______________________________________________________________________________________________________
MEMORANDUM
OFFICE FOR PROTECTION OF
RESEARCH SUBJECTS
2107
Ueberroth Building
169407
December 12, 2001
RE: Request for Additional
Information - Response To Be Reviewed by the Full Committee
HIV Replication and Thymopoiesis in Adolescents
The Medical Institutional
Review Board (M-IRB) wishes to thank you for your recent submission. Your above referenced study was reviewed by
the M-IRB during the meeting of December
05, 2001. After careful consideration,
the Committee found that more information is required before a decision on
whether to approve the study can be reached.
As a result, your response to the posed questions on the following pages
must be returned to the full Committee for review and discussion during a
convened meeting.
PLEASE NOTE: No subjects may be
contacted, recruited, or enrolled into this study until an Approval Notice and
approved informed consent form(s) have been issued.
If your response is received by the office on or
prior to January 09, 2001, it will be reviewed by the
Committee at the meeting scheduled for January 16,
2001. Please note that it is the UCLA
IRB policy that unless a response is received from you within 30 days of the
date of this letter, we will withdraw this submission from the approval
process. Therefore, should there be
reasons which make it impossible for you to respond before 30 days, please
advise as soon as possible. If you have
any questions, please contact Kathy Casey, Administrator, M-IRB at (310)825-5344.
Sincerely,
On behalf of the Medical
Institutional Review Board
Please return two
copies of your response to:
Office for Protection of Research Subjects
Medical Institutional Review
Board
2107 Ueberroth Building
Campus Mail Code 169407
A. Please respond to the following, and make the necessary changes
to the informed consent form(s) where appropriate; if you disagree with the
Committee’s requests for changes, please explain. (Respond separately to
each numbered item in sequence, employing the same number to identify your
response.)
1. UCLA’s Multiple Project Assurance with the National Institutes
of Health, Office for Protection from Research Risks (NIH/OPRR) stipulates that
the Committee is responsible for assessing the risks vs. anticipated benefits
of research performed under the auspices of UCLA. The Committee expressed
concern that though the risk/benefit ratio of the main portion of this study is
appropriate, the risk/benefit ratio for the substudy, as currently proposed,
cannot be approved, according to the 45 CFR 46, subpart B, as described in The
NIH/Office for Protection from Risks (NIH/OPRR), Institutional Review Board
Guidebook:
“The federal regulations
require IRBs to classify research involving children into one of four
categories and to document their discussions of the risks and benefits of the
research study. The four categories of research involving children that may be
approved by IRBs, based on degree of risk and benefit to individual subjects,
are as follows:
1. Research not involving
greater than minimal risk [45 CFR 46.404].
2. Research involving
greater than minimal risk, but presenting the prospect of direct benefit to an
individual subject. Research in this category is approvable provided: (a) the
risk is justified by the anticipated benefit to the subject; and (b) the
relationship of risk to benefit is at least as favorable as any available
alternative approach [45 CFR 46.405].
3. Research involving
greater than minimal risk with no prospect of direct benefit to individual
subjects, but likely to yield generalizable knowledge about the subject's
disorder or condition. Research in this category is approvable provided: (a)
the risk represents a minor increase over minimal risk; (b) the intervention or
procedure presents experiences to subjects that are reasonably commensurate
with those inherent in their actual or expected medical, dental, psychological,
social, or educational settings; and (c) the intervention or procedure is
likely to yield generalizable knowledge about the subject's disorder or
condition that is of vital importance for the understanding or amelioration of
the subject's disorder or condition [45 CFR 46.406].
4. Research that is not
otherwise approvable, but which presents an opportunity to understand, prevent,
or alleviate a serious problem affecting the health or welfare of children.
Research that is not approvable under 45 CFR 46.404, 46.405, or 46.406 may be
conducted or funded by DHHS provided that the IRB, and the Secretary, after
consultation with a panel of experts, finds that the research presents a
reasonable opportunity to further the understanding, prevention, or alleviation
of a significant problem affecting the health and welfare of children. The
panel of experts must also find that the research will be conducted in
accordance with sound ethical principles [45 CFR 46.407].”
Since the substudy proposes to administer deuterium
labeled glucose over a 24 hour period in healthy children, the substudy does
not appear to qualify for approval under the aforementioned categories for
research with children. In order for
the substudy to qualify for possible UCLA IRB approval, the Committee requests
that you review the above categories and consider whether the substudy could be
modified in order to conform to either 45 CFR 46.404, 46. 405 or 46.406. All proposed revisions to the substudy
should be detailed in your response to this correspondence as well as in the
protocol summary and consent forms.
a. If you wish to omit the substudy at this time and withdraw it
from further IRB consideration, please explain how that might impact the
scientific validity of the main portion of the study.
b. If you do not wish to conduct the substudy as currently
proposed, it will be forwarded to the Secretary of the DHHS for review, according
to 45 CFR 407.
Please also address the
following questions as they relate to the main study and substudy. Based upon your response to the above, some
of the following questions may not be relevant:
2. The protocol indicates that subjects would be enrolled into two
groups: 1) individuals who were infected perinatally, and 2) individuals who
were infected by “adult behavior.” Please clarify for the Committee and detail
in the protocol summary how the method or duration of HIV infection will be ascertained
for the two groups of infected adolescents/young adults.
3. Please clarify for the Committee the source of the deuterium
labeled glucose for intravenous infusion, as well as the deuterium labeled for
oral administration.
a. Please indicate the purity of the deuterium labeled glucose and
water to be used in this study.
b. Please clarify how the aliquot of water will be determined, and
indicate the interval between aliquots administered both in the General
Clinical Research Center (GCRC) and at the subject’s home.
c. Please verify for the Committee that the isotopically labeled
materials that will be employed in this study are approved for use in humans.
4. Please clarify for the
Committee and indicate in the consent form whether subjects must be willing to
allow the researchers to review their medical records in order to participate
in the study. If so, please indicate in
the “Procedures” section of the consent form that subjects will be asked to sign
a separate medical records release form in order for the researchers to access
their medical records.
a. If medical record review is not a
requirement for study participation, please include the following statement in
the “Procedures” section of the consent form:
“On the checklist at the end of
this consent form, you will be asked to indicate if you would permit the
researchers to access your medical records.”
i. Please provide check boxes before the
“Subject’s Signature” block for subjects to accept or decline to allow the
researchers to access his or her medical records for research purposes:
“Please
check the appropriate box below and initial:
___ I
agree to allow the researchers to review my medical records for research
purposes.
___ I do
not agree to allow the researchers to review my medical records for research
purposes.
5. Please clarify for the Committee and indicate in the protocol
summary and substudy consent form the number of subjects that will be enrolled
into the substudy.
6. Please clarify for the Committee and indicate in the protocol
summary how subjects will be selected and contacted regarding possible
participation in the substudy.
7. The “Payment for Participation” section of the substudy consent
form indicates that subjects will receive $75 for the overnight stay, $25 for
day 14 visit and $50 for day 28 visit.
Since the procedures for day 14 and day 28 appear identical, the
Committee requests that subjects be provided the same payment for each visit.
8. The consent forms indicate in the section entitled “Sample
Remaining at the End of the Study” that samples will be shared with other
researchers. However, the protocol does
not describe the sharing of samples.
Please clarify whether you intend to share the samples with other
researchers, and if so, please describe the reason for sharing the samples.
9. Your response to question 4 of the Summary Information (Section
III of the IRB application) indicates that the study will also be conducted at
Children’s Hospital, Los Angeles.
Please detail their role in this study and, if appropriate, forward to
the Committee a copy of the Approval Notice and approved consent documents for
this study from the Institutional Review Board (IRB) of the Children’s
Hospital, Los Angeles.
10. This study may fall under the purview of the Medical Radiation
Safety Committee (MRSC), because CT scans will be undertaken as part of the
study activities. Please forward to the Committee the determinations of the
MRSC for this study or documentation from the MRSC that they wish to exempt this
study from their review.
Please Note: If the M-IRB approves the
research, an approval notice will only be issued for administrative purposes
(no subjects may be contacted or recruited) and the related consent form held
on file until the MRSC approval or letter of exemption is received by the
M-IRB.
11. The Form 740 (“Investigators’ Statements of Financial Interest
Related to Sponsored Projects”) does not indicate whether the other
co-investigators have financial interests related to the project (please see
attached copy). Please submit a revised
Form 740 with the appropriate information included, along with your response to
this correspondence.
B. Please make the following modifications to the informed consent
and assent forms: (Please provide bold typeface or underline changes on one of each
copy for the reviewers and provide two clean copies of each to be used
as the official version of the documents.)
1. Please indicate in each consent form the number of subjects
expected to enroll in this study at UCLA and in total.
2. Please describe in the beginning of each consent form and
assent form the expected duration of the subject's participation in the
research study.
3. Please identify the sponsor of the study within the first
paragraph of each consent form (e.g., “This study is sponsored by a grant of
the National Institutes of Health (NIH).”).
4. Please clarify in each of the consent forms the types of blood
tests that may be performed on the samples collected during the study.
5. Please modify the consent and assent forms as indicated by the
markings on the enclosed copies.