grant number(s),
if applicable.
b. IBC Submission and Review Process:
The IBC and IRB submission process vary depending on whether the study is a multisite or single-site study. The process will also vary depending on whether it is
determined that review by the NIH RAC is needed.
i. RAC Review
Public RAC review and discussion of a human gene transfer experiment will be
initiated in two exceptional circumstances:
1. The NIH Director determines it is necessary, or
2. The IRB or IBC at any initial site(s) determine that a protocol would
significantly benefit from RAC review AND meets any of the following
criteria:
• The protocol uses a new vector, genetic material, or delivery
methodology that represents a first-in-human experience, thus
presenting an unknown risk; or
• The protocol relies on preclinical safety data that were obtained
using a new preclinical model system of unknown and unconfirmed
value; or
• The proposed vector, gene construct, or method of delivery is
associated with possible toxicities that are not widely known and that
may render it difficult for oversight bodies involved to evaluate the
protocol rigorously.
ii. Institutional Assessment for NIH RAC Submission:
Process A – UCLA is the initial/only study site: An assessment will need to be
performed by the UCLA IRB and IBC to determine if the study needs to be
submitted to the NIH RAC for review, based on the criteria described above. Below
is the process outline:
1.
2.
3.
4.
PI completes the RAC Review Assessment Form.
a. If the BUA is not ready for submission to the IBC, the PI may email the
completed form to [email protected] for the RAC assessment
process to commence. The PI may submit the BUA to the IBC
through SafetyNet at any time while the IBC RAC assessment is taking
place. Wait to submit to IRB.
b. If the BUA is ready for submission, the completed form should be
uploaded to the BUA in SafetyNet and the BUA should be submitted.
Wait to submit to IRB.
IBC staff provide the IRB staff with the completed RAC Review Assessment
Form and any supporting documentation.
IBC and IRB perform RAC assessment simultaneously.
IBC/IRB provide joint assessment determination letter to the PI via email
a. If IBC and/or IRB determines RAC review is needed:
i. IBC will not proceed with review of BUA. If BUA was previously
submitted, it will be returned to the PI temporarily until RAC review
is complete.
ii. PI submits to NIH RAC
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5.
6.
7.
8.
9.
iii. After NIH RAC review, PI submits BUA to IBC for re-review.
Simultaneously, PI submits to IRB for initial review. PI includes the
RAC determination letter from NIH with both applications.
b. If IBC and IRB determine RAC review is not needed, the following steps
may take place in parallel:
i. PI submits to IRB and JCCC Internal Scientific Peer Review
Committee (ISPRC) or School of Medicine Scientific Review
Committee (SOM SRC) at the same time
ii. IBC proceeds with review of BUA
PI registers the protocol with NIH OSP in accordance with NIH Guidelines
Appendix M-I-A (email documents to [email protected]). When
registration is complete, PI provides notification to IBC.
IBC approval is issued upon completion of IBC review process and confirmation
of NIH registration.
PI provides the final IBC and ISPRC or SOM SRC approvals to the IRB.
IRB approval is issued upon completion of IRB review process.
PI submits IBC approval, IRB approval, IRB-approved informed consent
documentation, NIH grant number (if applicable), and CV of PI to the NIH (via
email at [email protected]) within 30 days of enrollment.
NOTE: Additional UCLA approvals may be needed prior to study initiation.
Process B – UCLA is not the initial study site: The initial site will perform the
assessment to determine whether the study needs to be submitted to NIH RAC. This
should be done prior to submitting the study to the UCLA IBC for review so that the
RAC determination can be included in the submission. UCLA is not responsible for
making this assessment and the following will take place:
1. PI submits to IBC and IRB simultaneously.
2. IBC and IRB approvals are issued upon completion of respective reviews.
3. NIH registration is updated to include the new UCLA trial site. When registration
of the new site is complete, PI provides notification to IBC.
4. PI submits IBC approval, IRB approval, IRB-approved informed consent
documentation, NIH grant number (if applicable) to the NIH (via email
at [email protected]) within 30 days of enrollment.
NOTE: Additional UCLA approvals may be needed prior to study initiation.
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iii.
IBC Submission in SafetyNet
When submitting an application to the UCLA IBC, the following documentation must
be submitted in SafetyNet for review.
Document
Additional Information
Curriculum vitae of PI and co-PI(s)
RAC Review Assessment Form
RAC Application
(see NIH Guidelines Appendix M-I-A)
Letter from NIH RAC regarding outcome of
Public RAC Review
Only required for UCLA-initiated studies.
Required if RAC review was previously
performed (renewal or multi-site study).
For new UCLA-initiated studies, IBC will
assess whether submission to RAC is needed.
Required if RAC review was previously
performed (renewal or multi-site study).
For new UCLA-initiated studies, IBC will
assess whether submission to RAC is needed.
Clinical Protocol
Investigator’s Brochure
Explain if not applicable
Informed Consent Forms(s)
Must be site-specific. Draft version acceptable.
Pharmacy Manual (if available)
Annual Reports (for renewal applications only)
SOPs for all procedures involving the HGT
product, including product handling, transport,
administration, and disposal
Bloodborne Pathogen Exposure Control Plan
(if study involves collection of clinical specimens
or delivery of materials covered under the
Cal/OSHA BBP Standard)
Aerosol Transmissible Disease Exposure
Control Plan
(if study involves aerosol transmissible diseases
or pathogens)
See NIH Guidelines Appendix M-I-C-3
Must be site-specific and follow this
HGT SOP Template
For Health Systems locations, follow
Policy IC 006
For non-Health Systems locations, complete
the BBP Exposure Control Plan template
ATD Exposure Control Plan template
III. POST-APPROVAL REPORTING REQUIREMENTS
After initiation of an approved HGT Study, the following information and documents need to be
submitted to the UCLA IBC (and any other applicable agencies/committees).
1. Serious Adverse Event (SAE) Reports
o Refer to Appendix M-I-C-4 of the NIH Guidelines
o See attached Post-Approval Reporting Requirements Summary Sheet for further
information on what, when and how to report this information.
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2. Annual Reports
o Refer to Appendix M-1-C-3 of the NIH Guidelines
o See attached Post-Approval Reporting Requirements Summary Sheet for further
information on what, when and how to report this information.
3. Laboratory Animal Findings that Suggest a Significant Risk for Human Subjects
o Refer to Appendix M-1-C-4 of the NIH Guidelines
o See attached Post-Approval Reporting Requirements Summary Sheet for further
information on what, when and how to report this information.
4. Incidents (Biosafety-Related)
o See attached Post-Approval Reporting Requirements Summary Sheet for further
information on what, when and how to report this information.
5. Changes that Could Impact the Biosafety Risk Assessment
Any changes that could potentially impact the initial biosafety risk assessment need to
be submitted to the IBC for review prior to initiating these changes by creating an
amendment in SafetyNet. This may include, but is not limited to:
•
•
•
•
•
•
•
•
•
•
Changes to the gene transfer product,
Changes to the dosing route, dosage or dosing schedule of the gene transfer
product,
Changes to the inclusion/exclusion criteria,
Changes to any procedures involving handling the gene transfer product,
Changes to the locations where the gene transfer product will be handled, stored,
administered, etc.,
Changes to the personnel who will handle, transport, or administer the gene
transfer product or specimens collected from subjects,
Any new safety information related to the gene transfer product,
Changes in preconditioning and pre- and/or post-delivery concomitant
medications,
Changes in the monitoring/surveillance tests and/or procedures, and
Changes to the Informed Consent Documents related to the gene transfer
product.
The following information and documents DO NOT need to be submitted to the IBC after
initiation of an approved HGT Study:
•
•
•
Changes in the number of subjects enrolled in the study,
Changes in the statistical analysis,
Changes to staff that will be consenting subjects (if they will not be handling the
gene transfer product or other materials)
IV. STUDY CLOSURE AND LONG TERM FOLLOW-UP
A study may be closed in SafetyNet (submit a Closure Request) if the criteria listed below have
been met. Additionally, new studies which look at long-term follow-up of subjects previously
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enrolled in a HGT study do not need to be submitted to the IBC if the criteria listed below have
been met.
1.
2.
3.
4.
The study is closed to enrollment,
Subjects are not actively being dosed with recombinant materials,
There is no gene transfer product on sitea,
It has been over a year since the last subject’s last dose, with no intention to dose
further
5. Samples are not being collected from the subjectsb, and
6. The recombinant gene transfer product is not anticipated to persist in subjects >1 year
post-administration such that it may pose a risk of horizontal [or vertical] transmission of
recombinant materials to others.
a
If the product is stored on site, but all other criteria have been met, you may submit a BUA for
storage only.
b
If long-term follow-up involves collection of clinical specimens, there would still need to be a
BUA in place to cover the Bloodborne Pathogen exposure risks; however, the IBC would not
need to review all of the documentation associated with the study. Additionally, IRB approval
may still be required. Please consult with UCLA OHRPP to discuss IRB requirements.
V.
ATTACHMENTS
•
•
•
RAC Review Assessment Form
Human Gene Transfer: Post-Approval Reporting Requirements Summary Sheet
UCLA Human Gene Transfer Review Process Flow Chart
VI. REFERENCES
•
•
NIH Guidelines: FAQs about the Registration and Review Process for Human Gene
Transfer Protocols
NIH Guidelines: FAQs about the Vaccine Exemption in the NIH Guidelines
Important note: With the exception of providing institutional RAC assessment materials to the IRB
staff, the UCLA IBC is not responsible for forwarding document submissions or reports to the UCLA
IRB or NIH OSP. Principal investigators are responsible for all required paperwork submissions to
NIH OSP and the IRB.
Any questions should be directed to the IBC Administrative Staff at [email protected].
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RAC Review Assessment Form
DIRECTIONS:
•
•
•
•
•
This form only needs to be completed for studies where UCLA is the initial/only study site.
Complete all questions on this form.
References to other clinical trials can be obtained from NIH Genetic Modification Clinical Research
Information System (GeMCRIS): https://www.gemcris.od.nih.gov/Contents/GC_HOME.asp
To expedite the RAC assessment process, email the completed form and any supporting material
to [email protected]. This is recommended if you have not already completed the IBC
application in SafetyNet.
If you have already filled out the IBC application in SafetyNet and have not yet submitted the BUA,
upload this completed form and any supporting material to the Supporting Documents page of the
BUA. Remember to have the PI submit the application in SafetyNet once completed.
Study Title
Principal
Investigator
IBC # (if you have
started the IBC
application process)
1. Description of the human gene transfer product, including the vector, DNA insert(s), and
delivery methodology. Attach any supporting material where additional information can be
found (e.g., Investigator’s Brochure, vector maps, etc.).
2. Does the protocol use a new vector, genetic material, and/or delivery methodology that
represents a first-in-human experience, thus presenting an unknown risk?
Yes
No. Provide examples of previous clinical trials that have used the same or similar
vector, genetic material, and/or delivery methodology.
3. Was the preclinical safety data obtained using a new preclinical model system of
unknown or unconfirmed value?
No. Provide some of the previous clinical trials that have used this same preclinical
model system.
Yes. Provide a brief summary about the preclinical model system that was used and
explain why this novel model system was used instead of existing systems.
4. Provide information on the possible toxicities that are associated with the proposed vector,
gene construct or method of delivery. Please clarify why the specific vector, gene construct
and method of delivery was selected for this study.
**Reminder: All human gene transfer studies need to be registered with the NIH Office of
Science Policy, regardless of whether the IBC or IRB determine that submission to the NIH
Recombinant DNA Advisory Committee is warranted. In accordance with Appendix M-I-A of the
NIH Guidelines, submission involves sending the following documents
to [email protected]:
•
•
•
•
•
•
A scientific abstract
The proposed clinical protocol
A summary of preclinical studies
A description of the product
The proposed informed consent documents
Letter from the UCLA IBC and IRB regarding their assessment of whether public RAC
review is warranted
UCLA Institutional Biosafety Committee
HUMAN GENE TRANSFER
POST-APPROVAL REPORTING REQUIREMENTS SUMMARY SHEET
This table summarizes which events or information should be reported to the UCLA IBC and/or NIH Office of Science Policy (NIH OSP) and the reporting
window. Refer to the OHRPP website for information on post-approval reporting to the IRB. If a post-approval report warrants a change to the research (i.e.,
change in study status, informed consent form), submit an amendment in SafetyNet along with the report.
What to Report
SERIOUS ADVERSE EVENT (SAE)
INTERNAL (on-site) SAE that PI determines to be:
1) Fatal or life-threatening,
2) Unexpected, and
3) Associated or possibly associated with the use of the
HGT product c
INTERNAL (on-site) SAE that PI determines to be:
1) Not fatal or life-threatening,
2) Unexpected, and
3) Associated or possibly associated with the use of the
HGT product c
EXTERNAL (off-site) SAE
When to Report
How to Report
Within 7 calendar days after sponsor’s
initial receipt of information (i.e., at the
same time the event must be reported to
the FDA)a, b, d
Within 15 calendar days after sponsor’s
initial receipt of information (i.e., at the
same time the event must be reported to
the FDA) a, b, d
Use NIH OSP form, FDA MedWatch forms, or other
means, provided that all elements outlined in NIH
Guidelines Appendix M-I-C-4-a are included. Clearly
label as a “Safety Report”.
Report to:
 NIH OSP e
 UCLA IBC via email at [email protected]
UCLA Reporting Not Required
LABORATORY ANIMAL FINDINGS
Any finding from tests in laboratory animals that suggests a
significant risk for human research participants including
reports of mutagenicity, teratogenicity, or carcinogenicity.
Within 15 calendar days after sponsor’s
initial receipt of information (i.e., at the
same time the event must be reported to
the FDA) b
Reports must be submitted in a narrative format and
clearly labeled as a “Safety Report”.
Submit to:
 NIH OSP e
 UCLA IBC by creating and amendment in
SafetyNet
ANNUAL REPORTS
 Report must include all information set forth in NIH
Guidelines Appendix M-I-C-3
 When multiple studies are conducted under single IND, the
PI (or delegate) may choose to submit a single annual
report covering all studies, provided that each study is
identified by its OSP protocol number
1) Within 60 days after the one-year
anniversary of the date on which the
IND application went into effect, and
2) After each subsequent anniversary
until the trial is completed
Submit to:
 NIH OSP e
 UCLA IBC by creating and amendment in
SafetyNet (attach report to Human Gene Transfer
page of BUA)
INCIDENTS (BIOSAFETY-RELATED)
Biosafety-related incidents including spills, staff exposures,
etc. Refer to EH&S Website for additional information
a
b
c
d
e
Within 8 hours of Incident
Call EH&S Hotline (x59797, 310-825-9797)
If SAE 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 NIH OSP and UCLA IBC within 15
calendar days of the determination.
Changes to this schedule are permitted only where, under the FDA IND regulations, 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 NIH OSP and UCLA IBC within 15 days of the determination.
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.
Use one of the following methods to report to NIH Office of Science Policy (NIH OSP):
email to [email protected];
fax to 301-496-9839; or
mail to the Office of Science Policy, National Institutes of Health, MSC 7985, 6705 Rockledge Dr, Suite 750, Bethesda, MD 20892-7985)
UCLA Human Gene Transfer Review Process
Initiated
at UCLA
IBC application submission
and submission of RAC
Assessment Form*
(wait to submit to IRB)
RAC Review Criteria
Public RAC review and discussion of a human gene transfer
experiment will be initiated in two exceptional circumstances:
1. The IBC or IRB determines that:
a. The protocol would significantly benefit from RAC review; and
b. One or more of the criteria below are satisfied:
i. The protocol uses a new vector, genetic material, or
delivery methodology that represents a first-in-human
experience, thus presenting an unknown risk.
ii. The protocol relies on preclinical safety data that were
obtained using a new preclinical model system of
unknown and unconfirmed value.
iii. The proposed vector, gene construct, or method of
delivery is associated with possible toxicities that are not
widely known and that may render it difficult for oversight
bodies to evaluate the protocol rigorously.
2. The NIH Director, in consultation (if needed) with appropriate
regulatory authorities, determines that the submission:
a. Meets one or more of the criteria in 1b above and that public
RAC review and discussion would provide a clear and obvious
benefit to the scientific community or the public; or
b. Raises significant scientific, societal, or ethical concerns
UCLA added to a
multi-site study
*
IBC/IRB
application
submission
IBC provides RAC
assessment
materials to IRB;
IBC/IRB performs
concurrent
assessment
Joint letter
form IBC/IRB
informing PI of
RAC
assessment
outcome
NIH Protocol
Registration
confirmation
required for IBC
approval
RAC not
needed
RAC
needed
PI submits to RAC
[email protected]
IBC/IRB
review
concurrently
PI submits
to NIH OSP
IBC
approval,
release
of IRB
approval
Submit to IRB;
IBC/IRB
review
concurrently
RAC not
needed
NIH will let PI
know within 10
days whether
public RAC review
is warranted
IBC
approval,
release of
IRB
approval
RAC
needed
Enroll research
participants
Enroll
research
participants
Within
30 days
PI submits
to NIH
-
-
Submit to IRB;
IBC/IRB review concurrently
-
IBC approval
IRB approval
IRB approved
informed
consent
document
NIH grant
number, if
applicable
CV of PI
Public RAC review and
recommendations made
Within
30 days
PI submits to NIH
-
IBC approval
IRB approval
IRB approved informed consent document
NIH grant number, if applicable
To expedite the RAC assessment process, the PI may submit the RAC Review Assessment Form via email to [email protected] prior to completing the IBC application form in SafetyNet. If
done concurrently, the RAC Review Assessment Form should be uploaded to the Supporting Documents page of the BUA.