Report on Expert Panel
Review Under Subpart D of 45 CFR 46
Grant
Number 1 R01 DK59234-01
Investigator: Dr.
Wilfred Y. Fujimoto
Convened on August
13-14, 2001
On May 23, 2001, the Office for Human
Research Protections (OHRP) received a request from the
The panel of experts convened on August
13 and 14, 2001. This report summarizes
the experts= individual findings.
The principal responsibilities of the experts were to determine either (a) that
the research in fact satisfies the requirements of 45 CFR '46.404, '46.405, or '46.406, or (b) that
(i) the research presents a reasonable opportunity to understand, prevent, or
alleviate a serious problem affecting the health and welfare of children, (ii)
the research will be conducted in accordance with sound ethical principles, and
(iii) adequate provisions are made for soliciting the assent of children and
the permission of their parents and guardians.
The majority of the experts on the
panel, as individually expressed, found that the protocol presented a
reasonable opportunity to further the understanding, prevention, or alleviation
of a serious problem affecting the health and welfare of children, contingent
upon modifications to the protocol and consent forms to further minimize the
risks to the participants. Once these
recommended modifications have been implemented, the research would be
conducted in accordance with sound ethical principles, and adequate provision
would be made for soliciting the assent of children and the permission of their
parents or guardians, as set forth in '46.408; and would be in conformance with the
requirements of 45 CFR '46.407.
On May 23, 2001, the Office for Human
Research Protections (OHRP) received a request from the Children=s Hospital and
Regional Medical Center of Seattle, Washington for the Department of Health and
Human Services (HHS) to consult a panel of experts to examine the inclusion of
children as research subjects in an experimental protocol proposed at that
institution, entitled APrecursors to Diabetes
in Japanese American Youth@. The institution=s
designated Institutional Review Board (IRB) determined that the research could
not be approved under 45 CFR '46.404, '46.405, or '46.406,
but is suitable for review under 45 CFR '46.407. Although the IRB found that the research was
not designed to provide direct benefit to subjects, it found that the research
presented a reasonable opportunity to further the understanding, prevention or
alleviation of a serious problem affecting the health or welfare of children. The IRB considered the protocol to be
important research and was favorably impressed with the scientific approach of
the investigators.
As required under the regulations at 45
CFR '46.407, a panel of
experts was convened on August 13 and 14, 2001 to individually advise the Secretary of HHS, through OHRP, on
the acceptability of the protocol in
regard to requirements of 45 CFR '46.407.
Applicable Regulations
HHS regulations for the protection of human research subjects, 45 CFR part
46, include specific provisions regarding the involvement of children as
research subjects. Children may be
involved in such research only after the responsible IRB has determined that
the specific requirements detailed in Subpart D of 45 CFR part 46 have been
met.
Research involving children that
provides no direct, individual benefit to the subjects, that is not otherwise
approvable under Subpart D of 45 CFR part 46, can only be approved pursuant to
45 CFR '46.407. Under '46.407, (1) the IRB must find that the
research presents a reasonable opportunity to further the understanding,
prevention, or alleviation of a serious problem affecting the health and
welfare of children, and (2) the Secretary of HHS, after consultation with a
panel of experts in pertinent disciplines and following opportunities for
public review and comment, must determine either (a) that the research in fact
satisfies the conditions of 45 CFR '46.404,
'46.405, or '46.406, or (b) that
(i) the research presents a reasonable
opportunity to further the understanding, prevention, or alleviation of a
serious problem affecting the health and welfare of children, (ii) the research
will be conducted in accordance with sound ethical principles, and (iii)
adequate provisions are made for soliciting the assent of children and the
permission of their parents or guardians, as set forth in '46.408.
Scientific Background
Type 2 diabetes, characterized by
insulin resistance, is the most common form of diabetes in adults. It was rarely diagnosed in children until
about 10 years ago and since then there has been a dramatic, ten-fold
increase. This increase in the
prevalence of type 2 diabetes in children has been attributed to a simultaneous
increase in the incidence of childhood obesity.
Asian adults, despite a low prevalence
of obesity, have a predisposition to accumulate central, abdominal fat and have
an increased risk for type 2 diabetes.
While there are no data on the prevalence of type 2 diabetes in
Asian-American children, recent studies of Japanese school children in
The long-term aim of the proposed study
is to increase understanding about the metabolic changes that precede the
development of type 2 diabetes in children and the influence of Asian ethnicity
on the diabetes risk.
In this longitudinal study, it is proposed
that a cohort of 450 healthy children be enrolled who are 8 to 10 years of
age. Three hundred children will be of
Japanese ancestry, while the other 150 children will be their Caucasian
cousins. Each subject will have two
evaluations (two years apart, one at baseline and the other at the two year
follow-up). At each evaluation, the
subjects will undergo the following procedures: (i) medical and family history;
(ii) physical activity and dietary assessment; (iii) physical examination
including pubertal staging; (iv) blood drawn by venipunture to measure the
level of multiple hormones, lipids, and other serum factors and proteins; (v)
intravenous glucose tolerance test which involves placement of an intravenous
catheter, infusion of glucose, and serial measurements of serum levels of
glucose, and insulin, and other factors; and (vi) measurement of body
composition by means of DEXA and intra-abdominal fat determination by MRI.
The first hypothesis to be tested is
that features of the metabolic syndrome (abnormal response to insulin, high
blood pressure and abnormalities of blood cholesterol and other lipids) will be
found in some prepubertal children. The metabolic and obesity-related factors
associated with the insulin resistance syndrome will be determined. These factors include fasting plasma lipids
(cholesterol, triglycerides, HDL-cholesterol), LDL size, blood clotting factors
(plasminogen activator inhibitor-1, fibrinogen, C-reactive protein), glucose,
insulin, C-peptide, and proinsulin; glucose tolerance, total body fat; body fat
distribution; intra- abdominal fat measured by Magnetic Resonance Imaging
(MRI); and body mass index.
The ability of the beta cells of the
pancreas to make and secrete insulin will be assessed to test the hypothesis that
pancreatic beta-cell dysfunction will be evident in some children. Measurements of fasting plasma insulin,
C-peptide, proinsulin and the acute insulin response to glucose during an
intravenous glucose tolerance test (IVGTT) will be obtained.
The next hypothesis to be tested states
that puberty is associated with changes in body fat distribution and metabolic
parameters which could lead to higher risk of glucose intolerance and
cardiovascular disease. Diet and physical
activity, which are important predictors of body fat and metabolism, will be
assessed.
Finally, metabolic and obesity-related
factors will be determined to test the hypothesis that a higher proportion of
children with Japanese ancestry will be associated with a greater
predisposition to the metabolic syndrome and diminished insulin secretion. In addition, collection of DNA is proposed
for future genetic studies.
The panel of experts, as detailed in
their individual findings, found that the risks to the subjects had been
minimized and that subject recruitment was equitable, as required under 45 CFR '46.111. The experts further found that the study
represented greater than minimal risk for children who would not have the
prospect of direct, individual benefit and who did not have a disorder or
condition at the time of the proposed study, and thus can only be funded by HHS
if the requirements of '46.407 are met.
The panel of experts determined that
certain proposed test procedures caused the risks of the proposed research to
be classified as a minor increase over minimal risk. Discussion of proposed tests included intravenous
glucose tolerance test (IVGTT), DNA banking for future tests, and Magnetic
Resource Imaging (MRI).
To further minimize the risks to the
participants, the experts made the following recommendations:
1)
The IVGTT be
performed in a pediatric location with adequate pediatric expertise which would
include pediatricians, pediatric nursing and a pediatric phlebotomist;
2)
The risks from
the DNA banking be minimized by
protecting the confidentiality of the subjects by a) the absolute separation of
the genetic information from the medical record, b) re-consenting the children
when they reach the age of maturity specified by the State, c) providing
information about whom to call if the subject wishes to have the DNA removed
from the bank and destroyed and d) provision of a statement that the DNA will
not be available to the participant later to be used for other purposes; and
3)
Clear exclusion
criteria are put in place for MRI studies (i.e., testing for implanted metallic
subjects, claustrophobia, or the need for procedural sedation).
The experts found that there would be no direct benefit for the
participants of the proposed research project.
The majority of experts considered that the protocol represented a
reasonable opportunity to understand, prevent, or alleviate a serious problem
affecting the health and welfare of children, the investigators had adhered to
sound ethical principles and had written excellent recruitment materials,
parental permission, and assent forms.
The panel was supportive of the plan to re-assent the children at the
time of the second research evaluation.
The majority of the reviewing experts found that the proposed study
could be appropriately approved under '46.407,
subject to the stipulation that the protocol and consent forms be modified in
accordance with the recommendations for further minimization of risks to the children. The majority of experts felt that the
research design was sound, offered a reasonable opportunity to further the
understanding of an important health risk to children (the prevalence of type 2
diabetes in Japanese-American children and the influence of puberty on metabolism and obesityBrelated parameters), would be conducted in accord with
sound ethical principles, and that adequate provisions were in place to obtain
parental permission and child=s assent.
One member of the panel did not recommend approval under '46.407. Serious
design flaws were cited by this expert, such as:
1) By
the researcher=s own calculations, only 42 percent of the children to
be studied will have reached puberty.
This expert believed that the observation period appears to be too
short.
2) From
the sample size, the statistical probability is that only one subject would
ultimately become diabetic. This expert believed that the sample size is too
small.
3) Single
test determinations may not prove representative of the individual=s glucose metabolism or insulin resistance. Therefore, in one expert=s opinion this descriptive study will yield little, if
any, knowledge about the problem it intends to address. Furthermore, this expert believed that the
study would yield little, if any, reliable information that would help to
better understand, prevent, or alleviate the serious problem of type 2 diabetes
in children.
(06-17-02)